In November 2012, the Center for Medicare & Medicaid Services (CMS) finalized its 2013 physician fee schedule with two new transitional-care-management (TCM) codes, 99495 and 99496. These codes provide reimbursement for transitional-care services to patients for 30 days after hospital discharge. CMS estimates that two-thirds of the 10 million Medicare patients discharged annually from hospitals will have TCM services provided by an outpatient doctor. Why might hospitalists be interested in these outpatient codes? Read on.

As a post-discharge provider in a primary-care-based discharge clinic, I can say the new Medicare transitional codes read like our job description. Because I’ve worked in a post-discharge clinic for the past three years, I have learned that post-discharge care requires time and resource allocation beyond routine outpatient care. Because of the unique population we see, on average we bill at a higher level than the rest of the practice. Yet we, like all outpatient providers, remain constrained by the existing billing structure, which is intimately connected to physician face-to-face visits.

Here’s an illustration of a typical afternoon in the post-discharge clinic: A schizophrenic patient presents with renal failure, hypoglycemia, and confusion. Her home visiting nurse (VNA) administers her medications; the patient cannot tell you any of them. While you are calling the VNA to clarify her medications, trying to identify her healthcare proxy, and stopping her ACE inhibitor because her potassium is 5.6, the next patient arrives. She has end-stage liver disease and was recently in the hospital for liver failure, and now has worsening recurrent ascites. After clinic, you call interventional radiology to coordinate a therapeutic paracentesis and change diuretic doses after her labs return. Two weeks later, you arrange a repeat paracentesis, and subsequently a transition to comfort care in a hospice house. For this work, right now, you can at most bill a high-complexity office visit (99215), and the rest of the care coordination—by you, your nurse, or your administrative staff—is not compensated.

How Do the New Codes Work?

CMS created the new TCM codes to begin to change the outpatient fee schedule to emphasize primary care and care coordination for beneficiaries, particularly in the post-hospitalization period. The new TCM codes are a first step toward reimbursement for non-face-to-face activities, which are increasingly important in the evolving healthcare system.

The investment is estimated at more than $1 billion in 2013. The new codes are available to physicians, physician assistants, nurse practitioners, and other advanced-practice nurses only once within the 30 days after hospital discharge. During the 30 days after discharge, the two codes, 99495 and 99496, require a single face-to-face visit within seven days of discharge for the highest-risk patients and within 14 days of discharge for moderate-risk patients. The face-to-face visit is not billed separately. The codes also mandate telephone communication with the patient or caregiver within two business days of hospital discharge; the medical decision-making must be of either moderate or high complexity.

The average reimbursement for the codes will be $132.96 for 99495 and $231.11 for 99496, reflecting a higher wRVU than either hospital discharge day management or high-acuity outpatient visits. The code is billed at the end of the 30 days. The TCM code cannot be billed a second time if a patient is readmitted within the 30 days. Other E/M codes can be billed during the same time period for additional visits as necessary.

What’s the Impact on Hospitalists?

The new codes affect hospitalists in two ways. First, the hospitalists in the growing group of “transitionalists,” many of whom practice in outpatient clinics seeing patients after discharge, will be able to use these codes. As the codes require no pre-existing relationship with the patient, non-primary-care providers will be able to bill these codes, assuming that they fulfill the designated requirements. This concession enables hospitalists to fill a vital role for those patients who have inadequate access to immediate primary care post-hospitalization. It also provides a necessary bridge to appropriate primary care for those patients. This group of patients might be particularly vulnerable to adverse events, including hospital readmission, given their suboptimal connection with their primary-care providers.

Hospitalists who practice entirely as inpatient physicians will not be able to bill these new codes, but they will provide a valuable service to patients by helping identify the physicians who will provide their TCM and documenting this in the discharge documentation, already seen as a key element of discharge day management services.

Do These Codes Change the Business Case for Discharge Clinics?

Discharge clinics, either hospitalist-staffed or otherwise, have been actively discussed in the media in recent years.¹ Even without these transitional codes, discharge clinics have arisen where primary-care access is limited and as a potential, but as yet unproven, solution to high readmission rates. Despite this proliferation, discharge clinics have not yet proven to be cost-effective.

Implementation of these codes could change the calculus for organizations considering dedicating resources to a discharge clinic. The new codes could make discharge clinics more financially viable by increasing the reimbursement for care that often requires more than 30 minutes. However, based on the experience in our clinic, the increased revenue accurately reflects the intensity of service necessary to coordinate care in the post-discharge period.

The time intensity of care already is obvious from the structure of established discharge clinics. Examples include the comprehensive care centers at HealthCare Partners in Southern California, where multidisciplinary visits average 90 minutes, or at our clinic at Beth Israel Deaconess Medical Center in Boston.² While the visits in our clinic are less than half as long as those at HealthCare Partners, we are not including the time spent reviewing the discharge documentation, outstanding tests, and medication changes in advance of the visit, and the time spent after the visit, coordinating the patient’s care with visiting nurses and elder service agencies.³

What’s Next?

