Act I: The Negotiation

(A barren academic office, dimly lit, the pall of difficult negotiations afloat, backlit like dust in the air. Seated, under a strangely intense incandescent bulb, a man, who looks eerily like a good-looking version of me, sits uncomfortably adjusting himself in his seat. His eyes constrict on his counterpart, a miserly sort peering out from behind wire-rim glasses and a shock of hair improbably combed over from ear to ear. The tension crests.)

GOOD-LOOKING ME

(Voice cracking)

I’ve come to ask for a raise for our hospitalist group.

MISER

(Adjusts his clip-on tie)

We just gave you a raise in 2004.

GOOD-LOOKING ME

(Smiles uncomfortably)

That was very gracious, sir, but I think the numbers support another.

MISER

(Incredulous look at his watch)

But your work RVUs are thousands below what I’d like to see.

GOOD-LOOKING ME

(Dabs bead of sweat away from chiseled chin)

That’s because you’ve set your benchmark thousands above a reasonable number.

MISER

(Voice flitting with child-like condescension)

But those are the numbers my finance guy gave me. It’s the benchmark.

(Blackout and end of Act I.)

Mutual Agreement

Tony Award-winning stuff for sure—and based on a true story! In fact, this scene no doubt plays out annually for those of you unfortunate enough to have to negotiate with hospital executives for programmatic support. To be fair, hospital administrators deserve to know that they are getting what they pay for. Thus, the concepts of a benchmark are reasonable. The problem lies in setting mutually-agreed-upon standards.

Act II: Disbelief and Confusion

GOOD-LOOKING ME

(Unsteadily hands document to Miser)

Sir, I’ve highlighted the national benchmarks for you to see. Column four of this 2007-2008 SHM survey clearly shows that the average academic hospitalist should make $168,800 and achieve 2,813 work RVUs. We achieve the latter benchmark but are severely underpaid.

MISER

(Produces a folded cocktail napkin from his shirt pocket)

But look at this: My executive-friends-at-other-medical-centers-who-overwork-and-underpay-their-hospitalists benchmark shows that you should be well over 4,500 work RVUs. And besides, the SHM numbers are skewed; it’s a survey of hospitalists done by a group that represents hospitalists. I don’t believe them.

GOOD-LOOKING ME

(Eyes averted, adopts a tone of trepidation)

But sir, with all due respect, don’t your numbers reflect a survey of hospital administrators who might have a bias toward more expected productivity? Which benchmark should we believe?

(Blackout and end of Act II.)

A New HM Benchmark Arises

It’s all about the benchmark you choose to believe. For years, the best source of data regarding hospitalist compensation and productivity was that published every other year by SHM. It is a fair, but unfounded, concern that these data might tilt toward the benefit of hospitalists. Likewise, the hospital administrator I work most closely with (who, for the record, reads this publication and IS NOT miserly, has a FULL HEAD of hair, and is, for innumerable reasons, a TRULY GREAT man) will produce benchmarks from organizations like the Association of American Medical Colleges (AAMC) or the University HealthSystems Consortium (UHC), all of which show surprisingly disparate numbers dripping with a similar tilt toward the medical center.

Thus, the importance of the 2010 SHM/MGMA report. The Medical Group Management Association (MGMA) consists of administrators and leaders of medical group practices. Since 1926, they’ve been providing accurate, independent data on physician practice metrics. For most hospital administrators, it is the benchmark. The problem is that in the past, MGMA has struggled to identify hospitalists; the MGMA data were always underpowered and, therefore, suspect.

Enter SHM and its large database of HM groups. What has resulted in the new survey rivals those old commercials in which a person walking with a piece of chocolate slams into another with a jar of peanut butter, resulting in the creation of the Reese’s Peanut Butter Cup (apologies to those readers under the age of 35).

Act III: No Raise; Children Go Hungry

GOOD-LOOKING ME

(Unsheathing haloed document from his portfolio)

Perhaps we could agree to use these new SHM/MGMA numbers as our benchmark. It includes data from more than 440 HM groups and 4,200 hospitalists. And it appears to be fair and balanced.

MISER

(Eyes alight, peering through a shroud of compromise)

MGMA, huh? Let’s take a look. Hmmm. Well. But wait—this says the average hospitalist makes $215,000! That’s outrageous.

GOOD-LOOKING ME

(Smugly retorts)

Yes, sir, we are severely underpaid.

MISER

(Reading; a weasel-like countenance overtakes his face)

Let me take a closer look at this. Aha! Here it is. You see, this only included community hospitalist practices. You will be getting no raise!

(Blackout and end of Act III.)

A Cautionary Tale

Alas, the miser is right. It’s not always what the data say but also what they don’t say.

The one snag with the new data is that it only included a handful of academic HM groups (only 1% of respondents). In fact, the survey actively instructed academic HM practices to not complete the survey. Rather, we academic types were instructed to await the MGMA survey of academic practices completed every fall to be reported early next year.

This is emblematic of the need to dig deep when interpreting these data. As tempting as it is to use a sound bite or two of these data to your advantage, the truth lies in the details. It’s easy to say that all hospitalists should make $215,000, see 2,229 encounters, and achieve 4,107 wRVUs annually.

However, just as there is no average hospitalist, there are no average numbers. There are just too many variables (e.g., practice ownership, geography, group size, night coverage, staffing model, compensation structure) to say definitively what an individual hospitalist should look like or achieve. Rather, these numbers should be used as a guide, adapted to each individual situation.

Act IV: See You This Spring

(Standing, Good-Looking Me shakes his foe’s shriveled claw of a hand while looking him intensely in the eye—a look that says, “I’ll see you this spring.” In his rival’s eyes, the Miser sees his future—a future that involves another meeting, more practice-appropriate data, and a dusting off of his checkbook.)

(Blackout and end of Act IV.) TH

Dr. Glasheen is associate professor of medicine at the University of Colorado Denver, where he serves as director of the Hospital Medicine Program and the Hospitalist Training Program, and as associate program director of the Internal Medicine Residency Program.

Act I: The Negotiation

(A barren academic office, dimly lit, the pall of difficult negotiations afloat, backlit like dust in the air. Seated, under a strangely intense incandescent bulb, a man, who looks eerily like a good-looking version of me, sits uncomfortably adjusting himself in his seat. His eyes constrict on his counterpart, a miserly sort peering out from behind wire-rim glasses and a shock of hair improbably combed over from ear to ear. The tension crests.)

GOOD-LOOKING ME

(Voice cracking)

I’ve come to ask for a raise for our hospitalist group.

MISER

(Adjusts his clip-on tie)

We just gave you a raise in 2004.

GOOD-LOOKING ME

(Smiles uncomfortably)

That was very gracious, sir, but I think the numbers support another.

MISER

(Incredulous look at his watch)

But your work RVUs are thousands below what I’d like to see.

GOOD-LOOKING ME

(Dabs bead of sweat away from chiseled chin)

That’s because you’ve set your benchmark thousands above a reasonable number.

MISER

(Voice flitting with child-like condescension)

But those are the numbers my finance guy gave me. It’s the benchmark.

(Blackout and end of Act I.)

Mutual Agreement

Tony Award-winning stuff for sure—and based on a true story! In fact, this scene no doubt plays out annually for those of you unfortunate enough to have to negotiate with hospital executives for programmatic support. To be fair, hospital administrators deserve to know that they are getting what they pay for. Thus, the concepts of a benchmark are reasonable. The problem lies in setting mutually-agreed-upon standards.

Act II: Disbelief and Confusion

GOOD-LOOKING ME

(Unsteadily hands document to Miser)

Sir, I’ve highlighted the national benchmarks for you to see. Column four of this 2007-2008 SHM survey clearly shows that the average academic hospitalist should make $168,800 and achieve 2,813 work RVUs. We achieve the latter benchmark but are severely underpaid.

MISER

(Produces a folded cocktail napkin from his shirt pocket)

But look at this: My executive-friends-at-other-medical-centers-who-overwork-and-underpay-their-hospitalists benchmark shows that you should be well over 4,500 work RVUs. And besides, the SHM numbers are skewed; it’s a survey of hospitalists done by a group that represents hospitalists. I don’t believe them.

GOOD-LOOKING ME

(Eyes averted, adopts a tone of trepidation)

But sir, with all due respect, don’t your numbers reflect a survey of hospital administrators who might have a bias toward more expected productivity? Which benchmark should we believe?

(Blackout and end of Act II.)

A New HM Benchmark Arises

It’s all about the benchmark you choose to believe. For years, the best source of data regarding hospitalist compensation and productivity was that published every other year by SHM. It is a fair, but unfounded, concern that these data might tilt toward the benefit of hospitalists. Likewise, the hospital administrator I work most closely with (who, for the record, reads this publication and IS NOT miserly, has a FULL HEAD of hair, and is, for innumerable reasons, a TRULY GREAT man) will produce benchmarks from organizations like the Association of American Medical Colleges (AAMC) or the University HealthSystems Consortium (UHC), all of which show surprisingly disparate numbers dripping with a similar tilt toward the medical center.

Thus, the importance of the 2010 SHM/MGMA report. The Medical Group Management Association (MGMA) consists of administrators and leaders of medical group practices. Since 1926, they’ve been providing accurate, independent data on physician practice metrics. For most hospital administrators, it is the benchmark. The problem is that in the past, MGMA has struggled to identify hospitalists; the MGMA data were always underpowered and, therefore, suspect.

Enter SHM and its large database of HM groups. What has resulted in the new survey rivals those old commercials in which a person walking with a piece of chocolate slams into another with a jar of peanut butter, resulting in the creation of the Reese’s Peanut Butter Cup (apologies to those readers under the age of 35).

Act III: No Raise; Children Go Hungry

GOOD-LOOKING ME

(Unsheathing haloed document from his portfolio)

Perhaps we could agree to use these new SHM/MGMA numbers as our benchmark. It includes data from more than 440 HM groups and 4,200 hospitalists. And it appears to be fair and balanced.

MISER

(Eyes alight, peering through a shroud of compromise)

MGMA, huh? Let’s take a look. Hmmm. Well. But wait—this says the average hospitalist makes $215,000! That’s outrageous.

GOOD-LOOKING ME

(Smugly retorts)

Yes, sir, we are severely underpaid.

MISER

(Reading; a weasel-like countenance overtakes his face)

Let me take a closer look at this. Aha! Here it is. You see, this only included community hospitalist practices. You will be getting no raise!

(Blackout and end of Act III.)

A Cautionary Tale

Alas, the miser is right. It’s not always what the data say but also what they don’t say.

The one snag with the new data is that it only included a handful of academic HM groups (only 1% of respondents). In fact, the survey actively instructed academic HM practices to not complete the survey. Rather, we academic types were instructed to await the MGMA survey of academic practices completed every fall to be reported early next year.

This is emblematic of the need to dig deep when interpreting these data. As tempting as it is to use a sound bite or two of these data to your advantage, the truth lies in the details. It’s easy to say that all hospitalists should make $215,000, see 2,229 encounters, and achieve 4,107 wRVUs annually.

However, just as there is no average hospitalist, there are no average numbers. There are just too many variables (e.g., practice ownership, geography, group size, night coverage, staffing model, compensation structure) to say definitively what an individual hospitalist should look like or achieve. Rather, these numbers should be used as a guide, adapted to each individual situation.

Act IV: See You This Spring

(Standing, Good-Looking Me shakes his foe’s shriveled claw of a hand while looking him intensely in the eye—a look that says, “I’ll see you this spring.” In his rival’s eyes, the Miser sees his future—a future that involves another meeting, more practice-appropriate data, and a dusting off of his checkbook.)

(Blackout and end of Act IV.) TH

Dr. Glasheen is associate professor of medicine at the University of Colorado Denver, where he serves as director of the Hospital Medicine Program and the Hospitalist Training Program, and as associate program director of the Internal Medicine Residency Program.

Act I: The Negotiation

(A barren academic office, dimly lit, the pall of difficult negotiations afloat, backlit like dust in the air. Seated, under a strangely intense incandescent bulb, a man, who looks eerily like a good-looking version of me, sits uncomfortably adjusting himself in his seat. His eyes constrict on his counterpart, a miserly sort peering out from behind wire-rim glasses and a shock of hair improbably combed over from ear to ear. The tension crests.)

GOOD-LOOKING ME

(Voice cracking)

I’ve come to ask for a raise for our hospitalist group.

MISER

(Adjusts his clip-on tie)

We just gave you a raise in 2004.

GOOD-LOOKING ME

(Smiles uncomfortably)

That was very gracious, sir, but I think the numbers support another.

MISER

(Incredulous look at his watch)

But your work RVUs are thousands below what I’d like to see.

GOOD-LOOKING ME

(Dabs bead of sweat away from chiseled chin)

That’s because you’ve set your benchmark thousands above a reasonable number.

MISER

(Voice flitting with child-like condescension)

But those are the numbers my finance guy gave me. It’s the benchmark.

(Blackout and end of Act I.)

Mutual Agreement

Tony Award-winning stuff for sure—and based on a true story! In fact, this scene no doubt plays out annually for those of you unfortunate enough to have to negotiate with hospital executives for programmatic support. To be fair, hospital administrators deserve to know that they are getting what they pay for. Thus, the concepts of a benchmark are reasonable. The problem lies in setting mutually-agreed-upon standards.

Act II: Disbelief and Confusion

GOOD-LOOKING ME

(Unsteadily hands document to Miser)

Sir, I’ve highlighted the national benchmarks for you to see. Column four of this 2007-2008 SHM survey clearly shows that the average academic hospitalist should make $168,800 and achieve 2,813 work RVUs. We achieve the latter benchmark but are severely underpaid.

MISER

(Produces a folded cocktail napkin from his shirt pocket)

But look at this: My executive-friends-at-other-medical-centers-who-overwork-and-underpay-their-hospitalists benchmark shows that you should be well over 4,500 work RVUs. And besides, the SHM numbers are skewed; it’s a survey of hospitalists done by a group that represents hospitalists. I don’t believe them.

GOOD-LOOKING ME

(Eyes averted, adopts a tone of trepidation)

But sir, with all due respect, don’t your numbers reflect a survey of hospital administrators who might have a bias toward more expected productivity? Which benchmark should we believe?

(Blackout and end of Act II.)

A New HM Benchmark Arises

It’s all about the benchmark you choose to believe. For years, the best source of data regarding hospitalist compensation and productivity was that published every other year by SHM. It is a fair, but unfounded, concern that these data might tilt toward the benefit of hospitalists. Likewise, the hospital administrator I work most closely with (who, for the record, reads this publication and IS NOT miserly, has a FULL HEAD of hair, and is, for innumerable reasons, a TRULY GREAT man) will produce benchmarks from organizations like the Association of American Medical Colleges (AAMC) or the University HealthSystems Consortium (UHC), all of which show surprisingly disparate numbers dripping with a similar tilt toward the medical center.

Thus, the importance of the 2010 SHM/MGMA report. The Medical Group Management Association (MGMA) consists of administrators and leaders of medical group practices. Since 1926, they’ve been providing accurate, independent data on physician practice metrics. For most hospital administrators, it is the benchmark. The problem is that in the past, MGMA has struggled to identify hospitalists; the MGMA data were always underpowered and, therefore, suspect.

Enter SHM and its large database of HM groups. What has resulted in the new survey rivals those old commercials in which a person walking with a piece of chocolate slams into another with a jar of peanut butter, resulting in the creation of the Reese’s Peanut Butter Cup (apologies to those readers under the age of 35).

Act III: No Raise; Children Go Hungry

GOOD-LOOKING ME

(Unsheathing haloed document from his portfolio)

Perhaps we could agree to use these new SHM/MGMA numbers as our benchmark. It includes data from more than 440 HM groups and 4,200 hospitalists. And it appears to be fair and balanced.

MISER

(Eyes alight, peering through a shroud of compromise)

MGMA, huh? Let’s take a look. Hmmm. Well. But wait—this says the average hospitalist makes $215,000! That’s outrageous.

GOOD-LOOKING ME

(Smugly retorts)

Yes, sir, we are severely underpaid.

MISER

(Reading; a weasel-like countenance overtakes his face)

Let me take a closer look at this. Aha! Here it is. You see, this only included community hospitalist practices. You will be getting no raise!

(Blackout and end of Act III.)

A Cautionary Tale

Alas, the miser is right. It’s not always what the data say but also what they don’t say.

The one snag with the new data is that it only included a handful of academic HM groups (only 1% of respondents). In fact, the survey actively instructed academic HM practices to not complete the survey. Rather, we academic types were instructed to await the MGMA survey of academic practices completed every fall to be reported early next year.

This is emblematic of the need to dig deep when interpreting these data. As tempting as it is to use a sound bite or two of these data to your advantage, the truth lies in the details. It’s easy to say that all hospitalists should make $215,000, see 2,229 encounters, and achieve 4,107 wRVUs annually.

However, just as there is no average hospitalist, there are no average numbers. There are just too many variables (e.g., practice ownership, geography, group size, night coverage, staffing model, compensation structure) to say definitively what an individual hospitalist should look like or achieve. Rather, these numbers should be used as a guide, adapted to each individual situation.

Act IV: See You This Spring

(Standing, Good-Looking Me shakes his foe’s shriveled claw of a hand while looking him intensely in the eye—a look that says, “I’ll see you this spring.” In his rival’s eyes, the Miser sees his future—a future that involves another meeting, more practice-appropriate data, and a dusting off of his checkbook.)

(Blackout and end of Act IV.) TH

Dr. Glasheen is associate professor of medicine at the University of Colorado Denver, where he serves as director of the Hospital Medicine Program and the Hospitalist Training Program, and as associate program director of the Internal Medicine Residency Program.

Unpredictable workloads and frequent interruptions are the things I regard as the most stressful components of work as a hospitalist. Your list might be very different, but I bet unpredictable workloads ranks at least in the top five of every hospitalist’s list.

I’ve discussed interruptions previously (see “Really, It’s Switch-Tasking,” p. 68, November 2008; “Technological Advance or Workplace Setback?” p. 69, December 2008), but this month and next will turn to unpredictable workloads. In other words, what are the strategies available to a hospitalist practice to provide surge capacity in response to such unpredictable increases in patient volume as an uptick in census or daily admissions 50% to 100% above normal? I’ll leave to others the topic of how hospitals respond to such disasters as terrorist attacks, earthquakes, etc.

The Bottom Line

Sadly, there is no magic bullet for the “surge” problem, and no way to protect on-duty hospitalists from the need to work harder when it gets busy. But we needn’t feel too sorry for ourselves; doctors in most other specialties who practice in the hospital face the same problem and tend to rely heavily on simply working harder and longer when it is unusually busy. Sometimes they couple the “work harder” mantra with other strategies, such as calling another doctor in to help.

Hospitalists have a duty to ensure high patient volume doesn’t lead to deterioration in the quality of patient care, but occasionally working longer days than average probably poses a low risk, and might be less risky than the additional handoffs usually associated with having a doctor on “jeopardy” to be called in when it’s busy. Routinely or frequently working unreasonably long days is another story.

The trick for HM programs is to build some surge capacity into the routine daily staffing 1) without exceeding a reasonable budget, while 2) ensuring that the hospitalists don’t simply become accustomed to light workloads as the only reasonable norm, which could lead to them becoming unwilling to accept higher, but still reasonable, workloads when needed. (More on these issues later.) First, I’ll go through what I see as the pros and cons of several approaches to addressing surges in patient volume. All are in use with variable frequency around the country.

“Jeopardy” System

In its most common form, a jeopardy system has an unscheduled doctor each day who must remain available on short notice by pager. When patient volume surges, the unscheduled doctor is paged to come in and help. In most cases, this doctor focuses primarily—or exclusively—on admitting patients for a few hours. So it is most common for this doctor to be called in late in the afternoon or early in the evening. The jeopardy doctor usually turns over all admitted patients to another hospitalist in the group for all subsequent care. In addition to providing surge capacity, the jeopardy doctor almost always is used to cover unexpected absences of scheduled doctors, including illness-related absences.

Sometimes this doctor is paid extra for each day or week spent being “available” on jeopardy duty (not to be confused with jury duty, though it can be equally difficult to get exempted from). Then again, it is not uncommon to have jeopardy duty included in base compensation. However, once a jeopardy doctor is actually called in to work, most practices pay additional compensation, often based on an hourly rate that usually is higher than the average compensation generated per hour for nonjeopardy work.

There are a number of reasonable ways to compensate the jeopardy doctor. You probably can get some good ideas by talking with others in your hospital who function in a similar capacity, such as cath-lab technicians who get called in on nights and weekends.

No definitive data are available to show how common the jeopardy system is, but my experience is that 30% to 50% of HM groups use some form of it. Its popularity is proof that it is a reasonable system, but I’m not convinced. I think it is in use by a lot of groups not because it is an optimal way to ensure surge capacity, but because it is easy to conceptualize and put in place, and because many hospitalists came from residency programs in which the system was standard.