Whether these codes lead to an increased interest in hospitalist-staffed discharge clinics or to primary-care development of robust transitional-care structures, these new codes will help focus resources and attention on increasing services, with the goal of improving patient care during a period of extreme vulnerability. This alone is something to be grateful for, whether you are a transitionalist, hospitalist, primary-care doctor, caregiver, or patient.

Dr. Doctoroff is a hospitalist at Beth Israel Deaconess Medical Center in Boston and an instructor in medicine at Harvard Medical School. She is medical director of BIDMC’s Health Care Associates Post Discharge Clinic.

References

1. Andrews M. Post-discharge clinics try to cut hospital readmissions by helping patients. Washington Post website. Available at: http://articles.washingtonpost.com/2011-12-19/national/35288219_1_readmissions-discharge-vulnerable-patients. Accessed Jan. 7, 2013.
2. Feder JL. Predictive modeling and team care for high-need patients at HealthCare Partners. Health Aff (Millwood). 2011;30(3):416-418.
3. Doctoroff L. Interval examination: establishment of a hospitalist-staffed discharge clinic. J Gen Intern Med. 2012;27(10):1377-1382.

In November 2012, the Center for Medicare & Medicaid Services (CMS) finalized its 2013 physician fee schedule with two new transitional-care-management (TCM) codes, 99495 and 99496. These codes provide reimbursement for transitional-care services to patients for 30 days after hospital discharge. CMS estimates that two-thirds of the 10 million Medicare patients discharged annually from hospitals will have TCM services provided by an outpatient doctor. Why might hospitalists be interested in these outpatient codes? Read on.

As a post-discharge provider in a primary-care-based discharge clinic, I can say the new Medicare transitional codes read like our job description. Because I’ve worked in a post-discharge clinic for the past three years, I have learned that post-discharge care requires time and resource allocation beyond routine outpatient care. Because of the unique population we see, on average we bill at a higher level than the rest of the practice. Yet we, like all outpatient providers, remain constrained by the existing billing structure, which is intimately connected to physician face-to-face visits.

Here’s an illustration of a typical afternoon in the post-discharge clinic: A schizophrenic patient presents with renal failure, hypoglycemia, and confusion. Her home visiting nurse (VNA) administers her medications; the patient cannot tell you any of them. While you are calling the VNA to clarify her medications, trying to identify her healthcare proxy, and stopping her ACE inhibitor because her potassium is 5.6, the next patient arrives. She has end-stage liver disease and was recently in the hospital for liver failure, and now has worsening recurrent ascites. After clinic, you call interventional radiology to coordinate a therapeutic paracentesis and change diuretic doses after her labs return. Two weeks later, you arrange a repeat paracentesis, and subsequently a transition to comfort care in a hospice house. For this work, right now, you can at most bill a high-complexity office visit (99215), and the rest of the care coordination—by you, your nurse, or your administrative staff—is not compensated.

How Do the New Codes Work?

CMS created the new TCM codes to begin to change the outpatient fee schedule to emphasize primary care and care coordination for beneficiaries, particularly in the post-hospitalization period. The new TCM codes are a first step toward reimbursement for non-face-to-face activities, which are increasingly important in the evolving healthcare system.

The investment is estimated at more than $1 billion in 2013. The new codes are available to physicians, physician assistants, nurse practitioners, and other advanced-practice nurses only once within the 30 days after hospital discharge. During the 30 days after discharge, the two codes, 99495 and 99496, require a single face-to-face visit within seven days of discharge for the highest-risk patients and within 14 days of discharge for moderate-risk patients. The face-to-face visit is not billed separately. The codes also mandate telephone communication with the patient or caregiver within two business days of hospital discharge; the medical decision-making must be of either moderate or high complexity.

The average reimbursement for the codes will be $132.96 for 99495 and $231.11 for 99496, reflecting a higher wRVU than either hospital discharge day management or high-acuity outpatient visits. The code is billed at the end of the 30 days. The TCM code cannot be billed a second time if a patient is readmitted within the 30 days. Other E/M codes can be billed during the same time period for additional visits as necessary.

What’s the Impact on Hospitalists?

The new codes affect hospitalists in two ways. First, the hospitalists in the growing group of “transitionalists,” many of whom practice in outpatient clinics seeing patients after discharge, will be able to use these codes. As the codes require no pre-existing relationship with the patient, non-primary-care providers will be able to bill these codes, assuming that they fulfill the designated requirements. This concession enables hospitalists to fill a vital role for those patients who have inadequate access to immediate primary care post-hospitalization. It also provides a necessary bridge to appropriate primary care for those patients. This group of patients might be particularly vulnerable to adverse events, including hospital readmission, given their suboptimal connection with their primary-care providers.

Hospitalists who practice entirely as inpatient physicians will not be able to bill these new codes, but they will provide a valuable service to patients by helping identify the physicians who will provide their TCM and documenting this in the discharge documentation, already seen as a key element of discharge day management services.

Do These Codes Change the Business Case for Discharge Clinics?

Discharge clinics, either hospitalist-staffed or otherwise, have been actively discussed in the media in recent years.¹ Even without these transitional codes, discharge clinics have arisen where primary-care access is limited and as a potential, but as yet unproven, solution to high readmission rates. Despite this proliferation, discharge clinics have not yet proven to be cost-effective.

Implementation of these codes could change the calculus for organizations considering dedicating resources to a discharge clinic. The new codes could make discharge clinics more financially viable by increasing the reimbursement for care that often requires more than 30 minutes. However, based on the experience in our clinic, the increased revenue accurately reflects the intensity of service necessary to coordinate care in the post-discharge period.

The time intensity of care already is obvious from the structure of established discharge clinics. Examples include the comprehensive care centers at HealthCare Partners in Southern California, where multidisciplinary visits average 90 minutes, or at our clinic at Beth Israel Deaconess Medical Center in Boston.² While the visits in our clinic are less than half as long as those at HealthCare Partners, we are not including the time spent reviewing the discharge documentation, outstanding tests, and medication changes in advance of the visit, and the time spent after the visit, coordinating the patient’s care with visiting nurses and elder service agencies.³

What’s Next?

Whether these codes lead to an increased interest in hospitalist-staffed discharge clinics or to primary-care development of robust transitional-care structures, these new codes will help focus resources and attention on increasing services, with the goal of improving patient care during a period of extreme vulnerability. This alone is something to be grateful for, whether you are a transitionalist, hospitalist, primary-care doctor, caregiver, or patient.

Dr. Doctoroff is a hospitalist at Beth Israel Deaconess Medical Center in Boston and an instructor in medicine at Harvard Medical School. She is medical director of BIDMC’s Health Care Associates Post Discharge Clinic.

References

1. Andrews M. Post-discharge clinics try to cut hospital readmissions by helping patients. Washington Post website. Available at: http://articles.washingtonpost.com/2011-12-19/national/35288219_1_readmissions-discharge-vulnerable-patients. Accessed Jan. 7, 2013.
2. Feder JL. Predictive modeling and team care for high-need patients at HealthCare Partners. Health Aff (Millwood). 2011;30(3):416-418.
3. Doctoroff L. Interval examination: establishment of a hospitalist-staffed discharge clinic. J Gen Intern Med. 2012;27(10):1377-1382.

In November 2012, the Center for Medicare & Medicaid Services (CMS) finalized its 2013 physician fee schedule with two new transitional-care-management (TCM) codes, 99495 and 99496. These codes provide reimbursement for transitional-care services to patients for 30 days after hospital discharge. CMS estimates that two-thirds of the 10 million Medicare patients discharged annually from hospitals will have TCM services provided by an outpatient doctor. Why might hospitalists be interested in these outpatient codes? Read on.

As a post-discharge provider in a primary-care-based discharge clinic, I can say the new Medicare transitional codes read like our job description. Because I’ve worked in a post-discharge clinic for the past three years, I have learned that post-discharge care requires time and resource allocation beyond routine outpatient care. Because of the unique population we see, on average we bill at a higher level than the rest of the practice. Yet we, like all outpatient providers, remain constrained by the existing billing structure, which is intimately connected to physician face-to-face visits.

Here’s an illustration of a typical afternoon in the post-discharge clinic: A schizophrenic patient presents with renal failure, hypoglycemia, and confusion. Her home visiting nurse (VNA) administers her medications; the patient cannot tell you any of them. While you are calling the VNA to clarify her medications, trying to identify her healthcare proxy, and stopping her ACE inhibitor because her potassium is 5.6, the next patient arrives. She has end-stage liver disease and was recently in the hospital for liver failure, and now has worsening recurrent ascites. After clinic, you call interventional radiology to coordinate a therapeutic paracentesis and change diuretic doses after her labs return. Two weeks later, you arrange a repeat paracentesis, and subsequently a transition to comfort care in a hospice house. For this work, right now, you can at most bill a high-complexity office visit (99215), and the rest of the care coordination—by you, your nurse, or your administrative staff—is not compensated.

How Do the New Codes Work?

CMS created the new TCM codes to begin to change the outpatient fee schedule to emphasize primary care and care coordination for beneficiaries, particularly in the post-hospitalization period. The new TCM codes are a first step toward reimbursement for non-face-to-face activities, which are increasingly important in the evolving healthcare system.