The gaps between theoretical and realized benefits become evident once a practice implements a jeopardy system. For example, it might be really busy today, but Dr. Stravinsky doesn’t call in Dr. Copeland, who is on jeopardy, because next week their roles will be reversed and Dr. Stravinsky sure hopes he won’t be called in. No one wants to be the weak doctor who calls in the jeopardy doctor and spoils what was otherwise a day off.

I’ve worked with a lot of practices who say they have a jeopardy system in place, but when I ask for the last time the jeopardy doctor was called in, they say it has been more than a year, or in some cases never. So even if the policy manual says they have a jeopardy system, the doctors never activate it, so it provides no benefit.

Practices that do utilize the jeopardy doctor have their own problems, such as assigning that doctor’s admissions the next day. The jeopardy doctor might provide some relief today, but they essentially just delay the work of having to get to know all of those new patients until the morning, when everyone is very busy with rounds. So while there might be significant benefit in activating the jeopardy system today, it could just delay the problem of high workload until the next morning, which isn’t much of a net benefit for the practice.

A small number of practices call in the jeopardy doctor frequently, and sometimes have that doctor continue to round on admitted patients for the next few days. This usage might get the most value out of the system, but the practice should consider if it is more cost-effective, and less stressful for the doctors, if the system were reversed. For example, instead of having the doctor on jeopardy and called in as necessary, the doctor would report to work and be given the day off or let go early when it isn’t busy.

Despite my reservations, if you are convinced the jeopardy system is valuable and cost-effective, keep it in place. However, if your group is thinking about options to handle surge capacity, don’t be too quick to adopt a jeopardy system. It usually falls far short of a perfect solution.

Patient Volume Cap

Another way to address the problem of unpredictable increases in patient volume is to establish a patient volume (e.g., total census) cap for the whole hospitalist practice. Like the jeopardy system, this is an appealingly uncomplicated idea, and hospitalists who have finished residency within the last few years all worked with a cap.

Except for the rarest of exceptions, this is a poor idea and should be avoided if at all possible. I’ll leave for another time a discussion of all the political and financial costs of a cap system, but trust me on this one. It is best to avoid a cap.

Stay Tuned …

Next month, I’ll examine other strategies to provide surge capacity. I think they’re more valuable than the two I’ve mentioned here, but I need to warn you that they aren’t perfect and are more complicated to operationalize. TH

Dr. Nelson has been a practicing hospitalist since 1988 and is co-founder and past president of SHM. He is a principal in Nelson Flores Hospital Medicine Consultants, a national hospitalist practice management consulting firm (www.nelson flores.com). He is course co-director and faculty for SHM’s “Best Practices in Managing a Hospital Medicine Program” course. This column represents his views and is not intended to reflect an official position of SHM.

Unpredictable workloads and frequent interruptions are the things I regard as the most stressful components of work as a hospitalist. Your list might be very different, but I bet unpredictable workloads ranks at least in the top five of every hospitalist’s list.

I’ve discussed interruptions previously (see “Really, It’s Switch-Tasking,” p. 68, November 2008; “Technological Advance or Workplace Setback?” p. 69, December 2008), but this month and next will turn to unpredictable workloads. In other words, what are the strategies available to a hospitalist practice to provide surge capacity in response to such unpredictable increases in patient volume as an uptick in census or daily admissions 50% to 100% above normal? I’ll leave to others the topic of how hospitals respond to such disasters as terrorist attacks, earthquakes, etc.

The Bottom Line

Sadly, there is no magic bullet for the “surge” problem, and no way to protect on-duty hospitalists from the need to work harder when it gets busy. But we needn’t feel too sorry for ourselves; doctors in most other specialties who practice in the hospital face the same problem and tend to rely heavily on simply working harder and longer when it is unusually busy. Sometimes they couple the “work harder” mantra with other strategies, such as calling another doctor in to help.

Hospitalists have a duty to ensure high patient volume doesn’t lead to deterioration in the quality of patient care, but occasionally working longer days than average probably poses a low risk, and might be less risky than the additional handoffs usually associated with having a doctor on “jeopardy” to be called in when it’s busy. Routinely or frequently working unreasonably long days is another story.

The trick for HM programs is to build some surge capacity into the routine daily staffing 1) without exceeding a reasonable budget, while 2) ensuring that the hospitalists don’t simply become accustomed to light workloads as the only reasonable norm, which could lead to them becoming unwilling to accept higher, but still reasonable, workloads when needed. (More on these issues later.) First, I’ll go through what I see as the pros and cons of several approaches to addressing surges in patient volume. All are in use with variable frequency around the country.

“Jeopardy” System

In its most common form, a jeopardy system has an unscheduled doctor each day who must remain available on short notice by pager. When patient volume surges, the unscheduled doctor is paged to come in and help. In most cases, this doctor focuses primarily—or exclusively—on admitting patients for a few hours. So it is most common for this doctor to be called in late in the afternoon or early in the evening. The jeopardy doctor usually turns over all admitted patients to another hospitalist in the group for all subsequent care. In addition to providing surge capacity, the jeopardy doctor almost always is used to cover unexpected absences of scheduled doctors, including illness-related absences.

Sometimes this doctor is paid extra for each day or week spent being “available” on jeopardy duty (not to be confused with jury duty, though it can be equally difficult to get exempted from). Then again, it is not uncommon to have jeopardy duty included in base compensation. However, once a jeopardy doctor is actually called in to work, most practices pay additional compensation, often based on an hourly rate that usually is higher than the average compensation generated per hour for nonjeopardy work.

There are a number of reasonable ways to compensate the jeopardy doctor. You probably can get some good ideas by talking with others in your hospital who function in a similar capacity, such as cath-lab technicians who get called in on nights and weekends.

No definitive data are available to show how common the jeopardy system is, but my experience is that 30% to 50% of HM groups use some form of it. Its popularity is proof that it is a reasonable system, but I’m not convinced. I think it is in use by a lot of groups not because it is an optimal way to ensure surge capacity, but because it is easy to conceptualize and put in place, and because many hospitalists came from residency programs in which the system was standard.

The gaps between theoretical and realized benefits become evident once a practice implements a jeopardy system. For example, it might be really busy today, but Dr. Stravinsky doesn’t call in Dr. Copeland, who is on jeopardy, because next week their roles will be reversed and Dr. Stravinsky sure hopes he won’t be called in. No one wants to be the weak doctor who calls in the jeopardy doctor and spoils what was otherwise a day off.

I’ve worked with a lot of practices who say they have a jeopardy system in place, but when I ask for the last time the jeopardy doctor was called in, they say it has been more than a year, or in some cases never. So even if the policy manual says they have a jeopardy system, the doctors never activate it, so it provides no benefit.

Practices that do utilize the jeopardy doctor have their own problems, such as assigning that doctor’s admissions the next day. The jeopardy doctor might provide some relief today, but they essentially just delay the work of having to get to know all of those new patients until the morning, when everyone is very busy with rounds. So while there might be significant benefit in activating the jeopardy system today, it could just delay the problem of high workload until the next morning, which isn’t much of a net benefit for the practice.

A small number of practices call in the jeopardy doctor frequently, and sometimes have that doctor continue to round on admitted patients for the next few days. This usage might get the most value out of the system, but the practice should consider if it is more cost-effective, and less stressful for the doctors, if the system were reversed. For example, instead of having the doctor on jeopardy and called in as necessary, the doctor would report to work and be given the day off or let go early when it isn’t busy.

Despite my reservations, if you are convinced the jeopardy system is valuable and cost-effective, keep it in place. However, if your group is thinking about options to handle surge capacity, don’t be too quick to adopt a jeopardy system. It usually falls far short of a perfect solution.

Patient Volume Cap

Another way to address the problem of unpredictable increases in patient volume is to establish a patient volume (e.g., total census) cap for the whole hospitalist practice. Like the jeopardy system, this is an appealingly uncomplicated idea, and hospitalists who have finished residency within the last few years all worked with a cap.

Except for the rarest of exceptions, this is a poor idea and should be avoided if at all possible. I’ll leave for another time a discussion of all the political and financial costs of a cap system, but trust me on this one. It is best to avoid a cap.

Stay Tuned …

Next month, I’ll examine other strategies to provide surge capacity. I think they’re more valuable than the two I’ve mentioned here, but I need to warn you that they aren’t perfect and are more complicated to operationalize. TH

Dr. Nelson has been a practicing hospitalist since 1988 and is co-founder and past president of SHM. He is a principal in Nelson Flores Hospital Medicine Consultants, a national hospitalist practice management consulting firm (www.nelson flores.com). He is course co-director and faculty for SHM’s “Best Practices in Managing a Hospital Medicine Program” course. This column represents his views and is not intended to reflect an official position of SHM.

Unpredictable workloads and frequent interruptions are the things I regard as the most stressful components of work as a hospitalist. Your list might be very different, but I bet unpredictable workloads ranks at least in the top five of every hospitalist’s list.

I’ve discussed interruptions previously (see “Really, It’s Switch-Tasking,” p. 68, November 2008; “Technological Advance or Workplace Setback?” p. 69, December 2008), but this month and next will turn to unpredictable workloads. In other words, what are the strategies available to a hospitalist practice to provide surge capacity in response to such unpredictable increases in patient volume as an uptick in census or daily admissions 50% to 100% above normal? I’ll leave to others the topic of how hospitals respond to such disasters as terrorist attacks, earthquakes, etc.

The Bottom Line

Sadly, there is no magic bullet for the “surge” problem, and no way to protect on-duty hospitalists from the need to work harder when it gets busy. But we needn’t feel too sorry for ourselves; doctors in most other specialties who practice in the hospital face the same problem and tend to rely heavily on simply working harder and longer when it is unusually busy. Sometimes they couple the “work harder” mantra with other strategies, such as calling another doctor in to help.

Hospitalists have a duty to ensure high patient volume doesn’t lead to deterioration in the quality of patient care, but occasionally working longer days than average probably poses a low risk, and might be less risky than the additional handoffs usually associated with having a doctor on “jeopardy” to be called in when it’s busy. Routinely or frequently working unreasonably long days is another story.

The trick for HM programs is to build some surge capacity into the routine daily staffing 1) without exceeding a reasonable budget, while 2) ensuring that the hospitalists don’t simply become accustomed to light workloads as the only reasonable norm, which could lead to them becoming unwilling to accept higher, but still reasonable, workloads when needed. (More on these issues later.) First, I’ll go through what I see as the pros and cons of several approaches to addressing surges in patient volume. All are in use with variable frequency around the country.

“Jeopardy” System

In its most common form, a jeopardy system has an unscheduled doctor each day who must remain available on short notice by pager. When patient volume surges, the unscheduled doctor is paged to come in and help. In most cases, this doctor focuses primarily—or exclusively—on admitting patients for a few hours. So it is most common for this doctor to be called in late in the afternoon or early in the evening. The jeopardy doctor usually turns over all admitted patients to another hospitalist in the group for all subsequent care. In addition to providing surge capacity, the jeopardy doctor almost always is used to cover unexpected absences of scheduled doctors, including illness-related absences.

Sometimes this doctor is paid extra for each day or week spent being “available” on jeopardy duty (not to be confused with jury duty, though it can be equally difficult to get exempted from). Then again, it is not uncommon to have jeopardy duty included in base compensation. However, once a jeopardy doctor is actually called in to work, most practices pay additional compensation, often based on an hourly rate that usually is higher than the average compensation generated per hour for nonjeopardy work.

There are a number of reasonable ways to compensate the jeopardy doctor. You probably can get some good ideas by talking with others in your hospital who function in a similar capacity, such as cath-lab technicians who get called in on nights and weekends.

No definitive data are available to show how common the jeopardy system is, but my experience is that 30% to 50% of HM groups use some form of it. Its popularity is proof that it is a reasonable system, but I’m not convinced. I think it is in use by a lot of groups not because it is an optimal way to ensure surge capacity, but because it is easy to conceptualize and put in place, and because many hospitalists came from residency programs in which the system was standard.

The gaps between theoretical and realized benefits become evident once a practice implements a jeopardy system. For example, it might be really busy today, but Dr. Stravinsky doesn’t call in Dr. Copeland, who is on jeopardy, because next week their roles will be reversed and Dr. Stravinsky sure hopes he won’t be called in. No one wants to be the weak doctor who calls in the jeopardy doctor and spoils what was otherwise a day off.

I’ve worked with a lot of practices who say they have a jeopardy system in place, but when I ask for the last time the jeopardy doctor was called in, they say it has been more than a year, or in some cases never. So even if the policy manual says they have a jeopardy system, the doctors never activate it, so it provides no benefit.

Practices that do utilize the jeopardy doctor have their own problems, such as assigning that doctor’s admissions the next day. The jeopardy doctor might provide some relief today, but they essentially just delay the work of having to get to know all of those new patients until the morning, when everyone is very busy with rounds. So while there might be significant benefit in activating the jeopardy system today, it could just delay the problem of high workload until the next morning, which isn’t much of a net benefit for the practice.

A small number of practices call in the jeopardy doctor frequently, and sometimes have that doctor continue to round on admitted patients for the next few days. This usage might get the most value out of the system, but the practice should consider if it is more cost-effective, and less stressful for the doctors, if the system were reversed. For example, instead of having the doctor on jeopardy and called in as necessary, the doctor would report to work and be given the day off or let go early when it isn’t busy.

Despite my reservations, if you are convinced the jeopardy system is valuable and cost-effective, keep it in place. However, if your group is thinking about options to handle surge capacity, don’t be too quick to adopt a jeopardy system. It usually falls far short of a perfect solution.

Patient Volume Cap

Another way to address the problem of unpredictable increases in patient volume is to establish a patient volume (e.g., total census) cap for the whole hospitalist practice. Like the jeopardy system, this is an appealingly uncomplicated idea, and hospitalists who have finished residency within the last few years all worked with a cap.

Except for the rarest of exceptions, this is a poor idea and should be avoided if at all possible. I’ll leave for another time a discussion of all the political and financial costs of a cap system, but trust me on this one. It is best to avoid a cap.

Stay Tuned …

Next month, I’ll examine other strategies to provide surge capacity. I think they’re more valuable than the two I’ve mentioned here, but I need to warn you that they aren’t perfect and are more complicated to operationalize. TH

Dr. Nelson has been a practicing hospitalist since 1988 and is co-founder and past president of SHM. He is a principal in Nelson Flores Hospital Medicine Consultants, a national hospitalist practice management consulting firm (www.nelson flores.com). He is course co-director and faculty for SHM’s “Best Practices in Managing a Hospital Medicine Program” course. This column represents his views and is not intended to reflect an official position of SHM.

How much has Medicare saved by not paying hospitals when patients get infections?

Hugh Black, DO

Charlotte, N.C.

Dr. Hospitalist responds: Since 2007, the Centers for Medicare and Medicaid Services (CMS) has tried to reduce the number of high-cost, hospital-acquired conditions (HACs), including infections, by encouraging providers to adhere to evidence-based guidelines. Some examples of these hospital-acquired conditions include:

• Catheter-associated urinary tract infections;
• Foreign objects retained after surgery; and
• Stage III and IV pressure ulcers.

CMS requires that acute-care hospitals, “effective with discharges occurring on or after Oct. 1, 2007, submit information on Medicare claims specifying whether diagnoses were present on admission.” Effective Oct. 1, 2008, Medicare no longer pays for charges associated with these HACs. So, if a Medicare beneficiary developed a Stage III pressure ulcer during his stay at an acute-care hospital, CMS would not pay for the incremental cost of the care associated with the “HAC.”

click for large version

The U.S. government, in the May 4, 2010, edition of the Federal Register, reviewed the impact of this program. The data are based on Medicare claims data from October 2008 to June 2009. During this period of time, there were approximately 7.17 million acute-care hospital Medicare discharges.

The total net savings during this nine-month period for all HACs was $16.4 million. Three HACs (Stage III and IV pressure ulcers, DVT/PE after orthopedic procedure, and falls and trauma) accounted for more than $15.1 million in savings. Pro-rated for a 12-month period, the total net savings for all HACs would exceed $20 million.

Falls and trauma accounted for 34% of all HACs reported (11,253), followed by vascular catheter-associated infection (16%) and catheter-associated UTIs (16%). Air embolism and mediastinitis after CABG were the least recorded HACs; both were less than .01% if the total.

The goal is that, over time, with improvement in care, there would be a decrease in the number of hospital discharges where these conditions would be present. Therefore, the net savings would be expected to decline.

Medicare has considered a number of other HACs for this program, and reviewed the numbers of these conditions over the same nine-month period (see “Medicare’s Potential New Hospital-Acquired Conditions,” above). Despite some large numbers, CMS has stated it’s not proposing to add or remove HAC categories at this time. If you are interested in reviewing the entire report, visit http://edocket.access.gpo.gov/2010/pdf/ 2010-9163.pdf. TH

How much has Medicare saved by not paying hospitals when patients get infections?

Hugh Black, DO

Charlotte, N.C.

Dr. Hospitalist responds: Since 2007, the Centers for Medicare and Medicaid Services (CMS) has tried to reduce the number of high-cost, hospital-acquired conditions (HACs), including infections, by encouraging providers to adhere to evidence-based guidelines. Some examples of these hospital-acquired conditions include:

• Catheter-associated urinary tract infections;
• Foreign objects retained after surgery; and
• Stage III and IV pressure ulcers.

CMS requires that acute-care hospitals, “effective with discharges occurring on or after Oct. 1, 2007, submit information on Medicare claims specifying whether diagnoses were present on admission.” Effective Oct. 1, 2008, Medicare no longer pays for charges associated with these HACs. So, if a Medicare beneficiary developed a Stage III pressure ulcer during his stay at an acute-care hospital, CMS would not pay for the incremental cost of the care associated with the “HAC.”

click for large version

The U.S. government, in the May 4, 2010, edition of the Federal Register, reviewed the impact of this program. The data are based on Medicare claims data from October 2008 to June 2009. During this period of time, there were approximately 7.17 million acute-care hospital Medicare discharges.

The total net savings during this nine-month period for all HACs was $16.4 million. Three HACs (Stage III and IV pressure ulcers, DVT/PE after orthopedic procedure, and falls and trauma) accounted for more than $15.1 million in savings. Pro-rated for a 12-month period, the total net savings for all HACs would exceed $20 million.

Falls and trauma accounted for 34% of all HACs reported (11,253), followed by vascular catheter-associated infection (16%) and catheter-associated UTIs (16%). Air embolism and mediastinitis after CABG were the least recorded HACs; both were less than .01% if the total.

The goal is that, over time, with improvement in care, there would be a decrease in the number of hospital discharges where these conditions would be present. Therefore, the net savings would be expected to decline.

Medicare has considered a number of other HACs for this program, and reviewed the numbers of these conditions over the same nine-month period (see “Medicare’s Potential New Hospital-Acquired Conditions,” above). Despite some large numbers, CMS has stated it’s not proposing to add or remove HAC categories at this time. If you are interested in reviewing the entire report, visit http://edocket.access.gpo.gov/2010/pdf/ 2010-9163.pdf. TH

How much has Medicare saved by not paying hospitals when patients get infections?

Hugh Black, DO

Charlotte, N.C.

Dr. Hospitalist responds: Since 2007, the Centers for Medicare and Medicaid Services (CMS) has tried to reduce the number of high-cost, hospital-acquired conditions (HACs), including infections, by encouraging providers to adhere to evidence-based guidelines. Some examples of these hospital-acquired conditions include:

• Catheter-associated urinary tract infections;
• Foreign objects retained after surgery; and
• Stage III and IV pressure ulcers.

CMS requires that acute-care hospitals, “effective with discharges occurring on or after Oct. 1, 2007, submit information on Medicare claims specifying whether diagnoses were present on admission.” Effective Oct. 1, 2008, Medicare no longer pays for charges associated with these HACs. So, if a Medicare beneficiary developed a Stage III pressure ulcer during his stay at an acute-care hospital, CMS would not pay for the incremental cost of the care associated with the “HAC.”

click for large version

The U.S. government, in the May 4, 2010, edition of the Federal Register, reviewed the impact of this program. The data are based on Medicare claims data from October 2008 to June 2009. During this period of time, there were approximately 7.17 million acute-care hospital Medicare discharges.

The total net savings during this nine-month period for all HACs was $16.4 million. Three HACs (Stage III and IV pressure ulcers, DVT/PE after orthopedic procedure, and falls and trauma) accounted for more than $15.1 million in savings. Pro-rated for a 12-month period, the total net savings for all HACs would exceed $20 million.

Falls and trauma accounted for 34% of all HACs reported (11,253), followed by vascular catheter-associated infection (16%) and catheter-associated UTIs (16%). Air embolism and mediastinitis after CABG were the least recorded HACs; both were less than .01% if the total.