The investment is estimated at more than $1 billion in 2013. The new codes are available to physicians, physician assistants, nurse practitioners, and other advanced-practice nurses only once within the 30 days after hospital discharge. During the 30 days after discharge, the two codes, 99495 and 99496, require a single face-to-face visit within seven days of discharge for the highest-risk patients and within 14 days of discharge for moderate-risk patients. The face-to-face visit is not billed separately. The codes also mandate telephone communication with the patient or caregiver within two business days of hospital discharge; the medical decision-making must be of either moderate or high complexity.

The average reimbursement for the codes will be $132.96 for 99495 and $231.11 for 99496, reflecting a higher wRVU than either hospital discharge day management or high-acuity outpatient visits. The code is billed at the end of the 30 days. The TCM code cannot be billed a second time if a patient is readmitted within the 30 days. Other E/M codes can be billed during the same time period for additional visits as necessary.

What’s the Impact on Hospitalists?

The new codes affect hospitalists in two ways. First, the hospitalists in the growing group of “transitionalists,” many of whom practice in outpatient clinics seeing patients after discharge, will be able to use these codes. As the codes require no pre-existing relationship with the patient, non-primary-care providers will be able to bill these codes, assuming that they fulfill the designated requirements. This concession enables hospitalists to fill a vital role for those patients who have inadequate access to immediate primary care post-hospitalization. It also provides a necessary bridge to appropriate primary care for those patients. This group of patients might be particularly vulnerable to adverse events, including hospital readmission, given their suboptimal connection with their primary-care providers.

Hospitalists who practice entirely as inpatient physicians will not be able to bill these new codes, but they will provide a valuable service to patients by helping identify the physicians who will provide their TCM and documenting this in the discharge documentation, already seen as a key element of discharge day management services.

Do These Codes Change the Business Case for Discharge Clinics?

Discharge clinics, either hospitalist-staffed or otherwise, have been actively discussed in the media in recent years.¹ Even without these transitional codes, discharge clinics have arisen where primary-care access is limited and as a potential, but as yet unproven, solution to high readmission rates. Despite this proliferation, discharge clinics have not yet proven to be cost-effective.

Implementation of these codes could change the calculus for organizations considering dedicating resources to a discharge clinic. The new codes could make discharge clinics more financially viable by increasing the reimbursement for care that often requires more than 30 minutes. However, based on the experience in our clinic, the increased revenue accurately reflects the intensity of service necessary to coordinate care in the post-discharge period.

The time intensity of care already is obvious from the structure of established discharge clinics. Examples include the comprehensive care centers at HealthCare Partners in Southern California, where multidisciplinary visits average 90 minutes, or at our clinic at Beth Israel Deaconess Medical Center in Boston.² While the visits in our clinic are less than half as long as those at HealthCare Partners, we are not including the time spent reviewing the discharge documentation, outstanding tests, and medication changes in advance of the visit, and the time spent after the visit, coordinating the patient’s care with visiting nurses and elder service agencies.³

What’s Next?

Whether these codes lead to an increased interest in hospitalist-staffed discharge clinics or to primary-care development of robust transitional-care structures, these new codes will help focus resources and attention on increasing services, with the goal of improving patient care during a period of extreme vulnerability. This alone is something to be grateful for, whether you are a transitionalist, hospitalist, primary-care doctor, caregiver, or patient.

Dr. Doctoroff is a hospitalist at Beth Israel Deaconess Medical Center in Boston and an instructor in medicine at Harvard Medical School. She is medical director of BIDMC’s Health Care Associates Post Discharge Clinic.

References

1. Andrews M. Post-discharge clinics try to cut hospital readmissions by helping patients. Washington Post website. Available at: http://articles.washingtonpost.com/2011-12-19/national/35288219_1_readmissions-discharge-vulnerable-patients. Accessed Jan. 7, 2013.
2. Feder JL. Predictive modeling and team care for high-need patients at HealthCare Partners. Health Aff (Millwood). 2011;30(3):416-418.
3. Doctoroff L. Interval examination: establishment of a hospitalist-staffed discharge clinic. J Gen Intern Med. 2012;27(10):1377-1382.

The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons. AIHA is mediated by antibodies, and in the majority of cases immunglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C. This manual reviews the most common types of AIHA, with emphasis on diagnosis and treatment.

To read the full article in PDF:

Click here

The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons. AIHA is mediated by antibodies, and in the majority of cases immunglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C. This manual reviews the most common types of AIHA, with emphasis on diagnosis and treatment.

To read the full article in PDF:

Click here

The autoimmune hemolytic anemias (AIHA) are rare but important hematologic diseases. They can range in severity from mildly symptomatic illness to a rapidly fatal syndrome. The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000 persons. AIHA is mediated by antibodies, and in the majority of cases immunglobulin (Ig) G is the mediating antibody. This type of AIHA is referred to as "warm" AIHA because IgG antibodies bind best at body temperature. "Cold" AIHA is mediated by IgM antibodies, which bind maximally at temperatures below 37°C. This manual reviews the most common types of AIHA, with emphasis on diagnosis and treatment.

To read the full article in PDF:

Click here

Whenever a patient begins treatment with a glucocorticoid drug, we need to think about bone loss.

The American College of Rheumatology (ACR) issued recommendations for preventing and treating glucocorticoid-induced osteoporosis in 2010.¹ Compared with its previous guidelines,² the new ones are more tailored and nuanced but may be more difficult for physicians to follow. The guidelines call for assessing fracture risk using the computer-based Fracture Risk Assessment Tool, or FRAX (www/shef.ac.uk/FRAX), developed by the World Health Organization (WHO). For those without a computer or ready access to the Web, an application of FRAX is available for download on smartphones.

In this article, my purpose is to review the new recommendations and to offer my perspective, which does not necessarily reflect the opinions of the ACR.

DESPITE EVIDENCE, MANY PATIENTS RECEIVE NO INTERVENTION

Use of glucocorticoids is the most common cause of secondary osteoporosis. During the first 6 to 12 months of use, these drugs can cause a rapid loss of bone mass due to increased bone resorption; with continued use, they cause a slower but steady decline in bone mass due to reduced bone formation.³ Epidemiologic studies have found that the risk of fractures increases with dose, starting with doses as low as 2.5 mg per day of prednisone or its equivalent.⁴

Numerous clinical trials have evaluated the effect of bisphosphonates and teriparatide (Forteo) on bone mass and fracture risk in patients on glucocorticoid therapy. The bisphosphonates alendronate (Fosamax) and risedronate (Actonel) have both been shown to increase bone mass and reduce vertebral fracture risk in glucocorticoid recipients.^5–8 Zoledronic acid (Reclast), a parenteral bisphosphonate given in one annual dose, was shown to increase bone mass more than oral risedronate taken daily,⁹ and teriparatide, a formulation of parathyroid hormone, was better than alendronate.¹⁰

However, despite the known risk of fractures with glucocorticoid use and the demonstrated efficacy of available agents in preventing bone loss and fracture, many patients do not receive any intervention.^11,12

WHAT HAS HAPPENED SINCE 2001?

In the interval since 2001, several guidelines for managing glucocorticoid-induced osteoporosis have been published in other countries.^13–17 Broadly speaking, they recommend starting preventive drug therapy for patients at risk of fracture at the same time glucocorticoid drugs are started if the patient is expected to take glucocorticoids for more than 3 to 6 months in doses higher than 5 to 7.5 mg of prednisone or its equivalent daily.

Recommendations for patients who have been on glucocorticoids for longer than 3 to 6 months at initial evaluation have been based largely on T scores derived from dual-energy x-ray absorptiometry (DXA). Thresholds for initiating therapy have varied: the ACR in 2001 recommended preventive treatment if the T score is lower than −1.0, whereas British guidelines said −1.5 and Dutch guidelines said −2.5.

In the United States, since 2001 when the ACR published its last guidelines,² zoledronic acid and teriparatide have been approved for use in glucocorticoid-induced osteoporosis. In addition, guideline-development methodology has evolved and now is more scientifically rigorous. Finally, a risk-assessment tool has been developed that enables a more tailored approach (see below).

FRAX (www.shef.ac.uk/FRAX)

FRAX is a tool developed by the WHO to calculate the risk of fracture. If you go to the FRAX Web site and enter the required clinical information (race, age, sex, weight, height, previous fracture, family history of a fractured hip in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, consumption of three or more units of alcohol per day, and bone mineral density of the femoral neck), it will tell you the patient’s 10-year absolute (not relative) risk of major osteoporotic fracture and of hip fracture.

Since FRAX was unveiled in 2008, calculation of absolute fracture risk has become the standard method for making treatment decisions in patients with low bone mass who have not yet received any fracture-preventing treatment.¹⁸ The use of clinical risk factors in FRAX increases its ability to predict risk over and above the use of bone density by itself. And glucocorticoids are one of the clinical risk factors in FRAX.

But in which patients is treatment with a bisphosphonate or teriparatide cost-effective?

Thresholds for cost-effectiveness have been developed on the basis of economic assumptions that are country-specific. In the United States, the National Osteoporosis Foundation recommends drug therapy if the 10-year absolute risk of a major osteoporotic fracture of the hip, spine (clinical, not radiographic), wrist, or humerus is greater than 20% or if the risk of a hip fracture is greater than 3%.¹⁹

At equivalent bone densities, women taking glucocorticoids are at considerably higher risk of fracture than nonusers.²⁰ For example, consider a 65-year-old white woman, weight 59 kg, height 163 cm, no previous fractures, no parent with a fractured hip, no current smoking, no rheumatoid arthritis, no secondary osteoporosis, no excessive alcohol use, and a T score of −2.2 in the femoral neck. (Try this on the FRAX Web site.) If she does not use glucocorticoids, her 10-year risk of hip fracture is 2.0%; using glucocorticoids increases the risk to 3.6%. This is higher than the 3% National Osteoporosis Foundation guideline; thus, treatment would be recommended.