The goal is that, over time, with improvement in care, there would be a decrease in the number of hospital discharges where these conditions would be present. Therefore, the net savings would be expected to decline.

Medicare has considered a number of other HACs for this program, and reviewed the numbers of these conditions over the same nine-month period (see “Medicare’s Potential New Hospital-Acquired Conditions,” above). Despite some large numbers, CMS has stated it’s not proposing to add or remove HAC categories at this time. If you are interested in reviewing the entire report, visit http://edocket.access.gpo.gov/2010/pdf/ 2010-9163.pdf. TH

SHM Practice Analysis Committee member Troy Ahlstrom, MD, FHM, discusses the new compensation and productivity report, and gives advice on how best to use benchmarking data in your practice.

Click here to listen.

SHM Practice Analysis Committee member Troy Ahlstrom, MD, FHM, discusses the new compensation and productivity report, and gives advice on how best to use benchmarking data in your practice.

Click here to listen.

SHM Practice Analysis Committee member Troy Ahlstrom, MD, FHM, discusses the new compensation and productivity report, and gives advice on how best to use benchmarking data in your practice.

Click here to listen.

Primary care clinicians play a crucial role in the assessment and management of chronic pain. As many as one-third of primary care patients report having chronic pain. As a result, primary care clinicians are expected to have skills in a broad array of analgesic strategies, including analgesic pharmacotherapy. Ideally, drug treatments for pain are combined with nonpharmacologic strategies, including specific psychological and rehabilitative approaches that also may enhance comfort and promote functional restoration.

Primary care clinicians play a crucial role in the assessment and management of chronic pain. As many as one-third of primary care patients report having chronic pain. As a result, primary care clinicians are expected to have skills in a broad array of analgesic strategies, including analgesic pharmacotherapy. Ideally, drug treatments for pain are combined with nonpharmacologic strategies, including specific psychological and rehabilitative approaches that also may enhance comfort and promote functional restoration.

Primary care clinicians play a crucial role in the assessment and management of chronic pain. As many as one-third of primary care patients report having chronic pain. As a result, primary care clinicians are expected to have skills in a broad array of analgesic strategies, including analgesic pharmacotherapy. Ideally, drug treatments for pain are combined with nonpharmacologic strategies, including specific psychological and rehabilitative approaches that also may enhance comfort and promote functional restoration.

Several weeks before coming to our orthopedic surgery clinic, a 53-year-old man presented to an emergency department because of pain, swelling, and redness in his right foot, which began 3 days before. He recalled no overt trauma, but he was jogging when he first noticed the pain, which he described as a constant aching and rated as high as 8 on a scale of 10.

At that time, he had no fever, chills, or night sweats, no cough, and no shortness of breath. About 10 years ago he was diagnosed with diabetes mellitus, for which he currently takes rosiglitazone (Avandia) 2 mg/day and metformin (Glucophage XR) 500 mg four tablets daily. He also takes ramipril (Altace) 10 mg/day for hypertension, as well as a daily multivitamin. He has a history of hyperlipidemia and a family history of diabetes mellitus and Parkinson disease. He has never been hospitalized and has never undergone surgery.

His blood glucose level was 239 mg/dL (normal 70–110), hemoglobin A1c 9.7% (normal 4%–6%), and white blood cell count 13.41 × 109/L (normal 4.5–11.0).

Based on that evaluation, the patient was admitted to the hospital with a diagnosis of cellulitis. He received intravenous antibiotics for 3 days and then was discharged with a prescription for oral antibiotics. He visited his primary care physician several times over the next 2 to 4 weeks and then was referred to our orthopedic surgery clinic for further evaluation. A neurologic evaluation in our clinic revealed a loss of protective sensation, contraction of the toes, and dryness, consistent with peripheral neuropathy. Given what we know so far, which is the most likely diagnosis?

DIFFERENTIAL DIAGNOSIS

While cellulitis may seem to be the likely diagnosis, if a patient with long-standing diabetes, a history of poor glycemic control, and peripheral neuropathy presents with a red, hot, swollen foot with no history of open ulceration, then Charcot neuroarthropathy should be at the top of the list in the differential diagnosis. Other possibilities include osteomyelitis, acute gout, cellulitis, abscess, neuropathic fracture, and deep venous thrombosis. However, if the patient has no open ulceration or history of an open wound, infection is probably not the culprit. Most diabetic foot infections begin with a direct inoculation through an opening in the skin, such as a diabetic neuropathic foot ulcer.

Further, in the case of cellulitis or deep venous thrombosis, the predominating feature would be asymmetric edema of the leg. Also, the location of the edema and ecchymosis in our patient—namely, the midfoot—leads to suspicion of an acute musculoskeletal injury, particularly Charcot neuroarthropathy of the midfoot and neuropathic fractures in the region of the ecchymotic second and third digits. Acute gout could be discounted because gout pain is severe, with rapid onset, and slowly improves even without treatment.

A COMPLICATION OF DIABETES

Charcot neuroarthropathy presents as a warm, swollen, erythematous foot and ankle, a picture that may be indistinguishable from that of infection. Most patients are in their 50s or 60s, and most present on an emergency basis; they often present late in the process, ie, 2 to 3 months after the initial symptoms, because the symptoms often are not painful.

This condition has been reported to occur with leprosy, syringomyelia, toxic exposure, poliomyelitis, rheumatoid arthritis, multiple sclerosis, congenital neuropathy, traumatic injury, and tertiary syphilis.^1–4 Other conditions that reportedly trigger it include cellulitis, osteomyelitis, synovitis, surgery of the foot, and renal transplant surgery.^5–7 However, today, the most common cause is diabetes mellitus.^4,8

Other names for this condition are diabetic neuropathic osteoarthropathy and neuropathic arthropathy.

Current estimates of its prevalence range from 0.08% in the general diabetic population to 13% in high-risk diabetic patients.⁹

CHARCOT NEUROARTHROPATHY BEGINS WITH PERIPHERAL NEUROPATHY

The pathophysiologic mechanism of Charcot neuroarthropathy is not completely known, but it is thought to begin with peripheral neuropathy. Being insensitive to pain, patients may subject the joints of the foot (most commonly in the midfoot) to stress injuries that lead to the active Charcot process.^10–12 About half of Charcot patients present with pain, as did our patient.

Although our patient remembered no trauma, he was physically active at the time he first noticed the symptoms.

Four stages of Charcot neuroarthropathy are recognized^11–15:

Stage 0 (inflammation), also called Charcot in situ or pre-stage 1, is characterized by erythema, edema, and heat but no structural changes.^11,12,14,15

Stage 1 (development) is characterized by bone resorption, bone fragmentation, and joint dislocation. The swelling, warmth, and redness persist, but there are also radiographic changes such as evidence of debris formation at the articular margins, osseous fragmentation, and joint disruption.

Stage 2 (coalescence) involves bony consolidation, osteosclerosis, and fusion after bony destruction. Absorption of small bone fragments, fusion of joints, and sclerosis of the bone are noticeable.

Stage 3 (reconstruction) is characterized by osteogenesis, decreased osteosclerosis, and progressive fusion.¹³ Healing and new bone formation occur. Decreased sclerosis and bony remodeling signify that the deformity (for example, subluxation, incongruity, and dislocation) is permanent.⁴

MISDIAGNOSIS IS COMMON

Charcot neuroarthropathy is an often overlooked complication in diabetic patients with peripheral neuropathy. A group of experts reported that 25% of patients referred to their facility who had Charcot neuroarthropathy had not received a correct diagnosis at the referring institution.¹⁶ The incorrect diagnoses included infection, gout, arthritis, fracture, venous insufficiency, and tumor.

Laboratory tests can narrow the differential diagnosis

There are no laboratory criteria for the diagnosis of Charcot neuroarthropathy and no hematologic markers, but laboratory testing can help narrow the differential diagnosis. Leukocytosis, an elevated C-reactive protein and erythrocyte sedimentation rate, and recent unexplained hyperglycemia suggest infection.¹⁷ However, unremarkable results on clinical tests in this population may not comprehensively exclude infection.

Our patient’s elevated white blood cell count confused the diagnosis. Further, when he was treated with antibiotics, he reported having less pain, although the edema and erythema continued.

Imaging studies

Although advanced imaging may help confirm the diagnosis of Charcot neuropathy in some patients, it is not always necessary.

Radiography. Radiographic findings are important in diagnosing Charcot neuroarthropathy, although they are less helpful in patients with stage 0 disease, such as our patient, in whom the condition has not yet progressed to fracture or dislocation. All foot and ankle radiographs should be taken in the weight-bearing position. Subtle changes may be missed if non-weight-bearing images are taken.

Magnetic resonance imaging (MRI) can show changes in stage 0, thus enabling treatment to be started sooner,¹⁸ and it is increasingly being recommended for diagnosing Charcot neuroarthropathy, especially in the early stages.³ Although bone scintigraphy and white blood cell scans have been traditionally advocated, MRI offers the highest diagnostic accuracy.¹⁹ Signs on MRI consistent with Charcot neuroarthropathy include ligamentous disruption, concomitant joint deformity, and the center of signal enhancement within joints and subchondral bone.²⁰

MRI can also differentiate Charcot neuroarthropathy from transient regional osteoporosis. The latter has a different anatomic location and does not cause fractures and dislocations, and patients do not have a clinical history of pain.

Another condition MRI can identify is complex regional pain syndrome. In this condition, patients have no radiographic abnormalities except for periarticular osteopenia, but they may have severe pain out of proportion with the clinical appearance, and they may develop soft-tissue deformity in the late stages, which is not seen in Charcot neuroarthropathy.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose is also gaining support,²¹ especially when combined with computed tomography (CT). This PET-CT hybrid has better anatomic localization than PET alone.

PET-CT is very reliable for differentiating Charcot neuroarthropathy from osteomyelitis, a distinction that can be difficult to make when Charcot neuroarthropathy is complicated by adjacent loss of skin integrity. The sensitivity of PET-CT in this situation has been reported as 100%, and its sensitivity 93.8%.²²

Patients with Charcot neuroarthropathy demonstrate a low-intensity diffuse uptake that is easily distinguishable from normal joints on visual examination of the images. In addition, the maximum standardized uptake value, a quantitative measurement, is low to intermediate in Charcot neuroarthropathy but significantly higher in osteomyelitis. In one study,²² the mean standardized uptake values were 0.42 in normal feet, 1.3 in Charcot neuroarthropathy, and 4.38 in osteomyelitis.

TREATMENT: IMMOBILIZATION, BISPHOSPHONATES, SURGERY

The goals of treatment for acute or quiescent Charcot neuroarthropathy should be to maintain or achieve structural stability of the foot and ankle, to prevent skin ulceration, and to preserve the plantigrade shape of the foot so that prescription footwear can be used.

Patient and family education is important for compliance with the regimen, particularly because patients with diabetic neuropathy lack the protective pain response.

Immobilization. A total-contact cast is worn until the redness, swelling, and heat subside, generally 8 to 12 weeks, after which the patient should use removable braces or a Charcot restraint orthotic walker for a total of 4 to 6 months of treatment.²³ The cast is typically changed every 1 to 2 weeks as the swelling subsides to minimize irritation to the insensate limb.

Many physicians also recommend elastic stockings (eg, Stockinette) or an elastic tubular bandage (eg, Tubigrip) to reduce edema under the cast.

Bisphosphonates. Some clinicians also prescribe bisphosphonates in the early stages of treatment, as the bone mineral density of the affected foot is low.²⁴ Unfortunately, while these drugs can significantly reduce the levels of bone turnover markers, temperature, and pain, evidence of clinical benefit such as an earlier return to ambulation or radiographic improvement is weak at best.

Surgery is reserved for severe ankle and midfoot deformities that are susceptible to skin ulcerations and that make braces and orthotic devices difficult to use.

TREATMENT OUTCOME

The patient’s condition resolved, with eventual multiplanar deformity and with widening of the midfoot and increased pressure points, particularly to the first ray. He is able to wear an extra-depth shoe, with a custom totalcontact inlay. He continues his profession as an attorney and goes about his normal daily activities; however, he is no longer able to golf and must limit his walking. He subsequently developed ulcerations to both feet, but they resolved with conservative wound care and surgical care. He is seen in the diabetic foot clinic every 6 to 8 weeks.

Several weeks before coming to our orthopedic surgery clinic, a 53-year-old man presented to an emergency department because of pain, swelling, and redness in his right foot, which began 3 days before. He recalled no overt trauma, but he was jogging when he first noticed the pain, which he described as a constant aching and rated as high as 8 on a scale of 10.

At that time, he had no fever, chills, or night sweats, no cough, and no shortness of breath. About 10 years ago he was diagnosed with diabetes mellitus, for which he currently takes rosiglitazone (Avandia) 2 mg/day and metformin (Glucophage XR) 500 mg four tablets daily. He also takes ramipril (Altace) 10 mg/day for hypertension, as well as a daily multivitamin. He has a history of hyperlipidemia and a family history of diabetes mellitus and Parkinson disease. He has never been hospitalized and has never undergone surgery.

His blood glucose level was 239 mg/dL (normal 70–110), hemoglobin A1c 9.7% (normal 4%–6%), and white blood cell count 13.41 × 109/L (normal 4.5–11.0).

Based on that evaluation, the patient was admitted to the hospital with a diagnosis of cellulitis. He received intravenous antibiotics for 3 days and then was discharged with a prescription for oral antibiotics. He visited his primary care physician several times over the next 2 to 4 weeks and then was referred to our orthopedic surgery clinic for further evaluation. A neurologic evaluation in our clinic revealed a loss of protective sensation, contraction of the toes, and dryness, consistent with peripheral neuropathy. Given what we know so far, which is the most likely diagnosis?

DIFFERENTIAL DIAGNOSIS

While cellulitis may seem to be the likely diagnosis, if a patient with long-standing diabetes, a history of poor glycemic control, and peripheral neuropathy presents with a red, hot, swollen foot with no history of open ulceration, then Charcot neuroarthropathy should be at the top of the list in the differential diagnosis. Other possibilities include osteomyelitis, acute gout, cellulitis, abscess, neuropathic fracture, and deep venous thrombosis. However, if the patient has no open ulceration or history of an open wound, infection is probably not the culprit. Most diabetic foot infections begin with a direct inoculation through an opening in the skin, such as a diabetic neuropathic foot ulcer.

Further, in the case of cellulitis or deep venous thrombosis, the predominating feature would be asymmetric edema of the leg. Also, the location of the edema and ecchymosis in our patient—namely, the midfoot—leads to suspicion of an acute musculoskeletal injury, particularly Charcot neuroarthropathy of the midfoot and neuropathic fractures in the region of the ecchymotic second and third digits. Acute gout could be discounted because gout pain is severe, with rapid onset, and slowly improves even without treatment.

A COMPLICATION OF DIABETES

Charcot neuroarthropathy presents as a warm, swollen, erythematous foot and ankle, a picture that may be indistinguishable from that of infection. Most patients are in their 50s or 60s, and most present on an emergency basis; they often present late in the process, ie, 2 to 3 months after the initial symptoms, because the symptoms often are not painful.

This condition has been reported to occur with leprosy, syringomyelia, toxic exposure, poliomyelitis, rheumatoid arthritis, multiple sclerosis, congenital neuropathy, traumatic injury, and tertiary syphilis.^1–4 Other conditions that reportedly trigger it include cellulitis, osteomyelitis, synovitis, surgery of the foot, and renal transplant surgery.^5–7 However, today, the most common cause is diabetes mellitus.^4,8

Other names for this condition are diabetic neuropathic osteoarthropathy and neuropathic arthropathy.

Current estimates of its prevalence range from 0.08% in the general diabetic population to 13% in high-risk diabetic patients.⁹

CHARCOT NEUROARTHROPATHY BEGINS WITH PERIPHERAL NEUROPATHY

The pathophysiologic mechanism of Charcot neuroarthropathy is not completely known, but it is thought to begin with peripheral neuropathy. Being insensitive to pain, patients may subject the joints of the foot (most commonly in the midfoot) to stress injuries that lead to the active Charcot process.^10–12 About half of Charcot patients present with pain, as did our patient.

Although our patient remembered no trauma, he was physically active at the time he first noticed the symptoms.

Four stages of Charcot neuroarthropathy are recognized^11–15:

Stage 0 (inflammation), also called Charcot in situ or pre-stage 1, is characterized by erythema, edema, and heat but no structural changes.^11,12,14,15

Stage 1 (development) is characterized by bone resorption, bone fragmentation, and joint dislocation. The swelling, warmth, and redness persist, but there are also radiographic changes such as evidence of debris formation at the articular margins, osseous fragmentation, and joint disruption.

Stage 2 (coalescence) involves bony consolidation, osteosclerosis, and fusion after bony destruction. Absorption of small bone fragments, fusion of joints, and sclerosis of the bone are noticeable.

Stage 3 (reconstruction) is characterized by osteogenesis, decreased osteosclerosis, and progressive fusion.¹³ Healing and new bone formation occur. Decreased sclerosis and bony remodeling signify that the deformity (for example, subluxation, incongruity, and dislocation) is permanent.⁴

MISDIAGNOSIS IS COMMON

Charcot neuroarthropathy is an often overlooked complication in diabetic patients with peripheral neuropathy. A group of experts reported that 25% of patients referred to their facility who had Charcot neuroarthropathy had not received a correct diagnosis at the referring institution.¹⁶ The incorrect diagnoses included infection, gout, arthritis, fracture, venous insufficiency, and tumor.

Laboratory tests can narrow the differential diagnosis

There are no laboratory criteria for the diagnosis of Charcot neuroarthropathy and no hematologic markers, but laboratory testing can help narrow the differential diagnosis. Leukocytosis, an elevated C-reactive protein and erythrocyte sedimentation rate, and recent unexplained hyperglycemia suggest infection.¹⁷ However, unremarkable results on clinical tests in this population may not comprehensively exclude infection.

Our patient’s elevated white blood cell count confused the diagnosis. Further, when he was treated with antibiotics, he reported having less pain, although the edema and erythema continued.

Imaging studies

Although advanced imaging may help confirm the diagnosis of Charcot neuropathy in some patients, it is not always necessary.

Radiography. Radiographic findings are important in diagnosing Charcot neuroarthropathy, although they are less helpful in patients with stage 0 disease, such as our patient, in whom the condition has not yet progressed to fracture or dislocation. All foot and ankle radiographs should be taken in the weight-bearing position. Subtle changes may be missed if non-weight-bearing images are taken.

Magnetic resonance imaging (MRI) can show changes in stage 0, thus enabling treatment to be started sooner,¹⁸ and it is increasingly being recommended for diagnosing Charcot neuroarthropathy, especially in the early stages.³ Although bone scintigraphy and white blood cell scans have been traditionally advocated, MRI offers the highest diagnostic accuracy.¹⁹ Signs on MRI consistent with Charcot neuroarthropathy include ligamentous disruption, concomitant joint deformity, and the center of signal enhancement within joints and subchondral bone.²⁰

MRI can also differentiate Charcot neuroarthropathy from transient regional osteoporosis. The latter has a different anatomic location and does not cause fractures and dislocations, and patients do not have a clinical history of pain.

Another condition MRI can identify is complex regional pain syndrome. In this condition, patients have no radiographic abnormalities except for periarticular osteopenia, but they may have severe pain out of proportion with the clinical appearance, and they may develop soft-tissue deformity in the late stages, which is not seen in Charcot neuroarthropathy.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose is also gaining support,²¹ especially when combined with computed tomography (CT). This PET-CT hybrid has better anatomic localization than PET alone.

PET-CT is very reliable for differentiating Charcot neuroarthropathy from osteomyelitis, a distinction that can be difficult to make when Charcot neuroarthropathy is complicated by adjacent loss of skin integrity. The sensitivity of PET-CT in this situation has been reported as 100%, and its sensitivity 93.8%.²²

Patients with Charcot neuroarthropathy demonstrate a low-intensity diffuse uptake that is easily distinguishable from normal joints on visual examination of the images. In addition, the maximum standardized uptake value, a quantitative measurement, is low to intermediate in Charcot neuroarthropathy but significantly higher in osteomyelitis. In one study,²² the mean standardized uptake values were 0.42 in normal feet, 1.3 in Charcot neuroarthropathy, and 4.38 in osteomyelitis.

TREATMENT: IMMOBILIZATION, BISPHOSPHONATES, SURGERY

The goals of treatment for acute or quiescent Charcot neuroarthropathy should be to maintain or achieve structural stability of the foot and ankle, to prevent skin ulceration, and to preserve the plantigrade shape of the foot so that prescription footwear can be used.

Patient and family education is important for compliance with the regimen, particularly because patients with diabetic neuropathy lack the protective pain response.