Also using FRAX, a 55-year-old white woman with a T score of −1.8 and on glucocorticoid therapy has a 67% higher risk of major osteoporotic fracture and an 80% higher risk of hip fracture.

For a third example, a white woman age 60, weight 70 kg, height 168 cm, negative for all the other risk factors but with a T score of −2.1 and on glucocorticoids has a calculated 10-year fracture risk of 2.1%, which is below the National Osteoporosis Foundation treatment threshold. However, most clinicians would probably recommend treatment for her, depending on the anticipated dose and duration of glucocorticoid therapy.

A caveat. In FRAX, glucocorticoid therapy is a categorical variable—a yes-or-no question—and yes is defined as having ever used a glucocorticoid in a dose greater than 5 mg for more than 3 months. Therefore, according to FRAX, a patient who took 5 mg of prednisone for 3 months 5 years ago has the same fracture risk as a patient on 60 mg of prednisone after a diagnosis of temporal arteritis. For this reason, the FRAX tool is likely to underestimate fracture risk, especially in patients currently taking glucocorticoids and those on higher doses of these drugs.

Kanis et al used the General Practice Research Database to adjust the fracture risk for glucocorticoid use in FRAX.²¹ At doses higher than 7.5 mg, the fracture risk had to be revised upward by 10% to 25% depending on the fracture site (hip vs any major osteoporotic fracture) and age (greater at age 40 than at age 90).

The underestimation of fracture risk led the ACR Expert Advisory Panel to create risk strata for major osteoporotic fractures, ie, low (< 10% risk per 10 years), medium (10%–20%), and high (> 20%) and uses these cut points to make treatment recommendations.

HOW THE 2010 GUIDELINES WERE DEVELOPED

Whereas the 2001 recommendations were based on a more informal consensus approach, the 2010 recommendations use a more scientifically rigorous methodology for guideline development, the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness Method. The RAND/UCLA method combines the best available scientific evidence with expert opinion to develop practice guidelines.

In drawing up the 2010 recommendations the ACR used three panels of experts. The Core Executive Panel conducted a systematic review of controlled clinical trials of therapies currently approved for treating glucocorticoid-induced osteoporosis in the United States, Canada, or the European Union. They found 53 articles meeting their inclusion criteria; an evidence report was produced that informed the development of the recommendations. This evidence report and guideline development process is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658. The Expert Advisory Panel framed the recommendations, and the Task Force Panel voted on them. The Core Executive Panel and Expert Advisory Panel constructed 48 patient-specific clinical scenarios using four variables: sex, age, race/ethnicity, and femoral neck T scores.

The members of the Task Force Panel were asked to use the evidence report and their expert judgment to vote on and rate the appropriateness of using a specific therapy in the context of each scenario on a 9-point Likert scale (1 = appropriate; 9 = not appropriate). Agreement occurred when 7 or more of the 10 panel members rated a scenario 1, 2, or 3. Disagreements were defined as 3 or more of the 10 members rating the scenario between 4 and 9 while the other members rated it lower.

Disagreements in voting were discussed in an attempt to achieve consensus, and a second vote was conducted which determined the final recommendations. If disagreement remained after the vote, no recommendation was made.

No attempt was made to assign priority of one drug over another when multiple drugs were deemed appropriate, although the final recommendations did differentiate drugs based on patient categories.

START WITH COUNSELING, ASSESSMENT

For patients starting or already on glucocorticoid therapy that is expected to last at least 3 months, the first step is to counsel them on lifestyle modifications (Table 1) and to assess their risk factors (Figure 1). Recommendations for monitoring patients receiving glucocorticoid therapy for at least 3 months are presented in Table 2.

These recommendations are based on literature review, and the strength of evidence is graded:

• Grade A—derived from multiple randomized controlled trials or a meta-analysis
• Grade B—derived from a single randomized controlled trial or nonrandomized study
• Grade C—derived from consensus, expert opinion, or case series.

This system is the same one used by the American College of Cardiology and is based on clinical trial data.²²

Recommendations for calcium intake and vitamin D supplementation were graded A; all other recommendations were graded C (Tables 1 and 2). It is important to note that practices that receive a grade of C may still be accepted as standard of care, such as fall assessment and smoking cessation.

FOR POSTMENOPAUSAL WOMEN AND FOR MEN AGE 50 AND OLDER

FRAX low-risk group

Recall that “low risk” based on the new ACR guidelines means that the 10-year absolute risk of a major osteoporotic fracture, as calculated with FRAX, is less than 10%.

• If glucocorticoid use is expected to last or has already lasted at least 3 months and the dose is less than 7.5 mg/day, no pharmacologic treatment is recommended.
• If glucocorticoid use is expected to last or has already lasted at least 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended.

Comment. These are the most straightforward of the recommendations. All three bisphosphonates are recommended as treatment options if the glucocorticoid dose is at least 7.5 mg/day and the duration at least 3 months. Ibandronate (Boniva) was not included because it has no data from clinical trials.

“Medium risk” means that the 10-year absolute fracture risk of major osteoporotic fractures is 10% to 20%.

• If glucocorticoid use is anticipated to last or has lasted at least 3 months and the dose is less than 7.5 mg/day, alendronate or risedronate is recommended.
• If glucocorticoid use is anticipated to last or has lasted at least 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended.

Comment. Treatment is recommended at all glucocorticoid doses for patients in the medium-risk category if the duration of glucocorticoid treatment is at least 3 months, with one difference: zoledronic acid is recommended only if the glucocorticoid dose is 7.5 mg/day or higher. This inconsistency persisted after a second round of voting by the Task Force Panel.

FRAX high-risk group

In this group, the 10-year risk of major osteoporotic fractures is higher than 20%.

• If the glucocorticoid dose is less than 5 mg/day for up to 1 month, alendronate, risedronate, or zoledronic acid is recommended.
• If the dose is 5 mg/day or more for up to 1 month, or any dose for more than 1 month, alendronate, risedronate, zoledronic acid or teriparatide is recommended.

Comment. Based on current National Osteoporosis Foundation guidelines, all patients with a 10-year risk greater than 20% are recommended for treatment for any duration and dose of glucocorticoid use. However, teriparatide is recommended only if the duration of glucocorticoid therapy is more than 1 month.

FOR PREMENOPAUSAL WOMEN AND FOR MEN YOUNGER THAN AGE 50

Use of FRAX is not appropriate in premenopausal women or in men younger than 50 years.

Younger patients with no prevalent fracture

For men younger than 50 and premenopausal women who have not had a previous fracture, data were considered inadequate to make a recommendation, and no votes were taken.

Prevalent fracture in premenopausal women of nonchildbearing potential

In premenopausal women of nonchildbearing potential who have had a fracture:

• If the glucocorticoid duration is 1 to 3 months and the dose is 5 mg/day or higher, alendronate or risedronate is recommended.
• If the duration is 1 to 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended
• If the duration is more than 3 months, alendronate, risedronate, zoledronic acid, or teriparatide is recommended.

Comment. Treatment is recommended with any of the four medications in patients with a fracture and treated with glucocorticoids for more than 3 months. For shorter-duration glucocorticoid use (1–3 months) at 5 mg/day or higher, only alendronate and risedronate are recommended. If the dose is 7.5 mg/day or higher, any bisphosphonate is recommended. Zoledronic acid was consistently differentiated by the expert panel on the basis of dose and duration of glucocorticoid use, in view of its 1-year duration of effect after one dose.

Prevalent fracture in women of childbearing potential

• If the glucocorticoid duration is 1 to 3 months, there was no consensus (ie, voting disagreements could not be resolved).
• If the glucocorticoid duration is more than 3 months and the dose is 7.5 mg/day or more, alendronate, risedronate, or teriparatide is recommended.
• If the glucocorticoid duration is more than 3 months and the dose is less than 7.5 mg/day, there was no consensus.

Comment. Childbearing potential creates further complexities because of concern about fetal toxicity with bisphosphonates. For short-term glucocorticoid therapy at any dose and for therapy longer than 3 months at less than 7.5 mg, no consensus could be reached. For therapy longer than 3 months and with 7.5 mg/day or higher, treatment is recommended but not with zoledronic acid, based on the long half-life of the drug and concern for fetal toxicity.

Additional risk stratification

The panel recommended that if the following were present, a shift to a higher fracture risk category should be considered (low to medium, or medium to high):

• High daily dose of glucocorticoid
• High cumulative glucocorticoid dose
• Declining bone mineral density on serial DXA.

These are known risk factors that increase fracture risk but would not affect fracture risk in the FRAX model.

WHAT IS NEW IN THE 2010 RECOMMENDATIONS?

Recommendations for counseling now include fall risk assessment, height measurement, 25-hydroxyvitamin D measurement, and evaluation of patients for prevalent and incident fractures using vertebral fracture assessment by DXA or radiographic imaging of the spine.

Recommended drugs now include teriparatide and zoledronic acid, while estrogen and testosterone are no longer recommended as therapies for glucocorticoid-induced osteoporosis. Ibandronate is not included, since there have been no randomized controlled trials of this bisphosphonate in glucocorticoid-induced osteoporosis.

Recommendations for treatment in 2001 were based on T scores alone, while the 2010 recommendations use an assessment of absolute fracture risk based on FRAX for postmenopausal women and for men age 50 and older.

A clinician’s guide that summarizes the ACR recommendations is available at www.rheumatology.org/practice/clinical/guidelines/.