Immobilization. A total-contact cast is worn until the redness, swelling, and heat subside, generally 8 to 12 weeks, after which the patient should use removable braces or a Charcot restraint orthotic walker for a total of 4 to 6 months of treatment.²³ The cast is typically changed every 1 to 2 weeks as the swelling subsides to minimize irritation to the insensate limb.

Many physicians also recommend elastic stockings (eg, Stockinette) or an elastic tubular bandage (eg, Tubigrip) to reduce edema under the cast.

Bisphosphonates. Some clinicians also prescribe bisphosphonates in the early stages of treatment, as the bone mineral density of the affected foot is low.²⁴ Unfortunately, while these drugs can significantly reduce the levels of bone turnover markers, temperature, and pain, evidence of clinical benefit such as an earlier return to ambulation or radiographic improvement is weak at best.

Surgery is reserved for severe ankle and midfoot deformities that are susceptible to skin ulcerations and that make braces and orthotic devices difficult to use.

TREATMENT OUTCOME

The patient’s condition resolved, with eventual multiplanar deformity and with widening of the midfoot and increased pressure points, particularly to the first ray. He is able to wear an extra-depth shoe, with a custom totalcontact inlay. He continues his profession as an attorney and goes about his normal daily activities; however, he is no longer able to golf and must limit his walking. He subsequently developed ulcerations to both feet, but they resolved with conservative wound care and surgical care. He is seen in the diabetic foot clinic every 6 to 8 weeks.

Several weeks before coming to our orthopedic surgery clinic, a 53-year-old man presented to an emergency department because of pain, swelling, and redness in his right foot, which began 3 days before. He recalled no overt trauma, but he was jogging when he first noticed the pain, which he described as a constant aching and rated as high as 8 on a scale of 10.

At that time, he had no fever, chills, or night sweats, no cough, and no shortness of breath. About 10 years ago he was diagnosed with diabetes mellitus, for which he currently takes rosiglitazone (Avandia) 2 mg/day and metformin (Glucophage XR) 500 mg four tablets daily. He also takes ramipril (Altace) 10 mg/day for hypertension, as well as a daily multivitamin. He has a history of hyperlipidemia and a family history of diabetes mellitus and Parkinson disease. He has never been hospitalized and has never undergone surgery.

His blood glucose level was 239 mg/dL (normal 70–110), hemoglobin A1c 9.7% (normal 4%–6%), and white blood cell count 13.41 × 109/L (normal 4.5–11.0).

Based on that evaluation, the patient was admitted to the hospital with a diagnosis of cellulitis. He received intravenous antibiotics for 3 days and then was discharged with a prescription for oral antibiotics. He visited his primary care physician several times over the next 2 to 4 weeks and then was referred to our orthopedic surgery clinic for further evaluation. A neurologic evaluation in our clinic revealed a loss of protective sensation, contraction of the toes, and dryness, consistent with peripheral neuropathy. Given what we know so far, which is the most likely diagnosis?

DIFFERENTIAL DIAGNOSIS

While cellulitis may seem to be the likely diagnosis, if a patient with long-standing diabetes, a history of poor glycemic control, and peripheral neuropathy presents with a red, hot, swollen foot with no history of open ulceration, then Charcot neuroarthropathy should be at the top of the list in the differential diagnosis. Other possibilities include osteomyelitis, acute gout, cellulitis, abscess, neuropathic fracture, and deep venous thrombosis. However, if the patient has no open ulceration or history of an open wound, infection is probably not the culprit. Most diabetic foot infections begin with a direct inoculation through an opening in the skin, such as a diabetic neuropathic foot ulcer.

Further, in the case of cellulitis or deep venous thrombosis, the predominating feature would be asymmetric edema of the leg. Also, the location of the edema and ecchymosis in our patient—namely, the midfoot—leads to suspicion of an acute musculoskeletal injury, particularly Charcot neuroarthropathy of the midfoot and neuropathic fractures in the region of the ecchymotic second and third digits. Acute gout could be discounted because gout pain is severe, with rapid onset, and slowly improves even without treatment.

A COMPLICATION OF DIABETES

Charcot neuroarthropathy presents as a warm, swollen, erythematous foot and ankle, a picture that may be indistinguishable from that of infection. Most patients are in their 50s or 60s, and most present on an emergency basis; they often present late in the process, ie, 2 to 3 months after the initial symptoms, because the symptoms often are not painful.

This condition has been reported to occur with leprosy, syringomyelia, toxic exposure, poliomyelitis, rheumatoid arthritis, multiple sclerosis, congenital neuropathy, traumatic injury, and tertiary syphilis.^1–4 Other conditions that reportedly trigger it include cellulitis, osteomyelitis, synovitis, surgery of the foot, and renal transplant surgery.^5–7 However, today, the most common cause is diabetes mellitus.^4,8

Other names for this condition are diabetic neuropathic osteoarthropathy and neuropathic arthropathy.

Current estimates of its prevalence range from 0.08% in the general diabetic population to 13% in high-risk diabetic patients.⁹

CHARCOT NEUROARTHROPATHY BEGINS WITH PERIPHERAL NEUROPATHY

The pathophysiologic mechanism of Charcot neuroarthropathy is not completely known, but it is thought to begin with peripheral neuropathy. Being insensitive to pain, patients may subject the joints of the foot (most commonly in the midfoot) to stress injuries that lead to the active Charcot process.^10–12 About half of Charcot patients present with pain, as did our patient.

Although our patient remembered no trauma, he was physically active at the time he first noticed the symptoms.

Four stages of Charcot neuroarthropathy are recognized^11–15:

Stage 0 (inflammation), also called Charcot in situ or pre-stage 1, is characterized by erythema, edema, and heat but no structural changes.^11,12,14,15

Stage 1 (development) is characterized by bone resorption, bone fragmentation, and joint dislocation. The swelling, warmth, and redness persist, but there are also radiographic changes such as evidence of debris formation at the articular margins, osseous fragmentation, and joint disruption.

Stage 2 (coalescence) involves bony consolidation, osteosclerosis, and fusion after bony destruction. Absorption of small bone fragments, fusion of joints, and sclerosis of the bone are noticeable.

Stage 3 (reconstruction) is characterized by osteogenesis, decreased osteosclerosis, and progressive fusion.¹³ Healing and new bone formation occur. Decreased sclerosis and bony remodeling signify that the deformity (for example, subluxation, incongruity, and dislocation) is permanent.⁴

MISDIAGNOSIS IS COMMON

Charcot neuroarthropathy is an often overlooked complication in diabetic patients with peripheral neuropathy. A group of experts reported that 25% of patients referred to their facility who had Charcot neuroarthropathy had not received a correct diagnosis at the referring institution.¹⁶ The incorrect diagnoses included infection, gout, arthritis, fracture, venous insufficiency, and tumor.

Laboratory tests can narrow the differential diagnosis

There are no laboratory criteria for the diagnosis of Charcot neuroarthropathy and no hematologic markers, but laboratory testing can help narrow the differential diagnosis. Leukocytosis, an elevated C-reactive protein and erythrocyte sedimentation rate, and recent unexplained hyperglycemia suggest infection.¹⁷ However, unremarkable results on clinical tests in this population may not comprehensively exclude infection.

Our patient’s elevated white blood cell count confused the diagnosis. Further, when he was treated with antibiotics, he reported having less pain, although the edema and erythema continued.

Imaging studies

Although advanced imaging may help confirm the diagnosis of Charcot neuropathy in some patients, it is not always necessary.

Radiography. Radiographic findings are important in diagnosing Charcot neuroarthropathy, although they are less helpful in patients with stage 0 disease, such as our patient, in whom the condition has not yet progressed to fracture or dislocation. All foot and ankle radiographs should be taken in the weight-bearing position. Subtle changes may be missed if non-weight-bearing images are taken.

Magnetic resonance imaging (MRI) can show changes in stage 0, thus enabling treatment to be started sooner,¹⁸ and it is increasingly being recommended for diagnosing Charcot neuroarthropathy, especially in the early stages.³ Although bone scintigraphy and white blood cell scans have been traditionally advocated, MRI offers the highest diagnostic accuracy.¹⁹ Signs on MRI consistent with Charcot neuroarthropathy include ligamentous disruption, concomitant joint deformity, and the center of signal enhancement within joints and subchondral bone.²⁰

MRI can also differentiate Charcot neuroarthropathy from transient regional osteoporosis. The latter has a different anatomic location and does not cause fractures and dislocations, and patients do not have a clinical history of pain.

Another condition MRI can identify is complex regional pain syndrome. In this condition, patients have no radiographic abnormalities except for periarticular osteopenia, but they may have severe pain out of proportion with the clinical appearance, and they may develop soft-tissue deformity in the late stages, which is not seen in Charcot neuroarthropathy.

Positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose is also gaining support,²¹ especially when combined with computed tomography (CT). This PET-CT hybrid has better anatomic localization than PET alone.

PET-CT is very reliable for differentiating Charcot neuroarthropathy from osteomyelitis, a distinction that can be difficult to make when Charcot neuroarthropathy is complicated by adjacent loss of skin integrity. The sensitivity of PET-CT in this situation has been reported as 100%, and its sensitivity 93.8%.²²

Patients with Charcot neuroarthropathy demonstrate a low-intensity diffuse uptake that is easily distinguishable from normal joints on visual examination of the images. In addition, the maximum standardized uptake value, a quantitative measurement, is low to intermediate in Charcot neuroarthropathy but significantly higher in osteomyelitis. In one study,²² the mean standardized uptake values were 0.42 in normal feet, 1.3 in Charcot neuroarthropathy, and 4.38 in osteomyelitis.

TREATMENT: IMMOBILIZATION, BISPHOSPHONATES, SURGERY

The goals of treatment for acute or quiescent Charcot neuroarthropathy should be to maintain or achieve structural stability of the foot and ankle, to prevent skin ulceration, and to preserve the plantigrade shape of the foot so that prescription footwear can be used.

Patient and family education is important for compliance with the regimen, particularly because patients with diabetic neuropathy lack the protective pain response.

Immobilization. A total-contact cast is worn until the redness, swelling, and heat subside, generally 8 to 12 weeks, after which the patient should use removable braces or a Charcot restraint orthotic walker for a total of 4 to 6 months of treatment.²³ The cast is typically changed every 1 to 2 weeks as the swelling subsides to minimize irritation to the insensate limb.

Many physicians also recommend elastic stockings (eg, Stockinette) or an elastic tubular bandage (eg, Tubigrip) to reduce edema under the cast.

Bisphosphonates. Some clinicians also prescribe bisphosphonates in the early stages of treatment, as the bone mineral density of the affected foot is low.²⁴ Unfortunately, while these drugs can significantly reduce the levels of bone turnover markers, temperature, and pain, evidence of clinical benefit such as an earlier return to ambulation or radiographic improvement is weak at best.

Surgery is reserved for severe ankle and midfoot deformities that are susceptible to skin ulcerations and that make braces and orthotic devices difficult to use.

TREATMENT OUTCOME

The patient’s condition resolved, with eventual multiplanar deformity and with widening of the midfoot and increased pressure points, particularly to the first ray. He is able to wear an extra-depth shoe, with a custom totalcontact inlay. He continues his profession as an attorney and goes about his normal daily activities; however, he is no longer able to golf and must limit his walking. He subsequently developed ulcerations to both feet, but they resolved with conservative wound care and surgical care. He is seen in the diabetic foot clinic every 6 to 8 weeks.

A 45-year-old woman who has been undergoing hemodialysis for 20 years presents with diffuse bone pain, pruritic skin, muscle weakness, and disability. About 8 years ago, she was diagnosed with uremic hyperparathyroidism and underwent two parathyroidectomy procedures and eight sessions of percutaneous alcohol ablation of the parathyroid gland.

A technetium-99m sestamibi radionuclide scan shows bilateral parathyroid hyperplasia with no ectopic parathyroid adenomas. Although a surgeon she consulted 1 month ago declined to perform another parathyroidectomy for technical reasons, another surgeon agreed to do it at this time. Parathyroidectomy was successfully performed, after which the parathyroid hormone level decreased drastically, to 85 pg/mL.

To our surprise, her total body length increased by 6 to 7 cm after surgery, with partial straightening of the back and legs noted about 4 to 5 weeks after surgery. Furthermore, she was able to walk a short distance just a few weeks after surgery. Unfortunately, she died from sepsis the next year.

SEVERE UREMIC HYPERPARATHYROIDISM: A CLINICAL DILEMMA

The clinical appearance of reduced body length and diffuse bony deformity leading to “shrinking” as a consequence of prolonged severe uremic hyperparathyroidism has only rarely been reported.¹ However, it is not uncommon for surgeons to decide against parathyroidectomy because of concerns of extensive subcutaneous fibrosis and recurrent laryngeal nerve damage associated with previous operations. The result is that the patient’s uremic hyperparathyroidism goes untreated, increasing the risk of long-term complications, as in this patient.

TYPICAL RADIOGRAPHIC FEATURES

Why the body length increases after parathyroidectomy is not yet known, but plausible mechanisms are the effects of a recovery of muscle strength and the vigorous bony remineralization that strengthens weight-bearing bones after resolution of uremic hyperparathyroidism.

THE DANGERS OF DELAYED TREATMENT

Delaying parathyroidectomy may induce prolonged and severe uremic hyperparathyroidism, as in this patient. Nevertheless, despite the delay, surgery was able to partially ameliorate the symptoms of hyperparathyroidism and improve the extreme bone deformity. However, the patient’s informed consent, a detailed preoperative evaluation, and exclusion of ectopic parathyroid adenomas are imperative before surgical treatment.

A 45-year-old woman who has been undergoing hemodialysis for 20 years presents with diffuse bone pain, pruritic skin, muscle weakness, and disability. About 8 years ago, she was diagnosed with uremic hyperparathyroidism and underwent two parathyroidectomy procedures and eight sessions of percutaneous alcohol ablation of the parathyroid gland.

A technetium-99m sestamibi radionuclide scan shows bilateral parathyroid hyperplasia with no ectopic parathyroid adenomas. Although a surgeon she consulted 1 month ago declined to perform another parathyroidectomy for technical reasons, another surgeon agreed to do it at this time. Parathyroidectomy was successfully performed, after which the parathyroid hormone level decreased drastically, to 85 pg/mL.

To our surprise, her total body length increased by 6 to 7 cm after surgery, with partial straightening of the back and legs noted about 4 to 5 weeks after surgery. Furthermore, she was able to walk a short distance just a few weeks after surgery. Unfortunately, she died from sepsis the next year.

SEVERE UREMIC HYPERPARATHYROIDISM: A CLINICAL DILEMMA

The clinical appearance of reduced body length and diffuse bony deformity leading to “shrinking” as a consequence of prolonged severe uremic hyperparathyroidism has only rarely been reported.¹ However, it is not uncommon for surgeons to decide against parathyroidectomy because of concerns of extensive subcutaneous fibrosis and recurrent laryngeal nerve damage associated with previous operations. The result is that the patient’s uremic hyperparathyroidism goes untreated, increasing the risk of long-term complications, as in this patient.

TYPICAL RADIOGRAPHIC FEATURES

Why the body length increases after parathyroidectomy is not yet known, but plausible mechanisms are the effects of a recovery of muscle strength and the vigorous bony remineralization that strengthens weight-bearing bones after resolution of uremic hyperparathyroidism.

THE DANGERS OF DELAYED TREATMENT

Delaying parathyroidectomy may induce prolonged and severe uremic hyperparathyroidism, as in this patient. Nevertheless, despite the delay, surgery was able to partially ameliorate the symptoms of hyperparathyroidism and improve the extreme bone deformity. However, the patient’s informed consent, a detailed preoperative evaluation, and exclusion of ectopic parathyroid adenomas are imperative before surgical treatment.

A 45-year-old woman who has been undergoing hemodialysis for 20 years presents with diffuse bone pain, pruritic skin, muscle weakness, and disability. About 8 years ago, she was diagnosed with uremic hyperparathyroidism and underwent two parathyroidectomy procedures and eight sessions of percutaneous alcohol ablation of the parathyroid gland.

A technetium-99m sestamibi radionuclide scan shows bilateral parathyroid hyperplasia with no ectopic parathyroid adenomas. Although a surgeon she consulted 1 month ago declined to perform another parathyroidectomy for technical reasons, another surgeon agreed to do it at this time. Parathyroidectomy was successfully performed, after which the parathyroid hormone level decreased drastically, to 85 pg/mL.

To our surprise, her total body length increased by 6 to 7 cm after surgery, with partial straightening of the back and legs noted about 4 to 5 weeks after surgery. Furthermore, she was able to walk a short distance just a few weeks after surgery. Unfortunately, she died from sepsis the next year.

SEVERE UREMIC HYPERPARATHYROIDISM: A CLINICAL DILEMMA

The clinical appearance of reduced body length and diffuse bony deformity leading to “shrinking” as a consequence of prolonged severe uremic hyperparathyroidism has only rarely been reported.¹ However, it is not uncommon for surgeons to decide against parathyroidectomy because of concerns of extensive subcutaneous fibrosis and recurrent laryngeal nerve damage associated with previous operations. The result is that the patient’s uremic hyperparathyroidism goes untreated, increasing the risk of long-term complications, as in this patient.

TYPICAL RADIOGRAPHIC FEATURES

Why the body length increases after parathyroidectomy is not yet known, but plausible mechanisms are the effects of a recovery of muscle strength and the vigorous bony remineralization that strengthens weight-bearing bones after resolution of uremic hyperparathyroidism.

THE DANGERS OF DELAYED TREATMENT

Delaying parathyroidectomy may induce prolonged and severe uremic hyperparathyroidism, as in this patient. Nevertheless, despite the delay, surgery was able to partially ameliorate the symptoms of hyperparathyroidism and improve the extreme bone deformity. However, the patient’s informed consent, a detailed preoperative evaluation, and exclusion of ectopic parathyroid adenomas are imperative before surgical treatment.

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Reperfusion therapy decreases morbidity and mortality rates in patients with ST-segment elevation myocardial infarction (MI). Primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy as a reperfusion strategy when the delay in the time to treatment is short and the patient presents to a high-volume, well-equipped center with expert interventional cardiologists.

See related article

Compared with fibrinolytic therapy in randomized clinical trials, primary PCI produces higher rates of infarct artery patency, complete reperfusion (grade 3 by the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study), and access-site bleeding. It also produces lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage, and death.¹ If performed early and successfully, primary PCI also greatly decreases the rates of complications of ST-elevation MI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI is also the best reperfusion option in patients who present late after the onset of symptoms and in patients with cardiogenic shock, and it is the only option in patients who have contraindications to fibrinolytic therapy because of bleeding risk.

However, most hospitals do not have PCI capability. Two options at these hospitals are to transfer the patient to a PCI center quickly for primary PCI or to keep the patient on site and give fibrinolytic therapy, with its limitations. Earlier trials suggested that the transfer strategy was superior, but they had limitations: most patients received streptokinase, an inferior fibrinolytic agent, and door-to-door-to-balloon times were rapid, averaging only 95 minutes because of excellent logistical protocols and careful patient selection.² Most importantly, rescue PCI and routine PCI were seldom performed in patients receiving fibrinolytics, so fibrinolytic therapy was being tested as monotherapy.

In the real world, however, treatment delays are much longer, and fibrinolytic therapy has evolved into a strategy that includes crossover to rescue PCI or routine PCI. Therefore, the initial trials of transfer for primary PCI do not reflect current practice. In fact, recent registry data suggest that prehospital fibrinolytic therapy followed by early angiography is superior to primary PCI because most patients can be treated within 2 hours of symptom onset; they also suggest that on-site fibrinolytic therapy followed by early angiography is equal in efficacy to primary PCI as long as rescue PCI and routine PCI can be performed.^3,4

The most important modifiable predictor of outcome in ST-elevation MI is the time to treatment, a biological truth that continues to be supported by clinical evidence despite ideologic arguments by some interventional cardiology enthusiasts who claim that primary PCI is always superior to the fibrinolytic strategy, regardless of delays.

SURPRISINGLY, OUTCOMES WERE WORSE WITH FACILITATED PCI

It made sense, then, to conclude that the perfect strategy for hospitals without PCI capability would be a combined strategy of immediate fibrinolytic therapy to decrease the time delay associated with organizing PCI, and rapid transfer for immediate PCI to improve the limited reperfusion rates associated with fibrinolytic therapy.

Surprisingly, though, randomized trials found worse outcomes with this “facilitated PCI” strategy.⁵

Again, limitations in trial design might explain the lack of benefit in the trials. Inadequate anticoagulant and antiplatelet therapy were given to the fibrinolytic patients, and primary PCI patients had relatively short treatment delays, with many patients enrolled at hospitals with PCI capability.

PROGRESS IN REPERFUSION THERAPY

Great strides have been made in reperfusion therapy in recent years. Adjunctive therapy with clopidogrel (Plavix) and enoxaparin (Lovenox) has been shown to improve outcomes with fibrinolytic therapy. Bivalirudin (Angiomax) and stents have improved primary PCI’s performance. Reducing bleeding complications has become a clinical priority, with increasing emphasis on adjusting some drug doses according to renal function and using the radial artery for cardiac catheterization.

The American College of Cardiology initiative, “Door-to-Balloon (D2B): An Alliance for Quality,” focused much attention on organizing in-hospital systems of care for primary PCI, thus increasing the national rate of achieving a door-to-balloon time within 90 minutes from 50% to over 75% in patients who presented to hospitals with PCI capability.⁶

The American Heart Association has launched “Mission: Lifeline,” a national campaign to organize prehospital systems of care with their program,⁷ working within communities to address their unique needs, resources, and barriers to implementing systems of care for ST-elevation MI. The key aspect of this effort is to help geographic regions develop local solutions, an explicit recognition that there is no one-size-fits-all solution. Early triage by emergency medical services, rapid diagnosis with prehospital electrocardiography, destination and interhospital transfer protocols, and prehospital activation of the cardiac catheterization laboratory can greatly streamline emergency care and decrease treatment delays for primary PCI.

FOR OUTLYING HOSPITALS, A PHARMACOINVASIVE STRATEGY

So what about hospitals without PCI capability that cannot routinely transfer patients to a hospital with PCI capability within 90 minutes?

Lessons learned from the experiences with immediate PCI, rescue PCI, and facilitated PCI have evolved into the “pharmacoinvasive strategy.” Patients with ST-elevation MI are treated as rapidly as possible with a bolus of a fibrinolytic drug, eg, tenecteplase (TNKase) or reteplase (Retavase), and are also given aspirin, clopidogrel, and enoxaparin. Then, they are rapidly transferred to a PCI-capable hospital so that emergency PCI can be performed if reperfusion is not clinically apparent or if the patient develops pulmonary edema or cardiogenic shock. If the clinical signs suggest that reperfusion has been achieved (relief of chest pain, rapid resolution of ST-segment elevation, bursts of accelerated idioventricular rhythm), coronary angiography (and PCI, if indicated) can be performed within 3 to 24 hours of fibrinolytic therapy. This time frame allows the initial fibrinolytic effect to dissipate, while the antiplatelet and anticoagulant drugs achieve therapeutic levels.

Today, the goal is to treat every patient with the best reperfusion strategy available, given the limitations in resources and the geographic location of some centers, and to maximize the possibility of sustained patency of the infarct-related artery by implanting a stent, even if it takes several hours and transfer to another hospital to perform PCI.⁸ The pharmacoinvasive strategy of rapid administration of fibrinolytic therapy followed by PCI within 24 hours would be practical in most hospitals without PCI capability where treatment delays prohibit performance of primary PCI within 90 minutes of first medical contact.⁹

THE ‘STREAM’ TRIAL IS UNDER WAY

As proof of concept, the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial is enrolling 2,000 patients with ST-elevation MI presenting within 3 hours of symptom onset if primary PCI is not feasible within 60 minutes of first medical contact.¹⁰ Patients will be randomized to either of the following:

• Receive prehospital therapy with tenecteplase, aspirin, clopidogrel, and enoxaparin and undergo cardiac catheterization in 6 to 24 hours (or rescue PCI if reperfusion fails within 90 minutes of fibrinolysis)
• Undergo primary PCI performed according to local guidelines.

The primary measure of efficacy will be the composite rate of death, cardiogenic shock, heart failure, and reinfarction at 30 days. Measures of safety include the rates of ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding.

Reperfusion therapy decreases morbidity and mortality rates in patients with ST-segment elevation myocardial infarction (MI). Primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy as a reperfusion strategy when the delay in the time to treatment is short and the patient presents to a high-volume, well-equipped center with expert interventional cardiologists.

See related article

Compared with fibrinolytic therapy in randomized clinical trials, primary PCI produces higher rates of infarct artery patency, complete reperfusion (grade 3 by the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study), and access-site bleeding. It also produces lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage, and death.¹ If performed early and successfully, primary PCI also greatly decreases the rates of complications of ST-elevation MI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI is also the best reperfusion option in patients who present late after the onset of symptoms and in patients with cardiogenic shock, and it is the only option in patients who have contraindications to fibrinolytic therapy because of bleeding risk.

However, most hospitals do not have PCI capability. Two options at these hospitals are to transfer the patient to a PCI center quickly for primary PCI or to keep the patient on site and give fibrinolytic therapy, with its limitations. Earlier trials suggested that the transfer strategy was superior, but they had limitations: most patients received streptokinase, an inferior fibrinolytic agent, and door-to-door-to-balloon times were rapid, averaging only 95 minutes because of excellent logistical protocols and careful patient selection.² Most importantly, rescue PCI and routine PCI were seldom performed in patients receiving fibrinolytics, so fibrinolytic therapy was being tested as monotherapy.

In the real world, however, treatment delays are much longer, and fibrinolytic therapy has evolved into a strategy that includes crossover to rescue PCI or routine PCI. Therefore, the initial trials of transfer for primary PCI do not reflect current practice. In fact, recent registry data suggest that prehospital fibrinolytic therapy followed by early angiography is superior to primary PCI because most patients can be treated within 2 hours of symptom onset; they also suggest that on-site fibrinolytic therapy followed by early angiography is equal in efficacy to primary PCI as long as rescue PCI and routine PCI can be performed.^3,4

The most important modifiable predictor of outcome in ST-elevation MI is the time to treatment, a biological truth that continues to be supported by clinical evidence despite ideologic arguments by some interventional cardiology enthusiasts who claim that primary PCI is always superior to the fibrinolytic strategy, regardless of delays.

SURPRISINGLY, OUTCOMES WERE WORSE WITH FACILITATED PCI

It made sense, then, to conclude that the perfect strategy for hospitals without PCI capability would be a combined strategy of immediate fibrinolytic therapy to decrease the time delay associated with organizing PCI, and rapid transfer for immediate PCI to improve the limited reperfusion rates associated with fibrinolytic therapy.

Surprisingly, though, randomized trials found worse outcomes with this “facilitated PCI” strategy.⁵

Again, limitations in trial design might explain the lack of benefit in the trials. Inadequate anticoagulant and antiplatelet therapy were given to the fibrinolytic patients, and primary PCI patients had relatively short treatment delays, with many patients enrolled at hospitals with PCI capability.

PROGRESS IN REPERFUSION THERAPY

Great strides have been made in reperfusion therapy in recent years. Adjunctive therapy with clopidogrel (Plavix) and enoxaparin (Lovenox) has been shown to improve outcomes with fibrinolytic therapy. Bivalirudin (Angiomax) and stents have improved primary PCI’s performance. Reducing bleeding complications has become a clinical priority, with increasing emphasis on adjusting some drug doses according to renal function and using the radial artery for cardiac catheterization.

The American College of Cardiology initiative, “Door-to-Balloon (D2B): An Alliance for Quality,” focused much attention on organizing in-hospital systems of care for primary PCI, thus increasing the national rate of achieving a door-to-balloon time within 90 minutes from 50% to over 75% in patients who presented to hospitals with PCI capability.⁶

The American Heart Association has launched “Mission: Lifeline,” a national campaign to organize prehospital systems of care with their program,⁷ working within communities to address their unique needs, resources, and barriers to implementing systems of care for ST-elevation MI. The key aspect of this effort is to help geographic regions develop local solutions, an explicit recognition that there is no one-size-fits-all solution. Early triage by emergency medical services, rapid diagnosis with prehospital electrocardiography, destination and interhospital transfer protocols, and prehospital activation of the cardiac catheterization laboratory can greatly streamline emergency care and decrease treatment delays for primary PCI.

FOR OUTLYING HOSPITALS, A PHARMACOINVASIVE STRATEGY

So what about hospitals without PCI capability that cannot routinely transfer patients to a hospital with PCI capability within 90 minutes?

Lessons learned from the experiences with immediate PCI, rescue PCI, and facilitated PCI have evolved into the “pharmacoinvasive strategy.” Patients with ST-elevation MI are treated as rapidly as possible with a bolus of a fibrinolytic drug, eg, tenecteplase (TNKase) or reteplase (Retavase), and are also given aspirin, clopidogrel, and enoxaparin. Then, they are rapidly transferred to a PCI-capable hospital so that emergency PCI can be performed if reperfusion is not clinically apparent or if the patient develops pulmonary edema or cardiogenic shock. If the clinical signs suggest that reperfusion has been achieved (relief of chest pain, rapid resolution of ST-segment elevation, bursts of accelerated idioventricular rhythm), coronary angiography (and PCI, if indicated) can be performed within 3 to 24 hours of fibrinolytic therapy. This time frame allows the initial fibrinolytic effect to dissipate, while the antiplatelet and anticoagulant drugs achieve therapeutic levels.

Today, the goal is to treat every patient with the best reperfusion strategy available, given the limitations in resources and the geographic location of some centers, and to maximize the possibility of sustained patency of the infarct-related artery by implanting a stent, even if it takes several hours and transfer to another hospital to perform PCI.⁸ The pharmacoinvasive strategy of rapid administration of fibrinolytic therapy followed by PCI within 24 hours would be practical in most hospitals without PCI capability where treatment delays prohibit performance of primary PCI within 90 minutes of first medical contact.⁹

THE ‘STREAM’ TRIAL IS UNDER WAY

As proof of concept, the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial is enrolling 2,000 patients with ST-elevation MI presenting within 3 hours of symptom onset if primary PCI is not feasible within 60 minutes of first medical contact.¹⁰ Patients will be randomized to either of the following:

• Receive prehospital therapy with tenecteplase, aspirin, clopidogrel, and enoxaparin and undergo cardiac catheterization in 6 to 24 hours (or rescue PCI if reperfusion fails within 90 minutes of fibrinolysis)
• Undergo primary PCI performed according to local guidelines.

The primary measure of efficacy will be the composite rate of death, cardiogenic shock, heart failure, and reinfarction at 30 days. Measures of safety include the rates of ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding.

Reperfusion therapy decreases morbidity and mortality rates in patients with ST-segment elevation myocardial infarction (MI). Primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy as a reperfusion strategy when the delay in the time to treatment is short and the patient presents to a high-volume, well-equipped center with expert interventional cardiologists.

See related article

Compared with fibrinolytic therapy in randomized clinical trials, primary PCI produces higher rates of infarct artery patency, complete reperfusion (grade 3 by the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study), and access-site bleeding. It also produces lower rates of recurrent ischemia, reinfarction, emergency repeat revascularization procedures, intracranial hemorrhage, and death.¹ If performed early and successfully, primary PCI also greatly decreases the rates of complications of ST-elevation MI that result from longer ischemic times or unsuccessful fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities. Primary PCI is also the best reperfusion option in patients who present late after the onset of symptoms and in patients with cardiogenic shock, and it is the only option in patients who have contraindications to fibrinolytic therapy because of bleeding risk.

However, most hospitals do not have PCI capability. Two options at these hospitals are to transfer the patient to a PCI center quickly for primary PCI or to keep the patient on site and give fibrinolytic therapy, with its limitations. Earlier trials suggested that the transfer strategy was superior, but they had limitations: most patients received streptokinase, an inferior fibrinolytic agent, and door-to-door-to-balloon times were rapid, averaging only 95 minutes because of excellent logistical protocols and careful patient selection.² Most importantly, rescue PCI and routine PCI were seldom performed in patients receiving fibrinolytics, so fibrinolytic therapy was being tested as monotherapy.

In the real world, however, treatment delays are much longer, and fibrinolytic therapy has evolved into a strategy that includes crossover to rescue PCI or routine PCI. Therefore, the initial trials of transfer for primary PCI do not reflect current practice. In fact, recent registry data suggest that prehospital fibrinolytic therapy followed by early angiography is superior to primary PCI because most patients can be treated within 2 hours of symptom onset; they also suggest that on-site fibrinolytic therapy followed by early angiography is equal in efficacy to primary PCI as long as rescue PCI and routine PCI can be performed.^3,4

The most important modifiable predictor of outcome in ST-elevation MI is the time to treatment, a biological truth that continues to be supported by clinical evidence despite ideologic arguments by some interventional cardiology enthusiasts who claim that primary PCI is always superior to the fibrinolytic strategy, regardless of delays.

SURPRISINGLY, OUTCOMES WERE WORSE WITH FACILITATED PCI

It made sense, then, to conclude that the perfect strategy for hospitals without PCI capability would be a combined strategy of immediate fibrinolytic therapy to decrease the time delay associated with organizing PCI, and rapid transfer for immediate PCI to improve the limited reperfusion rates associated with fibrinolytic therapy.

Surprisingly, though, randomized trials found worse outcomes with this “facilitated PCI” strategy.⁵

Again, limitations in trial design might explain the lack of benefit in the trials. Inadequate anticoagulant and antiplatelet therapy were given to the fibrinolytic patients, and primary PCI patients had relatively short treatment delays, with many patients enrolled at hospitals with PCI capability.

PROGRESS IN REPERFUSION THERAPY

Great strides have been made in reperfusion therapy in recent years. Adjunctive therapy with clopidogrel (Plavix) and enoxaparin (Lovenox) has been shown to improve outcomes with fibrinolytic therapy. Bivalirudin (Angiomax) and stents have improved primary PCI’s performance. Reducing bleeding complications has become a clinical priority, with increasing emphasis on adjusting some drug doses according to renal function and using the radial artery for cardiac catheterization.

The American College of Cardiology initiative, “Door-to-Balloon (D2B): An Alliance for Quality,” focused much attention on organizing in-hospital systems of care for primary PCI, thus increasing the national rate of achieving a door-to-balloon time within 90 minutes from 50% to over 75% in patients who presented to hospitals with PCI capability.⁶

The American Heart Association has launched “Mission: Lifeline,” a national campaign to organize prehospital systems of care with their program,⁷ working within communities to address their unique needs, resources, and barriers to implementing systems of care for ST-elevation MI. The key aspect of this effort is to help geographic regions develop local solutions, an explicit recognition that there is no one-size-fits-all solution. Early triage by emergency medical services, rapid diagnosis with prehospital electrocardiography, destination and interhospital transfer protocols, and prehospital activation of the cardiac catheterization laboratory can greatly streamline emergency care and decrease treatment delays for primary PCI.

FOR OUTLYING HOSPITALS, A PHARMACOINVASIVE STRATEGY

So what about hospitals without PCI capability that cannot routinely transfer patients to a hospital with PCI capability within 90 minutes?

Lessons learned from the experiences with immediate PCI, rescue PCI, and facilitated PCI have evolved into the “pharmacoinvasive strategy.” Patients with ST-elevation MI are treated as rapidly as possible with a bolus of a fibrinolytic drug, eg, tenecteplase (TNKase) or reteplase (Retavase), and are also given aspirin, clopidogrel, and enoxaparin. Then, they are rapidly transferred to a PCI-capable hospital so that emergency PCI can be performed if reperfusion is not clinically apparent or if the patient develops pulmonary edema or cardiogenic shock. If the clinical signs suggest that reperfusion has been achieved (relief of chest pain, rapid resolution of ST-segment elevation, bursts of accelerated idioventricular rhythm), coronary angiography (and PCI, if indicated) can be performed within 3 to 24 hours of fibrinolytic therapy. This time frame allows the initial fibrinolytic effect to dissipate, while the antiplatelet and anticoagulant drugs achieve therapeutic levels.

Today, the goal is to treat every patient with the best reperfusion strategy available, given the limitations in resources and the geographic location of some centers, and to maximize the possibility of sustained patency of the infarct-related artery by implanting a stent, even if it takes several hours and transfer to another hospital to perform PCI.⁸ The pharmacoinvasive strategy of rapid administration of fibrinolytic therapy followed by PCI within 24 hours would be practical in most hospitals without PCI capability where treatment delays prohibit performance of primary PCI within 90 minutes of first medical contact.⁹

THE ‘STREAM’ TRIAL IS UNDER WAY

As proof of concept, the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial is enrolling 2,000 patients with ST-elevation MI presenting within 3 hours of symptom onset if primary PCI is not feasible within 60 minutes of first medical contact.¹⁰ Patients will be randomized to either of the following:

• Receive prehospital therapy with tenecteplase, aspirin, clopidogrel, and enoxaparin and undergo cardiac catheterization in 6 to 24 hours (or rescue PCI if reperfusion fails within 90 minutes of fibrinolysis)
• Undergo primary PCI performed according to local guidelines.

The primary measure of efficacy will be the composite rate of death, cardiogenic shock, heart failure, and reinfarction at 30 days. Measures of safety include the rates of ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding.

Effective and rapid reperfusion is crucial in patients with acute ST-segment elevation myocardial infarction (MI). The preferred strategy for reperfusion—when it can be performed in a timely fashion at an experienced facility—is primary percutaneous coronary intervention (PCI), which produces outcomes superior to those of pharmacologic thrombolysis.¹

See related editorial

Unfortunately, in the United States about half of patients present to hospitals that do not have PCI capability,² and in one analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes, with a mean of 152 minutes.³ (In this case, the door-to-balloon time was the time that elapsed between entry into the first hospital and inflation of the PCI balloon at the second hospital.)

In situations such as these, a combined approach may be appropriate, with thrombolysis delivered by paramedics or at a local facility, followed by transfer to a PCI facility and performance of PCI within a few hours. However, this is feasible only if standardized community-based or regional protocols for prompt transfer and reperfusion are in place.

In this paper we discuss the rationale and the clinical data behind several approaches to combined reperfusion, as well as experiences with community-based care protocols.

WITHIN 3 HOURS OF SYMPTOM ONSET, THROMBOLYSIS IS AS GOOD AS PCI

The PRAGUE-2 Trial

In the randomized PRAGUE-2 trial,⁴ patients with ST-elevation MI who presented to a non-PCI facility had better outcomes if they were transferred promptly for PCI (median door-to-balloon time 97 minutes), as opposed to receiving local therapy with streptokinase. However, for patients presenting within 3 hours of symptom onset, the mortality rates were comparable with either strategy.⁴

See the glossary of clinical trial names below

The CAPTIM trial

In the CAPTIM trial,⁵ patients who presented within 2 hours of symptom onset and who were randomized to receive prehospital thrombolysis had outcomes similar to those of patients treated with primary PCI, despite a short door-to-balloon time (82 minutes).

The Vienna STEMI Registry

In the Vienna STEMI Registry,⁶ the mortality rates with primary PCI and with thrombolysis were similar when patients presented within 2 hours of symptom onset. However, as the time from symptom onset increased, primary PCI appeared to offer an increasing survival benefit compared with thrombolysis.

Comments: Thrombolysis is effective mostly in the first 2 to 3 hours, with some benefit up to 12 hours

Previous studies have shown that the sooner thrombolysis is given after symptom onset, the more effective it is. If it is given within an hour of symptom onset, the relative reduction in the mortality rate is 50% and the absolute reduction is 6.5% compared with no reperfusion therapy. If it is started in the second hour, the absolute reduction in the mortality rate drops to 4%, and a lesser benefit extends to patients presenting up to 12 hours after symptom onset.⁷ This time-dependent benefit is due to the fact that very early reperfusion of the occluded coronary artery may lead to full recovery of ischemic tissue and thus prevent necrosis. In addition, thrombolysis in the first 2 hours is highly efficacious in lysing a fresh thrombus.

These data support the current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA), which state no preference for either thrombolytic therapy or PCI in ST-elevation MI if the presentation is less than 3 hours after symptom onset.⁸

Of note, in the CAPTIM trial and in the Vienna STEMI Registry, rescue PCI was available and was in fact used after thrombolysis in about 25% of patients, which might have contributed to the benefit of early thrombolysis.

PRIMARY PCI MAY NOT BE SUPERIOR IF TRANSFER TIME IS LONG

Another time-related factor to consider is the PCI-related delay, ie, the theoretical difference between the expected time from first medical contact to balloon inflation (if the patient undergoes primary PCI) and the time from first medical contact to the start of thrombolytic therapy (if the patient undergoes primary thrombolysis).

A meta-analysis of 13 trials comparing PCI and thrombolysis showed that a PCI-related delay of more than 60 minutes might negate the potential advantage of primary PCI over immediate thrombolysis in terms of deaths.⁹

This observation has been further refined by data from the National Registry of Myocardial Infarction.¹⁰ In this analysis, patient factors, including age, duration of symptoms, and infarct location, significantly affected the point at which the PCI-related delay negated the survival advantage of primary PCI. The survival advantage of primary PCI was lost more rapidly—with a PCI-related delay as short as 40 minutes—in patients who presented sooner, were younger, or had anterior MI. Primary PCI maintained its survival advantage even with a PCI-related delay longer than 100 minutes in older patients or patients with nonanterior MI presenting more than 3 hours after symptom onset. Given that median door-to-balloon times in the United States may exceed 150 minutes when transfer is involved, ³ primary PCI may be no better than primary thrombolysis in transferred patients who present early or who have large infarcts.

Although these results were derived from a post hoc analysis of a registry and the delay times reported were sometimes inaccurate, they suggest that both the PCI-related delay time and patient characteristics should be considered when selecting a reperfusion strategy. Thrombolytic therapy before and in conjunction with primary PCI was considered a potential solution to these concerns.

In addition, while the benefit of any reperfusion strategy depends on the time of presentation, the loss in benefit by later presentation is less pronounced with primary PCI than with thrombolysis, making thrombolysis less attractive in later presentations (> 3 hours).¹¹

Also, while thrombolytic therapy in patients older than 75 years was associated with a lower mortality rate compared with no therapy in a large Swedish registry,¹² this benefit was less striking than in younger patients. A meta-analysis of thrombolysis trials failed to show a similar benefit in patients over age 75 vs younger patients,¹³ whereas primary PCI remained effective and superior to thrombolysis in the elderly, with more absolute reduction in mortality rates in the elderly subgroup than with younger patients. ¹⁴ This makes thrombolysis less attractive in the elderly, either as a stand-alone therapy or in conjunction with PCI. Studies of combined thrombolysis and PCI included very few patients over age 75.^15–17

THREE COMBINATION REPERFUSION STRATEGIES

Facilitated PCI is a strategy of thrombolysis immediately followed by PCI, with a planned door-to-balloon time of 90 to 120 minutes.

Pharmacoinvasive therapy means giving thrombolysis at a non-PCI facility and then promptly and systematically transferring the patient to a PCI facility, where PCI is performed 2 to 24 hours after the start of thrombolytic therapy, regardless of whether thrombolysis results in successful reperfusion. ¹⁵ Thus, the time to PCI is longer than with facilitated PCI. Facilitated PCI addresses the value of pretreatment with thrombolytics or glycoprotein IIb/IIIa inhibitors in patients otherwise eligible for primary PCI, whereas pharmacoinvasive therapy addresses the value of routine early PCI after thrombolysis in patients who are not eligible for primary PCI.¹⁶

Rescue PCI refers to PCI that is performed urgently if thrombolysis fails, failure being defined as persistent hemodynamic or electrical instability, persistent ischemic symptoms, or failure to achieve at least a 50% to 70% resolution of the maximal ST-segment elevation 90 minutes after the infusion is started.

FACILITATED PCI: NEGATIVE RESULTS IN CLINICAL TRIALS

ASSENT-4 PCI trial

In the ASSENT-4 PCI trial,¹⁸ patients receiving full thrombolytic therapy before PCI had a higher rate of in-hospital death, bleeding, and cardiovascular events at 90 days than patients treated with primary PCI.

This trial recruited patients arriving at hospitals with or without PCI capability. The door-to-balloon time was about 110 minutes in both groups, which might not have been prolonged enough to show a benefit from a timely addition of thrombolysis. In addition, antiplatelet therapy was limited in these patients: glycoprotein IIb/IIIa inhibitors were not given, and clopidogrel (Plavix) was not appropriately preloaded, and this might have offset the potential benefit of early PCI. In fact, data suggest that platelet activation and aggregation are heightened after thrombolysis, ^21–23 and that glycoprotein IIb/IIIa antagonists can inhibit these effects.²³

The FINESSE trial

In the FINESSE trial,¹⁹ patients were randomized to undergo primary PCI, to undergo PCI facilitated (ie, preceded) by abciximab (Reo-Pro), or to undergo PCI facilitated by half-dose reteplase (Retavase) and full-dose abciximab. Despite a median door-to-balloon time of 132 minutes, the three strategies were associated with similar rates of death, heart failure, or ischemic outcome at 90 days. Even though the dosage of heparin was weight-adjusted, more major bleeding events occurred with the facilitated strategies.

Comments: Some subgroups may still benefit from facilitated PCI

The results of ASSENT-4 PCI and FINESSE led to the conclusion that PCI facilitated by full-dose thrombolysis should be avoided, and called into question the value of PCI facilitation using glycoprotein IIb/IIIa inhibitors with or without half-dose thrombolytic therapy.

However, subgroup analyses of these trials identified some subgroups that may benefit from a facilitated strategy. In ASSENT-4 PCI, 45% of patients were enrolled at PCI hospitals with a minimal PCI-related delay time. These patients had the worst outcome with the facilitated strategy. In contrast, patients who had a short time from pain onset to thrombolysis (2 to 3 hours) and who were given prehospital thrombolysis had a trend toward better outcomes with facilitated PCI.²⁴ And in FINESSE, 60% of patients were enrolled at centers with PCI capability. Analysis of a small subgroup of patients with a Thrombolysis in Myocardial Infarction study (TIMI) risk score of 3 or greater presenting to non-PCI hospitals within 4 hours of symptom onset suggested a potential reduction of ischemic events with the facilitated strategy in these patients.²⁵

Thus, for patients seen in the first 2 to 3 hours after symptom onset, immediate thrombolysis is recommended if PCI will likely be delayed, with or without plans for subsequent early PCI. “Time is muscle,” especially during the first 3 hours.

PHARMACOINVASIVE STRATEGY: GOOD RESULTS IN HIGH-RISK PATIENTS

A number of randomized studies during the last 10 years have examined the value of a pharmacoinvasive strategy.^{15,16,26–29}

The TRANSFER-AMI trial

The TRANSFER-AMI trial¹⁵ randomized 1,059 patients with high-risk ST-elevation MI (ie, anterior or high-risk inferior) at non-PCI centers to undergo either pharmacoinvasive care, ie, full-dose tenecteplase (TNKase) with immediate transfer for PCI or standard care, ie, tenecteplase with transfer for rescue PCI if the patient had persistent ST-segment elevation, chest pain, or hemodynamic instability.¹⁵ The goal was to perform PCI within 6 hours of thrombolysis, and the median time to PCI was 3.9 hours (range 2–6 hours). In the standard-care group, 35% of patients needed to be transferred for rescue PCI. Unlike in the ASSENT-4 trial, over 80% of patients received aggressive antiplatelet therapy with both 300 mg of clopidogrel and glycoprotein IIb/IIIa inhibitors.

The rate of cardiovascular events at 30 days was significantly lower with pharmacoinvasive therapy than with standard care and rescue PCI (11% vs 17%, P = .004). This difference was driven by lower rates of recurrent ischemia, reinfarction, and heart failure.

The CARESS-in-AMI study

The CARESS-in-AMI study¹⁶ found a similar improvement in ischemic outcomes in 600 patients with high-risk ST-elevation MI arriving at non-PCI centers if they had received pharmacoinvasive therapy. Patients received half-dose reteplase and abciximab and were randomized either to be immediately transferred for PCI (median time to PCI 2.25 hours) or to be transferred only if they had persistent ST-segment elevation or clinical deterioration.¹⁶ The event rate was low with pharmacoinvasive therapy, comparable to that achieved in primary PCI trials.

Interestingly, no significant increase was seen in the risk of major and minor bleeding in these two trials despite the use of a femoral approach for PCI in over 80% of the cases; this is probably due to the delays between thrombolytic administration and PCI and to the use of a highly fibrin-specific thrombolytic agent and adjusted-dose heparin.

Meta-analysis of pharmacoinvasive trials

A meta-analysis²⁹ of studies of systematic early PCI (mainly with stenting) within 24 hours of thrombolysis showed a reduction in the rates of mortality and reinfarction with this strategy, without an increase in the risk of major or intracranial bleeding.³⁰ In contrast to the results of the trials of facilitated PCI, a pharmacoinvasive strategy improved outcomes in these trials because the delay between thrombolysis and PCI was more than 2 hours, ie, long enough to prevent bleeding complications, and because most patients randomized in these trials presented within 2 to 3 hours of symptom onset, when the time to reperfusion is critical. After 3 hours, the PCI-mediated myocardial salvage is less time-dependent. Moreover, trials of pharmacoinvasive strategy used aggressive antiplatelet therapy with clopidogrel and glycoprotein IIb/IIIa inhibitors.

Comment: Pharmacoinvasive strategy in the guidelines

These results and those of the subgroup analysis from the FINESSE trial suggest that patients with high-risk ST-elevation MI treated at non-PCI hospitals have better outcomes without an increase in major bleeding events when given thrombolysis and then immediately transferred for routine PCI, rather than being transferred only if reperfusion fails.

Hence, the 2009 update of the ACC/AHA guidelines³¹ gives a class IIa recommendation for transferring patients with anterior ST-elevation MI or high-risk inferior ST-elevation MI treated with thrombolysis to a PCI-capable facility where PCI is performed as part of a pharmacoinvasive or rescue strategy soon after thrombolysis.

This strategy has been particularly studied in patients younger than 75 years presenting with high-risk types of ST-elevation MI early (< 3 hours) after symptom onset. If not at high risk, the patient may be transferred to a PCI facility after receiving thrombolysis or observed in the initial facility (class IIb recommendation). Consideration should be given to starting anticoagulant and antiplatelet therapy before and during transfer—ie, 300 mg of clopidogrel before transfer for PCI and glycoprotein IIb/IIIa inhibitor therapy during PCI.

The European Society of Cardiology (ESC) guidelines³² recommend early routine angiography 3 to 24 hours after successful thrombolysis. This time window was selected to avoid PCI during the prothrombotic period in the first few hours after thrombolysis and to minimize the risk of reocclusion with PCI delays of more than 24 hours (class IIa recommendation).

Larger randomized trials are still needed to establish whether the pharmacoinvasive strategy confers a survival benefit, to determine its usefulness in low-risk inferior or lateral ST-elevation MI, and to further refine the time window when PCI is both safe and beneficial after thrombolysis.³³

RESCUE PCI REDUCES MORTALITY RATES

Rescue PCI is the most accepted form of thrombolysis-PCI combination.

The REACT trial

The REACT trial²⁰ showed that rescue PCI performed at a mean of 4.5 hours after failed thrombolysis reduces the rate of adverse cardiovascular events by more than 50% at 6 to 12 months and reduces the 5-year mortality rate by more than 50% compared with conservative management.²⁰ As in the pharmacoinvasive strategy, aggressive antiplatelet regimens were used in the REACT trial.

A meta-analysis of rescue PCI trials

A meta-analysis of rescue PCI trials³⁴ confirmed these results, showing a reduction in heart failure and reinfarction and a trend toward a lower mortality rate with rescue PCI.³⁴ After thrombolysis, 40% of patients do not achieve grade 3 TIMI flow, which explains why in modern clinical trials 30% of patients treated with thrombolysis require rescue PCI.^5,15,16,35

For patients with high-risk ST-elevation MI, current ACC/AHA guidelines assign a class IIa recommendation to rescue PCI.³¹

WHEN PATIENTS WITH ST-ELEVATION MI PRESENT TO A NON-PCI HOSPITAL

Transfer for primary PCI vs thrombolysis at the non-PCI hospital

The DANAMI-2 trial³⁶ found that immediate transfer for PCI was superior to onsite thrombolytic therapy, as measured by a reduction in the rate of ischemic events (composite of death, myocardial infarction, or stroke at 30 days): 8.5% vs 14.2% (P < .001). There were no deaths during transfer.³

The PRAGUE-2 trial⁴ showed similar results for patients presenting 3 to 12 hours after symptom onset (30-day mortality rate 6% with immediate transfer vs 15.3% with on-site thrombolysis, P < .002), whereas patients presenting within 3 hours of symptom onset had a similar mortality rate with either therapy.⁴

Comment. These trials showed that transfer for primary PCI is superior to thrombolytic therapy when performed in a timely fashion. However, they were done in countries with established transfer networks and short distances between community hospitals and PCI centers, with a PCI-related delay of only 44 minutes and a door-to-balloon time of 90 minutes despite transfer. The large-scale application of this prompt transfer policy is not practical in most regions in the United States. Thus, a strategy of local thrombolysis followed by routine early transfer for routine or rescue PCI seems warranted when the door-to-balloon time or the PCI-related delay time is expected to be too long.

Experiences with community-based systems of care and prehospital thrombolysis

In Minnesota, Henry et al³⁷ developed a PCI-based treatment system and an integrated transfer program for ST-elevation MI involving 30 hospitals within 210 miles of the Minneapolis Heart Institute. Participating hospitals were divided into two zones: zone 1 hospitals were within 60 miles, and zone 2 facilities were between 60 and 210 miles from the Heart Institute. Zone 2 patients received half-dose tenecteplase (if thrombolytic therapy was not contraindicated) in anticipation of a lengthy transfer time.

The median door-to-balloon time for zone 1 patients was 95 minutes (interquartile range 82 and 116 minutes) and for zone 2 patients 120 minutes (interquartile range 100 and 145 minutes). The diagnosis of ST-elevation MI was made by the emergency department physician, who activated the system with a phone call. The patient was then directly transferred to the catheterization laboratory, most often by helicopter.

The in-hospital death rate for patients who presented to the PCI center and for patients in zones 1 and 2 was similarly low (about 5%).³⁷

In France, the FAST-MI registry,¹⁷ which collected outcome data for different reperfusion strategies, found that thrombolysis yielded in-hospital and midterm results that were comparable to those of primary PCI. Of note, thrombolysis was started early after symptom onset (about 2 hours), and was started in the ambulance in two-thirds of cases. Nearly all patients underwent a pharmacoinvasive strategy that combined thrombolysis with coronary angiography and PCI within 24 hours of symptom onset. These findings suggest that timely thrombolysis followed by semiurgent transfer for PCI is an alternative to primary PCI for patients presenting to hospitals with no PCI capability, and that this alternative offers similar benefit to that of primary PCI.

Five centers in the United States have reported their experience with half-dose thrombolysis in the prehospital setting (in the field or during transfer) or at a non-PCI hospital, followed by prompt transfer to a PCI facility. In this registry of almost 3,000 patients,³⁸ patients treated with thrombolysis had better outcomes than patients directly transferred for primary PCI, with a significantly lower 30-day mortality rate (3.8% vs from 6.4%), and no increase in bleeding.^38,39 The mean door-to-balloon time was long (168 minutes in the primary PCI group and 196 minutes in the thrombolysis-PCI group), which might explain the benefit achieved with prompt thrombolysis.

CARDIOGENIC SHOCK

Patients presenting with left ventricular cardiogenic shock derive a large mortality benefit from revascularization, whether they are transferred or directly admitted to a PCI center. ⁴⁰ Moreover, in the SHOCK registry, patients with predominant right ventricular cardiogenic shock had an in-hospital mortality rate similar to that of patients with predominant left ventricular cardiogenic shock, and revascularization (PCI or surgical revascularization) was associated with a strikingly lower mortality rate in both groups.⁴¹

Thus, all patients with left or right cardiogenic shock should be revascularized on an emergency basis, either surgically or percutaneously.

While trials of pharmacoinvasive therapy excluded patients with cardiogenic shock,^15,16 thrombolytic therapy was associated with improved outcomes in the drug-therapy group of the SHOCK trial and in hypotensive patients randomized in the early thrombolysis trials.¹³ Thus, the ACC/AHA guidelines recommend thrombolytic therapy before transfer if a patient presents in shock within 3 to 6 hours of onset of the MI and delays in transport and intervention are anticipated.⁸

PUTTING IT ALL TOGETHER: MANAGEMENT STRATEGIES

If an effective transfer system is in place, primary PCI not preceded by thrombolytic therapy or glycoprotein IIb/IIIa inhibitor therapy is the preferred approach, according to ACC/AHA and ESC guidelines.^31,32 Giving thrombolytics immediately before PCI is harmful and thus should be avoided when the expected door-to-balloon time is 90 minutes or less.

All hospitals (whether or not they offer PCI) and regional emergency medical services should participate in a community-based system of care for ST-elevation MI, with protocols for expeditious transfer as defined and coordinated by the American Heart Association initiative “Mission: Lifeline.” In addition, a system of field triage and direct transport to the catheterization laboratory of a PCI facility after field activation significantly reduces door-to-balloon times and improves outcomes.⁴²

If such a system is not in place, then a pharmacoinvasive strategy seems best: ie, local full-dose thrombolysis (if not contraindicated) followed by transfer to a PCI facility and routine performance of PCI 2 to 6 hours after thrombolysis—in conjunction with aggressive early dual oral antiplatelet therapy and “downstream” glycoprotein IIb/IIIa inhibition. This approach is associated with outcomes similar to those of primary PCI.^15–17,37

Prehospital thrombolysis delivered by paramedics and followed by early transfer to a PCI facility has been associated with further reduction in mortality rates compared with in-hospital thrombolysis (as in the Swedish registry⁴³), and a reduction in death rate comparable to that of primary PCI in patients presenting early. This is an adequate strategy in regions where such a system can be established.^{5,17,38,43,44}

Patients presenting more than 3 to 4 hours after symptom onset, older patients, and patients with lower-risk MI or a higher risk of bleeding may still be suited for primary PCI even when the door-to-balloon time is 90 to 120 minutes, as stated by the European guidelines,³² or when the PCI-related delay time is as long as 100 minutes. ¹⁰ On the other hand, while the ACC/AHA guidelines recognize that in these patients the mortality advantage of primary PCI vs thrombolytic therapy is maintained with more prolonged door-to-balloon times, they nevertheless state that the focus should be on developing systems of care to increase the number of patients with access to primary PCI in less than 90 minutes rather than extending the acceptable window for door-to-balloon time.

In conclusion, for patients presenting with ST-elevation MI who cannot undergo timely primary PCI, the best approach seems to be prehospital thrombolysis delivered by paramedics or local thrombolysis at the non-PCI hospital followed by transferring the patient and performing PCI within a few hours. This is especially important in patients with high-risk ST-elevation MI who present early after symptom onset, when the extent of myocardial necrosis associated with delayed primary PCI is largest.

In addition, every community should develop a coordinated transfer strategy between non-PCI and PCI hospitals.

Effective and rapid reperfusion is crucial in patients with acute ST-segment elevation myocardial infarction (MI). The preferred strategy for reperfusion—when it can be performed in a timely fashion at an experienced facility—is primary percutaneous coronary intervention (PCI), which produces outcomes superior to those of pharmacologic thrombolysis.¹

See related editorial

Unfortunately, in the United States about half of patients present to hospitals that do not have PCI capability,² and in one analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes, with a mean of 152 minutes.³ (In this case, the door-to-balloon time was the time that elapsed between entry into the first hospital and inflation of the PCI balloon at the second hospital.)

In situations such as these, a combined approach may be appropriate, with thrombolysis delivered by paramedics or at a local facility, followed by transfer to a PCI facility and performance of PCI within a few hours. However, this is feasible only if standardized community-based or regional protocols for prompt transfer and reperfusion are in place.

In this paper we discuss the rationale and the clinical data behind several approaches to combined reperfusion, as well as experiences with community-based care protocols.

WITHIN 3 HOURS OF SYMPTOM ONSET, THROMBOLYSIS IS AS GOOD AS PCI

The PRAGUE-2 Trial

In the randomized PRAGUE-2 trial,⁴ patients with ST-elevation MI who presented to a non-PCI facility had better outcomes if they were transferred promptly for PCI (median door-to-balloon time 97 minutes), as opposed to receiving local therapy with streptokinase. However, for patients presenting within 3 hours of symptom onset, the mortality rates were comparable with either strategy.⁴

See the glossary of clinical trial names below

The CAPTIM trial

In the CAPTIM trial,⁵ patients who presented within 2 hours of symptom onset and who were randomized to receive prehospital thrombolysis had outcomes similar to those of patients treated with primary PCI, despite a short door-to-balloon time (82 minutes).

The Vienna STEMI Registry

In the Vienna STEMI Registry,⁶ the mortality rates with primary PCI and with thrombolysis were similar when patients presented within 2 hours of symptom onset. However, as the time from symptom onset increased, primary PCI appeared to offer an increasing survival benefit compared with thrombolysis.

Comments: Thrombolysis is effective mostly in the first 2 to 3 hours, with some benefit up to 12 hours

Previous studies have shown that the sooner thrombolysis is given after symptom onset, the more effective it is. If it is given within an hour of symptom onset, the relative reduction in the mortality rate is 50% and the absolute reduction is 6.5% compared with no reperfusion therapy. If it is started in the second hour, the absolute reduction in the mortality rate drops to 4%, and a lesser benefit extends to patients presenting up to 12 hours after symptom onset.⁷ This time-dependent benefit is due to the fact that very early reperfusion of the occluded coronary artery may lead to full recovery of ischemic tissue and thus prevent necrosis. In addition, thrombolysis in the first 2 hours is highly efficacious in lysing a fresh thrombus.

These data support the current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA), which state no preference for either thrombolytic therapy or PCI in ST-elevation MI if the presentation is less than 3 hours after symptom onset.⁸

Of note, in the CAPTIM trial and in the Vienna STEMI Registry, rescue PCI was available and was in fact used after thrombolysis in about 25% of patients, which might have contributed to the benefit of early thrombolysis.

PRIMARY PCI MAY NOT BE SUPERIOR IF TRANSFER TIME IS LONG

Another time-related factor to consider is the PCI-related delay, ie, the theoretical difference between the expected time from first medical contact to balloon inflation (if the patient undergoes primary PCI) and the time from first medical contact to the start of thrombolytic therapy (if the patient undergoes primary thrombolysis).

A meta-analysis of 13 trials comparing PCI and thrombolysis showed that a PCI-related delay of more than 60 minutes might negate the potential advantage of primary PCI over immediate thrombolysis in terms of deaths.⁹

This observation has been further refined by data from the National Registry of Myocardial Infarction.¹⁰ In this analysis, patient factors, including age, duration of symptoms, and infarct location, significantly affected the point at which the PCI-related delay negated the survival advantage of primary PCI. The survival advantage of primary PCI was lost more rapidly—with a PCI-related delay as short as 40 minutes—in patients who presented sooner, were younger, or had anterior MI. Primary PCI maintained its survival advantage even with a PCI-related delay longer than 100 minutes in older patients or patients with nonanterior MI presenting more than 3 hours after symptom onset. Given that median door-to-balloon times in the United States may exceed 150 minutes when transfer is involved, ³ primary PCI may be no better than primary thrombolysis in transferred patients who present early or who have large infarcts.

Although these results were derived from a post hoc analysis of a registry and the delay times reported were sometimes inaccurate, they suggest that both the PCI-related delay time and patient characteristics should be considered when selecting a reperfusion strategy. Thrombolytic therapy before and in conjunction with primary PCI was considered a potential solution to these concerns.

In addition, while the benefit of any reperfusion strategy depends on the time of presentation, the loss in benefit by later presentation is less pronounced with primary PCI than with thrombolysis, making thrombolysis less attractive in later presentations (> 3 hours).¹¹

Also, while thrombolytic therapy in patients older than 75 years was associated with a lower mortality rate compared with no therapy in a large Swedish registry,¹² this benefit was less striking than in younger patients. A meta-analysis of thrombolysis trials failed to show a similar benefit in patients over age 75 vs younger patients,¹³ whereas primary PCI remained effective and superior to thrombolysis in the elderly, with more absolute reduction in mortality rates in the elderly subgroup than with younger patients. ¹⁴ This makes thrombolysis less attractive in the elderly, either as a stand-alone therapy or in conjunction with PCI. Studies of combined thrombolysis and PCI included very few patients over age 75.^15–17

THREE COMBINATION REPERFUSION STRATEGIES

Facilitated PCI is a strategy of thrombolysis immediately followed by PCI, with a planned door-to-balloon time of 90 to 120 minutes.

Pharmacoinvasive therapy means giving thrombolysis at a non-PCI facility and then promptly and systematically transferring the patient to a PCI facility, where PCI is performed 2 to 24 hours after the start of thrombolytic therapy, regardless of whether thrombolysis results in successful reperfusion. ¹⁵ Thus, the time to PCI is longer than with facilitated PCI. Facilitated PCI addresses the value of pretreatment with thrombolytics or glycoprotein IIb/IIIa inhibitors in patients otherwise eligible for primary PCI, whereas pharmacoinvasive therapy addresses the value of routine early PCI after thrombolysis in patients who are not eligible for primary PCI.¹⁶

Rescue PCI refers to PCI that is performed urgently if thrombolysis fails, failure being defined as persistent hemodynamic or electrical instability, persistent ischemic symptoms, or failure to achieve at least a 50% to 70% resolution of the maximal ST-segment elevation 90 minutes after the infusion is started.

FACILITATED PCI: NEGATIVE RESULTS IN CLINICAL TRIALS

ASSENT-4 PCI trial

In the ASSENT-4 PCI trial,¹⁸ patients receiving full thrombolytic therapy before PCI had a higher rate of in-hospital death, bleeding, and cardiovascular events at 90 days than patients treated with primary PCI.

This trial recruited patients arriving at hospitals with or without PCI capability. The door-to-balloon time was about 110 minutes in both groups, which might not have been prolonged enough to show a benefit from a timely addition of thrombolysis. In addition, antiplatelet therapy was limited in these patients: glycoprotein IIb/IIIa inhibitors were not given, and clopidogrel (Plavix) was not appropriately preloaded, and this might have offset the potential benefit of early PCI. In fact, data suggest that platelet activation and aggregation are heightened after thrombolysis, ^21–23 and that glycoprotein IIb/IIIa antagonists can inhibit these effects.²³

The FINESSE trial

In the FINESSE trial,¹⁹ patients were randomized to undergo primary PCI, to undergo PCI facilitated (ie, preceded) by abciximab (Reo-Pro), or to undergo PCI facilitated by half-dose reteplase (Retavase) and full-dose abciximab. Despite a median door-to-balloon time of 132 minutes, the three strategies were associated with similar rates of death, heart failure, or ischemic outcome at 90 days. Even though the dosage of heparin was weight-adjusted, more major bleeding events occurred with the facilitated strategies.

Comments: Some subgroups may still benefit from facilitated PCI

The results of ASSENT-4 PCI and FINESSE led to the conclusion that PCI facilitated by full-dose thrombolysis should be avoided, and called into question the value of PCI facilitation using glycoprotein IIb/IIIa inhibitors with or without half-dose thrombolytic therapy.

However, subgroup analyses of these trials identified some subgroups that may benefit from a facilitated strategy. In ASSENT-4 PCI, 45% of patients were enrolled at PCI hospitals with a minimal PCI-related delay time. These patients had the worst outcome with the facilitated strategy. In contrast, patients who had a short time from pain onset to thrombolysis (2 to 3 hours) and who were given prehospital thrombolysis had a trend toward better outcomes with facilitated PCI.²⁴ And in FINESSE, 60% of patients were enrolled at centers with PCI capability. Analysis of a small subgroup of patients with a Thrombolysis in Myocardial Infarction study (TIMI) risk score of 3 or greater presenting to non-PCI hospitals within 4 hours of symptom onset suggested a potential reduction of ischemic events with the facilitated strategy in these patients.²⁵

Thus, for patients seen in the first 2 to 3 hours after symptom onset, immediate thrombolysis is recommended if PCI will likely be delayed, with or without plans for subsequent early PCI. “Time is muscle,” especially during the first 3 hours.

PHARMACOINVASIVE STRATEGY: GOOD RESULTS IN HIGH-RISK PATIENTS

A number of randomized studies during the last 10 years have examined the value of a pharmacoinvasive strategy.^{15,16,26–29}

The TRANSFER-AMI trial

The TRANSFER-AMI trial¹⁵ randomized 1,059 patients with high-risk ST-elevation MI (ie, anterior or high-risk inferior) at non-PCI centers to undergo either pharmacoinvasive care, ie, full-dose tenecteplase (TNKase) with immediate transfer for PCI or standard care, ie, tenecteplase with transfer for rescue PCI if the patient had persistent ST-segment elevation, chest pain, or hemodynamic instability.¹⁵ The goal was to perform PCI within 6 hours of thrombolysis, and the median time to PCI was 3.9 hours (range 2–6 hours). In the standard-care group, 35% of patients needed to be transferred for rescue PCI. Unlike in the ASSENT-4 trial, over 80% of patients received aggressive antiplatelet therapy with both 300 mg of clopidogrel and glycoprotein IIb/IIIa inhibitors.

The rate of cardiovascular events at 30 days was significantly lower with pharmacoinvasive therapy than with standard care and rescue PCI (11% vs 17%, P = .004). This difference was driven by lower rates of recurrent ischemia, reinfarction, and heart failure.

The CARESS-in-AMI study

The CARESS-in-AMI study¹⁶ found a similar improvement in ischemic outcomes in 600 patients with high-risk ST-elevation MI arriving at non-PCI centers if they had received pharmacoinvasive therapy. Patients received half-dose reteplase and abciximab and were randomized either to be immediately transferred for PCI (median time to PCI 2.25 hours) or to be transferred only if they had persistent ST-segment elevation or clinical deterioration.¹⁶ The event rate was low with pharmacoinvasive therapy, comparable to that achieved in primary PCI trials.

Interestingly, no significant increase was seen in the risk of major and minor bleeding in these two trials despite the use of a femoral approach for PCI in over 80% of the cases; this is probably due to the delays between thrombolytic administration and PCI and to the use of a highly fibrin-specific thrombolytic agent and adjusted-dose heparin.

Meta-analysis of pharmacoinvasive trials

A meta-analysis²⁹ of studies of systematic early PCI (mainly with stenting) within 24 hours of thrombolysis showed a reduction in the rates of mortality and reinfarction with this strategy, without an increase in the risk of major or intracranial bleeding.³⁰ In contrast to the results of the trials of facilitated PCI, a pharmacoinvasive strategy improved outcomes in these trials because the delay between thrombolysis and PCI was more than 2 hours, ie, long enough to prevent bleeding complications, and because most patients randomized in these trials presented within 2 to 3 hours of symptom onset, when the time to reperfusion is critical. After 3 hours, the PCI-mediated myocardial salvage is less time-dependent. Moreover, trials of pharmacoinvasive strategy used aggressive antiplatelet therapy with clopidogrel and glycoprotein IIb/IIIa inhibitors.

Comment: Pharmacoinvasive strategy in the guidelines

These results and those of the subgroup analysis from the FINESSE trial suggest that patients with high-risk ST-elevation MI treated at non-PCI hospitals have better outcomes without an increase in major bleeding events when given thrombolysis and then immediately transferred for routine PCI, rather than being transferred only if reperfusion fails.

Hence, the 2009 update of the ACC/AHA guidelines³¹ gives a class IIa recommendation for transferring patients with anterior ST-elevation MI or high-risk inferior ST-elevation MI treated with thrombolysis to a PCI-capable facility where PCI is performed as part of a pharmacoinvasive or rescue strategy soon after thrombolysis.

This strategy has been particularly studied in patients younger than 75 years presenting with high-risk types of ST-elevation MI early (< 3 hours) after symptom onset. If not at high risk, the patient may be transferred to a PCI facility after receiving thrombolysis or observed in the initial facility (class IIb recommendation). Consideration should be given to starting anticoagulant and antiplatelet therapy before and during transfer—ie, 300 mg of clopidogrel before transfer for PCI and glycoprotein IIb/IIIa inhibitor therapy during PCI.

The European Society of Cardiology (ESC) guidelines³² recommend early routine angiography 3 to 24 hours after successful thrombolysis. This time window was selected to avoid PCI during the prothrombotic period in the first few hours after thrombolysis and to minimize the risk of reocclusion with PCI delays of more than 24 hours (class IIa recommendation).

Larger randomized trials are still needed to establish whether the pharmacoinvasive strategy confers a survival benefit, to determine its usefulness in low-risk inferior or lateral ST-elevation MI, and to further refine the time window when PCI is both safe and beneficial after thrombolysis.³³

RESCUE PCI REDUCES MORTALITY RATES

Rescue PCI is the most accepted form of thrombolysis-PCI combination.

The REACT trial

The REACT trial²⁰ showed that rescue PCI performed at a mean of 4.5 hours after failed thrombolysis reduces the rate of adverse cardiovascular events by more than 50% at 6 to 12 months and reduces the 5-year mortality rate by more than 50% compared with conservative management.²⁰ As in the pharmacoinvasive strategy, aggressive antiplatelet regimens were used in the REACT trial.

A meta-analysis of rescue PCI trials

A meta-analysis of rescue PCI trials³⁴ confirmed these results, showing a reduction in heart failure and reinfarction and a trend toward a lower mortality rate with rescue PCI.³⁴ After thrombolysis, 40% of patients do not achieve grade 3 TIMI flow, which explains why in modern clinical trials 30% of patients treated with thrombolysis require rescue PCI.^5,15,16,35

For patients with high-risk ST-elevation MI, current ACC/AHA guidelines assign a class IIa recommendation to rescue PCI.³¹

WHEN PATIENTS WITH ST-ELEVATION MI PRESENT TO A NON-PCI HOSPITAL

Transfer for primary PCI vs thrombolysis at the non-PCI hospital

The DANAMI-2 trial³⁶ found that immediate transfer for PCI was superior to onsite thrombolytic therapy, as measured by a reduction in the rate of ischemic events (composite of death, myocardial infarction, or stroke at 30 days): 8.5% vs 14.2% (P < .001). There were no deaths during transfer.³

The PRAGUE-2 trial⁴ showed similar results for patients presenting 3 to 12 hours after symptom onset (30-day mortality rate 6% with immediate transfer vs 15.3% with on-site thrombolysis, P < .002), whereas patients presenting within 3 hours of symptom onset had a similar mortality rate with either therapy.⁴

Comment. These trials showed that transfer for primary PCI is superior to thrombolytic therapy when performed in a timely fashion. However, they were done in countries with established transfer networks and short distances between community hospitals and PCI centers, with a PCI-related delay of only 44 minutes and a door-to-balloon time of 90 minutes despite transfer. The large-scale application of this prompt transfer policy is not practical in most regions in the United States. Thus, a strategy of local thrombolysis followed by routine early transfer for routine or rescue PCI seems warranted when the door-to-balloon time or the PCI-related delay time is expected to be too long.

Experiences with community-based systems of care and prehospital thrombolysis

In Minnesota, Henry et al³⁷ developed a PCI-based treatment system and an integrated transfer program for ST-elevation MI involving 30 hospitals within 210 miles of the Minneapolis Heart Institute. Participating hospitals were divided into two zones: zone 1 hospitals were within 60 miles, and zone 2 facilities were between 60 and 210 miles from the Heart Institute. Zone 2 patients received half-dose tenecteplase (if thrombolytic therapy was not contraindicated) in anticipation of a lengthy transfer time.

The median door-to-balloon time for zone 1 patients was 95 minutes (interquartile range 82 and 116 minutes) and for zone 2 patients 120 minutes (interquartile range 100 and 145 minutes). The diagnosis of ST-elevation MI was made by the emergency department physician, who activated the system with a phone call. The patient was then directly transferred to the catheterization laboratory, most often by helicopter.

The in-hospital death rate for patients who presented to the PCI center and for patients in zones 1 and 2 was similarly low (about 5%).³⁷

In France, the FAST-MI registry,¹⁷ which collected outcome data for different reperfusion strategies, found that thrombolysis yielded in-hospital and midterm results that were comparable to those of primary PCI. Of note, thrombolysis was started early after symptom onset (about 2 hours), and was started in the ambulance in two-thirds of cases. Nearly all patients underwent a pharmacoinvasive strategy that combined thrombolysis with coronary angiography and PCI within 24 hours of symptom onset. These findings suggest that timely thrombolysis followed by semiurgent transfer for PCI is an alternative to primary PCI for patients presenting to hospitals with no PCI capability, and that this alternative offers similar benefit to that of primary PCI.

Five centers in the United States have reported their experience with half-dose thrombolysis in the prehospital setting (in the field or during transfer) or at a non-PCI hospital, followed by prompt transfer to a PCI facility. In this registry of almost 3,000 patients,³⁸ patients treated with thrombolysis had better outcomes than patients directly transferred for primary PCI, with a significantly lower 30-day mortality rate (3.8% vs from 6.4%), and no increase in bleeding.^38,39 The mean door-to-balloon time was long (168 minutes in the primary PCI group and 196 minutes in the thrombolysis-PCI group), which might explain the benefit achieved with prompt thrombolysis.

CARDIOGENIC SHOCK

Patients presenting with left ventricular cardiogenic shock derive a large mortality benefit from revascularization, whether they are transferred or directly admitted to a PCI center. ⁴⁰ Moreover, in the SHOCK registry, patients with predominant right ventricular cardiogenic shock had an in-hospital mortality rate similar to that of patients with predominant left ventricular cardiogenic shock, and revascularization (PCI or surgical revascularization) was associated with a strikingly lower mortality rate in both groups.⁴¹

Thus, all patients with left or right cardiogenic shock should be revascularized on an emergency basis, either surgically or percutaneously.

While trials of pharmacoinvasive therapy excluded patients with cardiogenic shock,^15,16 thrombolytic therapy was associated with improved outcomes in the drug-therapy group of the SHOCK trial and in hypotensive patients randomized in the early thrombolysis trials.¹³ Thus, the ACC/AHA guidelines recommend thrombolytic therapy before transfer if a patient presents in shock within 3 to 6 hours of onset of the MI and delays in transport and intervention are anticipated.⁸

PUTTING IT ALL TOGETHER: MANAGEMENT STRATEGIES

If an effective transfer system is in place, primary PCI not preceded by thrombolytic therapy or glycoprotein IIb/IIIa inhibitor therapy is the preferred approach, according to ACC/AHA and ESC guidelines.^31,32 Giving thrombolytics immediately before PCI is harmful and thus should be avoided when the expected door-to-balloon time is 90 minutes or less.

All hospitals (whether or not they offer PCI) and regional emergency medical services should participate in a community-based system of care for ST-elevation MI, with protocols for expeditious transfer as defined and coordinated by the American Heart Association initiative “Mission: Lifeline.” In addition, a system of field triage and direct transport to the catheterization laboratory of a PCI facility after field activation significantly reduces door-to-balloon times and improves outcomes.⁴²

If such a system is not in place, then a pharmacoinvasive strategy seems best: ie, local full-dose thrombolysis (if not contraindicated) followed by transfer to a PCI facility and routine performance of PCI 2 to 6 hours after thrombolysis—in conjunction with aggressive early dual oral antiplatelet therapy and “downstream” glycoprotein IIb/IIIa inhibition. This approach is associated with outcomes similar to those of primary PCI.^15–17,37

Prehospital thrombolysis delivered by paramedics and followed by early transfer to a PCI facility has been associated with further reduction in mortality rates compared with in-hospital thrombolysis (as in the Swedish registry⁴³), and a reduction in death rate comparable to that of primary PCI in patients presenting early. This is an adequate strategy in regions where such a system can be established.^{5,17,38,43,44}

Patients presenting more than 3 to 4 hours after symptom onset, older patients, and patients with lower-risk MI or a higher risk of bleeding may still be suited for primary PCI even when the door-to-balloon time is 90 to 120 minutes, as stated by the European guidelines,³² or when the PCI-related delay time is as long as 100 minutes. ¹⁰ On the other hand, while the ACC/AHA guidelines recognize that in these patients the mortality advantage of primary PCI vs thrombolytic therapy is maintained with more prolonged door-to-balloon times, they nevertheless state that the focus should be on developing systems of care to increase the number of patients with access to primary PCI in less than 90 minutes rather than extending the acceptable window for door-to-balloon time.

In conclusion, for patients presenting with ST-elevation MI who cannot undergo timely primary PCI, the best approach seems to be prehospital thrombolysis delivered by paramedics or local thrombolysis at the non-PCI hospital followed by transferring the patient and performing PCI within a few hours. This is especially important in patients with high-risk ST-elevation MI who present early after symptom onset, when the extent of myocardial necrosis associated with delayed primary PCI is largest.

In addition, every community should develop a coordinated transfer strategy between non-PCI and PCI hospitals.

Effective and rapid reperfusion is crucial in patients with acute ST-segment elevation myocardial infarction (MI). The preferred strategy for reperfusion—when it can be performed in a timely fashion at an experienced facility—is primary percutaneous coronary intervention (PCI), which produces outcomes superior to those of pharmacologic thrombolysis.¹

See related editorial

Unfortunately, in the United States about half of patients present to hospitals that do not have PCI capability,² and in one analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes, with a mean of 152 minutes.³ (In this case, the door-to-balloon time was the time that elapsed between entry into the first hospital and inflation of the PCI balloon at the second hospital.)

In situations such as these, a combined approach may be appropriate, with thrombolysis delivered by paramedics or at a local facility, followed by transfer to a PCI facility and performance of PCI within a few hours. However, this is feasible only if standardized community-based or regional protocols for prompt transfer and reperfusion are in place.

In this paper we discuss the rationale and the clinical data behind several approaches to combined reperfusion, as well as experiences with community-based care protocols.

WITHIN 3 HOURS OF SYMPTOM ONSET, THROMBOLYSIS IS AS GOOD AS PCI

The PRAGUE-2 Trial

In the randomized PRAGUE-2 trial,⁴ patients with ST-elevation MI who presented to a non-PCI facility had better outcomes if they were transferred promptly for PCI (median door-to-balloon time 97 minutes), as opposed to receiving local therapy with streptokinase. However, for patients presenting within 3 hours of symptom onset, the mortality rates were comparable with either strategy.⁴

See the glossary of clinical trial names below

The CAPTIM trial

In the CAPTIM trial,⁵ patients who presented within 2 hours of symptom onset and who were randomized to receive prehospital thrombolysis had outcomes similar to those of patients treated with primary PCI, despite a short door-to-balloon time (82 minutes).

The Vienna STEMI Registry

In the Vienna STEMI Registry,⁶ the mortality rates with primary PCI and with thrombolysis were similar when patients presented within 2 hours of symptom onset. However, as the time from symptom onset increased, primary PCI appeared to offer an increasing survival benefit compared with thrombolysis.

Comments: Thrombolysis is effective mostly in the first 2 to 3 hours, with some benefit up to 12 hours

Previous studies have shown that the sooner thrombolysis is given after symptom onset, the more effective it is. If it is given within an hour of symptom onset, the relative reduction in the mortality rate is 50% and the absolute reduction is 6.5% compared with no reperfusion therapy. If it is started in the second hour, the absolute reduction in the mortality rate drops to 4%, and a lesser benefit extends to patients presenting up to 12 hours after symptom onset.⁷ This time-dependent benefit is due to the fact that very early reperfusion of the occluded coronary artery may lead to full recovery of ischemic tissue and thus prevent necrosis. In addition, thrombolysis in the first 2 hours is highly efficacious in lysing a fresh thrombus.

These data support the current guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA), which state no preference for either thrombolytic therapy or PCI in ST-elevation MI if the presentation is less than 3 hours after symptom onset.⁸

Of note, in the CAPTIM trial and in the Vienna STEMI Registry, rescue PCI was available and was in fact used after thrombolysis in about 25% of patients, which might have contributed to the benefit of early thrombolysis.

PRIMARY PCI MAY NOT BE SUPERIOR IF TRANSFER TIME IS LONG

Another time-related factor to consider is the PCI-related delay, ie, the theoretical difference between the expected time from first medical contact to balloon inflation (if the patient undergoes primary PCI) and the time from first medical contact to the start of thrombolytic therapy (if the patient undergoes primary thrombolysis).

A meta-analysis of 13 trials comparing PCI and thrombolysis showed that a PCI-related delay of more than 60 minutes might negate the potential advantage of primary PCI over immediate thrombolysis in terms of deaths.⁹

This observation has been further refined by data from the National Registry of Myocardial Infarction.¹⁰ In this analysis, patient factors, including age, duration of symptoms, and infarct location, significantly affected the point at which the PCI-related delay negated the survival advantage of primary PCI. The survival advantage of primary PCI was lost more rapidly—with a PCI-related delay as short as 40 minutes—in patients who presented sooner, were younger, or had anterior MI. Primary PCI maintained its survival advantage even with a PCI-related delay longer than 100 minutes in older patients or patients with nonanterior MI presenting more than 3 hours after symptom onset. Given that median door-to-balloon times in the United States may exceed 150 minutes when transfer is involved, ³ primary PCI may be no better than primary thrombolysis in transferred patients who present early or who have large infarcts.

Although these results were derived from a post hoc analysis of a registry and the delay times reported were sometimes inaccurate, they suggest that both the PCI-related delay time and patient characteristics should be considered when selecting a reperfusion strategy. Thrombolytic therapy before and in conjunction with primary PCI was considered a potential solution to these concerns.

In addition, while the benefit of any reperfusion strategy depends on the time of presentation, the loss in benefit by later presentation is less pronounced with primary PCI than with thrombolysis, making thrombolysis less attractive in later presentations (> 3 hours).¹¹

Also, while thrombolytic therapy in patients older than 75 years was associated with a lower mortality rate compared with no therapy in a large Swedish registry,¹² this benefit was less striking than in younger patients. A meta-analysis of thrombolysis trials failed to show a similar benefit in patients over age 75 vs younger patients,¹³ whereas primary PCI remained effective and superior to thrombolysis in the elderly, with more absolute reduction in mortality rates in the elderly subgroup than with younger patients. ¹⁴ This makes thrombolysis less attractive in the elderly, either as a stand-alone therapy or in conjunction with PCI. Studies of combined thrombolysis and PCI included very few patients over age 75.^15–17

THREE COMBINATION REPERFUSION STRATEGIES

Facilitated PCI is a strategy of thrombolysis immediately followed by PCI, with a planned door-to-balloon time of 90 to 120 minutes.

Pharmacoinvasive therapy means giving thrombolysis at a non-PCI facility and then promptly and systematically transferring the patient to a PCI facility, where PCI is performed 2 to 24 hours after the start of thrombolytic therapy, regardless of whether thrombolysis results in successful reperfusion. ¹⁵ Thus, the time to PCI is longer than with facilitated PCI. Facilitated PCI addresses the value of pretreatment with thrombolytics or glycoprotein IIb/IIIa inhibitors in patients otherwise eligible for primary PCI, whereas pharmacoinvasive therapy addresses the value of routine early PCI after thrombolysis in patients who are not eligible for primary PCI.¹⁶

Rescue PCI refers to PCI that is performed urgently if thrombolysis fails, failure being defined as persistent hemodynamic or electrical instability, persistent ischemic symptoms, or failure to achieve at least a 50% to 70% resolution of the maximal ST-segment elevation 90 minutes after the infusion is started.

FACILITATED PCI: NEGATIVE RESULTS IN CLINICAL TRIALS

ASSENT-4 PCI trial

In the ASSENT-4 PCI trial,¹⁸ patients receiving full thrombolytic therapy before PCI had a higher rate of in-hospital death, bleeding, and cardiovascular events at 90 days than patients treated with primary PCI.

This trial recruited patients arriving at hospitals with or without PCI capability. The door-to-balloon time was about 110 minutes in both groups, which might not have been prolonged enough to show a benefit from a timely addition of thrombolysis. In addition, antiplatelet therapy was limited in these patients: glycoprotein IIb/IIIa inhibitors were not given, and clopidogrel (Plavix) was not appropriately preloaded, and this might have offset the potential benefit of early PCI. In fact, data suggest that platelet activation and aggregation are heightened after thrombolysis, ^21–23 and that glycoprotein IIb/IIIa antagonists can inhibit these effects.²³

The FINESSE trial

In the FINESSE trial,¹⁹ patients were randomized to undergo primary PCI, to undergo PCI facilitated (ie, preceded) by abciximab (Reo-Pro), or to undergo PCI facilitated by half-dose reteplase (Retavase) and full-dose abciximab. Despite a median door-to-balloon time of 132 minutes, the three strategies were associated with similar rates of death, heart failure, or ischemic outcome at 90 days. Even though the dosage of heparin was weight-adjusted, more major bleeding events occurred with the facilitated strategies.

Comments: Some subgroups may still benefit from facilitated PCI

The results of ASSENT-4 PCI and FINESSE led to the conclusion that PCI facilitated by full-dose thrombolysis should be avoided, and called into question the value of PCI facilitation using glycoprotein IIb/IIIa inhibitors with or without half-dose thrombolytic therapy.

However, subgroup analyses of these trials identified some subgroups that may benefit from a facilitated strategy. In ASSENT-4 PCI, 45% of patients were enrolled at PCI hospitals with a minimal PCI-related delay time. These patients had the worst outcome with the facilitated strategy. In contrast, patients who had a short time from pain onset to thrombolysis (2 to 3 hours) and who were given prehospital thrombolysis had a trend toward better outcomes with facilitated PCI.²⁴ And in FINESSE, 60% of patients were enrolled at centers with PCI capability. Analysis of a small subgroup of patients with a Thrombolysis in Myocardial Infarction study (TIMI) risk score of 3 or greater presenting to non-PCI hospitals within 4 hours of symptom onset suggested a potential reduction of ischemic events with the facilitated strategy in these patients.²⁵

Thus, for patients seen in the first 2 to 3 hours after symptom onset, immediate thrombolysis is recommended if PCI will likely be delayed, with or without plans for subsequent early PCI. “Time is muscle,” especially during the first 3 hours.

PHARMACOINVASIVE STRATEGY: GOOD RESULTS IN HIGH-RISK PATIENTS

A number of randomized studies during the last 10 years have examined the value of a pharmacoinvasive strategy.^{15,16,26–29}

The TRANSFER-AMI trial

The TRANSFER-AMI trial¹⁵ randomized 1,059 patients with high-risk ST-elevation MI (ie, anterior or high-risk inferior) at non-PCI centers to undergo either pharmacoinvasive care, ie, full-dose tenecteplase (TNKase) with immediate transfer for PCI or standard care, ie, tenecteplase with transfer for rescue PCI if the patient had persistent ST-segment elevation, chest pain, or hemodynamic instability.¹⁵ The goal was to perform PCI within 6 hours of thrombolysis, and the median time to PCI was 3.9 hours (range 2–6 hours). In the standard-care group, 35% of patients needed to be transferred for rescue PCI. Unlike in the ASSENT-4 trial, over 80% of patients received aggressive antiplatelet therapy with both 300 mg of clopidogrel and glycoprotein IIb/IIIa inhibitors.

The rate of cardiovascular events at 30 days was significantly lower with pharmacoinvasive therapy than with standard care and rescue PCI (11% vs 17%, P = .004). This difference was driven by lower rates of recurrent ischemia, reinfarction, and heart failure.

The CARESS-in-AMI study

The CARESS-in-AMI study¹⁶ found a similar improvement in ischemic outcomes in 600 patients with high-risk ST-elevation MI arriving at non-PCI centers if they had received pharmacoinvasive therapy. Patients received half-dose reteplase and abciximab and were randomized either to be immediately transferred for PCI (median time to PCI 2.25 hours) or to be transferred only if they had persistent ST-segment elevation or clinical deterioration.¹⁶ The event rate was low with pharmacoinvasive therapy, comparable to that achieved in primary PCI trials.

Interestingly, no significant increase was seen in the risk of major and minor bleeding in these two trials despite the use of a femoral approach for PCI in over 80% of the cases; this is probably due to the delays between thrombolytic administration and PCI and to the use of a highly fibrin-specific thrombolytic agent and adjusted-dose heparin.

Meta-analysis of pharmacoinvasive trials

A meta-analysis²⁹ of studies of systematic early PCI (mainly with stenting) within 24 hours of thrombolysis showed a reduction in the rates of mortality and reinfarction with this strategy, without an increase in the risk of major or intracranial bleeding.³⁰ In contrast to the results of the trials of facilitated PCI, a pharmacoinvasive strategy improved outcomes in these trials because the delay between thrombolysis and PCI was more than 2 hours, ie, long enough to prevent bleeding complications, and because most patients randomized in these trials presented within 2 to 3 hours of symptom onset, when the time to reperfusion is critical. After 3 hours, the PCI-mediated myocardial salvage is less time-dependent. Moreover, trials of pharmacoinvasive strategy used aggressive antiplatelet therapy with clopidogrel and glycoprotein IIb/IIIa inhibitors.

Comment: Pharmacoinvasive strategy in the guidelines

These results and those of the subgroup analysis from the FINESSE trial suggest that patients with high-risk ST-elevation MI treated at non-PCI hospitals have better outcomes without an increase in major bleeding events when given thrombolysis and then immediately transferred for routine PCI, rather than being transferred only if reperfusion fails.

Hence, the 2009 update of the ACC/AHA guidelines³¹ gives a class IIa recommendation for transferring patients with anterior ST-elevation MI or high-risk inferior ST-elevation MI treated with thrombolysis to a PCI-capable facility where PCI is performed as part of a pharmacoinvasive or rescue strategy soon after thrombolysis.

This strategy has been particularly studied in patients younger than 75 years presenting with high-risk types of ST-elevation MI early (< 3 hours) after symptom onset. If not at high risk, the patient may be transferred to a PCI facility after receiving thrombolysis or observed in the initial facility (class IIb recommendation). Consideration should be given to starting anticoagulant and antiplatelet therapy before and during transfer—ie, 300 mg of clopidogrel before transfer for PCI and glycoprotein IIb/IIIa inhibitor therapy during PCI.

The European Society of Cardiology (ESC) guidelines³² recommend early routine angiography 3 to 24 hours after successful thrombolysis. This time window was selected to avoid PCI during the prothrombotic period in the first few hours after thrombolysis and to minimize the risk of reocclusion with PCI delays of more than 24 hours (class IIa recommendation).

Larger randomized trials are still needed to establish whether the pharmacoinvasive strategy confers a survival benefit, to determine its usefulness in low-risk inferior or lateral ST-elevation MI, and to further refine the time window when PCI is both safe and beneficial after thrombolysis.³³

RESCUE PCI REDUCES MORTALITY RATES

Rescue PCI is the most accepted form of thrombolysis-PCI combination.

The REACT trial

The REACT trial²⁰ showed that rescue PCI performed at a mean of 4.5 hours after failed thrombolysis reduces the rate of adverse cardiovascular events by more than 50% at 6 to 12 months and reduces the 5-year mortality rate by more than 50% compared with conservative management.²⁰ As in the pharmacoinvasive strategy, aggressive antiplatelet regimens were used in the REACT trial.

A meta-analysis of rescue PCI trials

A meta-analysis of rescue PCI trials³⁴ confirmed these results, showing a reduction in heart failure and reinfarction and a trend toward a lower mortality rate with rescue PCI.³⁴ After thrombolysis, 40% of patients do not achieve grade 3 TIMI flow, which explains why in modern clinical trials 30% of patients treated with thrombolysis require rescue PCI.^5,15,16,35

For patients with high-risk ST-elevation MI, current ACC/AHA guidelines assign a class IIa recommendation to rescue PCI.³¹

WHEN PATIENTS WITH ST-ELEVATION MI PRESENT TO A NON-PCI HOSPITAL

Transfer for primary PCI vs thrombolysis at the non-PCI hospital

The DANAMI-2 trial³⁶ found that immediate transfer for PCI was superior to onsite thrombolytic therapy, as measured by a reduction in the rate of ischemic events (composite of death, myocardial infarction, or stroke at 30 days): 8.5% vs 14.2% (P < .001). There were no deaths during transfer.³

The PRAGUE-2 trial⁴ showed similar results for patients presenting 3 to 12 hours after symptom onset (30-day mortality rate 6% with immediate transfer vs 15.3% with on-site thrombolysis, P < .002), whereas patients presenting within 3 hours of symptom onset had a similar mortality rate with either therapy.⁴

Comment. These trials showed that transfer for primary PCI is superior to thrombolytic therapy when performed in a timely fashion. However, they were done in countries with established transfer networks and short distances between community hospitals and PCI centers, with a PCI-related delay of only 44 minutes and a door-to-balloon time of 90 minutes despite transfer. The large-scale application of this prompt transfer policy is not practical in most regions in the United States. Thus, a strategy of local thrombolysis followed by routine early transfer for routine or rescue PCI seems warranted when the door-to-balloon time or the PCI-related delay time is expected to be too long.

Experiences with community-based systems of care and prehospital thrombolysis

In Minnesota, Henry et al³⁷ developed a PCI-based treatment system and an integrated transfer program for ST-elevation MI involving 30 hospitals within 210 miles of the Minneapolis Heart Institute. Participating hospitals were divided into two zones: zone 1 hospitals were within 60 miles, and zone 2 facilities were between 60 and 210 miles from the Heart Institute. Zone 2 patients received half-dose tenecteplase (if thrombolytic therapy was not contraindicated) in anticipation of a lengthy transfer time.

The median door-to-balloon time for zone 1 patients was 95 minutes (interquartile range 82 and 116 minutes) and for zone 2 patients 120 minutes (interquartile range 100 and 145 minutes). The diagnosis of ST-elevation MI was made by the emergency department physician, who activated the system with a phone call. The patient was then directly transferred to the catheterization laboratory, most often by helicopter.

The in-hospital death rate for patients who presented to the PCI center and for patients in zones 1 and 2 was similarly low (about 5%).³⁷

In France, the FAST-MI registry,¹⁷ which collected outcome data for different reperfusion strategies, found that thrombolysis yielded in-hospital and midterm results that were comparable to those of primary PCI. Of note, thrombolysis was started early after symptom onset (about 2 hours), and was started in the ambulance in two-thirds of cases. Nearly all patients underwent a pharmacoinvasive strategy that combined thrombolysis with coronary angiography and PCI within 24 hours of symptom onset. These findings suggest that timely thrombolysis followed by semiurgent transfer for PCI is an alternative to primary PCI for patients presenting to hospitals with no PCI capability, and that this alternative offers similar benefit to that of primary PCI.

Five centers in the United States have reported their experience with half-dose thrombolysis in the prehospital setting (in the field or during transfer) or at a non-PCI hospital, followed by prompt transfer to a PCI facility. In this registry of almost 3,000 patients,³⁸ patients treated with thrombolysis had better outcomes than patients directly transferred for primary PCI, with a significantly lower 30-day mortality rate (3.8% vs from 6.4%), and no increase in bleeding.^38,39 The mean door-to-balloon time was long (168 minutes in the primary PCI group and 196 minutes in the thrombolysis-PCI group), which might explain the benefit achieved with prompt thrombolysis.

CARDIOGENIC SHOCK

Patients presenting with left ventricular cardiogenic shock derive a large mortality benefit from revascularization, whether they are transferred or directly admitted to a PCI center. ⁴⁰ Moreover, in the SHOCK registry, patients with predominant right ventricular cardiogenic shock had an in-hospital mortality rate similar to that of patients with predominant left ventricular cardiogenic shock, and revascularization (PCI or surgical revascularization) was associated with a strikingly lower mortality rate in both groups.⁴¹

Thus, all patients with left or right cardiogenic shock should be revascularized on an emergency basis, either surgically or percutaneously.

While trials of pharmacoinvasive therapy excluded patients with cardiogenic shock,^15,16 thrombolytic therapy was associated with improved outcomes in the drug-therapy group of the SHOCK trial and in hypotensive patients randomized in the early thrombolysis trials.¹³ Thus, the ACC/AHA guidelines recommend thrombolytic therapy before transfer if a patient presents in shock within 3 to 6 hours of onset of the MI and delays in transport and intervention are anticipated.⁸

PUTTING IT ALL TOGETHER: MANAGEMENT STRATEGIES

If an effective transfer system is in place, primary PCI not preceded by thrombolytic therapy or glycoprotein IIb/IIIa inhibitor therapy is the preferred approach, according to ACC/AHA and ESC guidelines.^31,32 Giving thrombolytics immediately before PCI is harmful and thus should be avoided when the expected door-to-balloon time is 90 minutes or less.

All hospitals (whether or not they offer PCI) and regional emergency medical services should participate in a community-based system of care for ST-elevation MI, with protocols for expeditious transfer as defined and coordinated by the American Heart Association initiative “Mission: Lifeline.” In addition, a system of field triage and direct transport to the catheterization laboratory of a PCI facility after field activation significantly reduces door-to-balloon times and improves outcomes.⁴²

If such a system is not in place, then a pharmacoinvasive strategy seems best: ie, local full-dose thrombolysis (if not contraindicated) followed by transfer to a PCI facility and routine performance of PCI 2 to 6 hours after thrombolysis—in conjunction with aggressive early dual oral antiplatelet therapy and “downstream” glycoprotein IIb/IIIa inhibition. This approach is associated with outcomes similar to those of primary PCI.^15–17,37

Prehospital thrombolysis delivered by paramedics and followed by early transfer to a PCI facility has been associated with further reduction in mortality rates compared with in-hospital thrombolysis (as in the Swedish registry⁴³), and a reduction in death rate comparable to that of primary PCI in patients presenting early. This is an adequate strategy in regions where such a system can be established.^{5,17,38,43,44}

Patients presenting more than 3 to 4 hours after symptom onset, older patients, and patients with lower-risk MI or a higher risk of bleeding may still be suited for primary PCI even when the door-to-balloon time is 90 to 120 minutes, as stated by the European guidelines,³² or when the PCI-related delay time is as long as 100 minutes. ¹⁰ On the other hand, while the ACC/AHA guidelines recognize that in these patients the mortality advantage of primary PCI vs thrombolytic therapy is maintained with more prolonged door-to-balloon times, they nevertheless state that the focus should be on developing systems of care to increase the number of patients with access to primary PCI in less than 90 minutes rather than extending the acceptable window for door-to-balloon time.

In conclusion, for patients presenting with ST-elevation MI who cannot undergo timely primary PCI, the best approach seems to be prehospital thrombolysis delivered by paramedics or local thrombolysis at the non-PCI hospital followed by transferring the patient and performing PCI within a few hours. This is especially important in patients with high-risk ST-elevation MI who present early after symptom onset, when the extent of myocardial necrosis associated with delayed primary PCI is largest.

In addition, every community should develop a coordinated transfer strategy between non-PCI and PCI hospitals.