RECOMMENDATIONS DO NOT REPLACE CLINICAL JUDGMENT

Although the 2010 recommendations were more rigorous in their development process than those of 2001, they have limitations and they should not replace clinical judgment. Rather, they are intended to provide an evidence-based approach to guide clinicians in making treatment choices in patients on glucocorticoid therapy.

CONSIDERING ABSOLUTE FRACTURE RISK IN TREATMENT DECISIONS

The 2001 ACR guidelines recommended fracture-preventing treatment in all patients starting glucocorticoid therapy at more than 5 mg/day if the planned duration of treatment was at least 3 months, and in patients on long-term glucocorticoid therapy if the T score was less than −1.0. While these guidelines were simple and easy to use, they were not specific enough to provide useful guidance in specific scenarios.

A model of absolute fracture risk was not available in 2001. A 55-year old white woman with a T score of −1.1 who smoked, who had been using 5 mg of prednisone for the last 12 months, and who had stable bone mass on serial DXA scans would have been recommended for treatment based on the 2001 recommendations. If this patient’s FRAX-calculated 10-year absolute risk of a major osteoporotic fracture is less than 10%, that would be well below the National Osteoporosis Foundation’s cost-effective treatment threshold of 20%. The new guidelines suggest no treatment is needed, since the risk category is low and the dose is less than 7.5 mg. However, if on serial DXA this patient had a significant decline in bone mass, the guidelines suggest shifting the patient to a higher risk category, ie, from low to medium risk, which would result in a recommendation in favor of treatment.

The 2010 recommendations are not as simple to use as those from 2001. They encourage using FRAX to calculate fracture risk; thus, knowledge of the strengths and limitations of FRAX is required. Access to the internet in the examination room or use of the FRAX tool on a smartphone as well as willingness to spend a minute to calculate fracture risk are needed. For those who cannot or choose not to use the FRAX tool, the ACR publication provides tables for patient risk assessment based on age and T score. However, the tables would have to be readily available in the clinic, which may not be practical.

The 2010 recommendation provide a more nuanced approach to treatment in patients on glucocorticoid therapy and are likely to change treatment decisions based on their use, just as FRAX has altered treatment decisions in patients with primary osteoporosis.²³

FRAX has limitations

FRAX underestimates the effect of glucocorticoids on fracture risk because steroid use is a yes-or-no question and its weight represents the average risk in a population that has ever used steroids, most of whom were using doses between 2.5 and 7.5 mg.

The WHO recognized this limitation and suggested an upward adjustment of risk for patients on 7.5 mg or more, ranging from 10% to 25%.²¹ For patients on high doses of steroids, this adjustment is still likely to result in underestimation of fracture risk and undertreatment of glucocorticoid-treated patients.

The 2010 recommendations adjust for this limitation, recommending treatment in the low-risk and medium-risk categories if the glucocorticoid dose is 7.5 mg or higher. If a patient is using high daily doses of steroids or has a declining bone density, the 2010 recommendations suggest increasing the risk category from low to medium or medium to high.

FRAX risk factors are dichotomous (yes/no) and are not adjusted for dose effects such as multiple fractures (vs a single fracture), heavy smoking (vs light smoking), heavy alcohol use (6 units per day vs 3 units), or severe rheumatoid arthritis (vs mild disease). Family history of osteoporosis in the FRAX is limited to parents with a hip fracture—vertebral fractures in a family member do not count.

Since FRAX uses the bone mineral density in the hip, it underestimates fracture risk in patients with low spine density but normal hip density. It may also underestimate fracture risk in patients with declining bone mass; the 2010 recommendations suggest the clinician should increase the risk category in this situation.

LIMITATIONS OF THE GUIDELINES

The 2010 recommendations do not include several important groups in which steroids are used, including transplant recipients, children, and patients on inhaled corticosteroids. The panel thought that there were insufficient data to make recommendations for these populations, as well as for premenopausal women and men younger than 50 years who did not have a prevalent fracture. The absence of a recommendation in these situations should not be considered a recommendation for no treatment; it is an acknowledgment of a lack of evidence, a lack of consensus among experts, and the need for additional clinical trials.

For premenopausal women and men under age 50 with a fracture, the recommendations are complicated and not intuitive. Zoledronic acid is not recommended for women of non-childbearing potential with a glucocorticoid duration of 1 to 3 months unless the steroid dose is at least 7.5 mg. This recommendation was based on panel voting and consensus that giving zoledronic acid, a medication with a 1-year duration of effect, in a patient on steroids for only 1 to 3 months was not warranted.

Teriparatide was recommended only if glucocorticoids are used for at least 3 months, although anyone who already has a fracture might be considered at high enough risk to warrant anabolic therapy regardless of steroid use or duration.

Zoledronic acid was excluded in women of childbearing potential, based on panel voting and consensus that drugs given in smaller amounts over 1 year might be less harmful to a fetus than one with a longer half-life given in a larger bolus once a year.

The panel could reach no consensus on women of childbearing potential with a prevalent fracture who were using less than 7.5 mg/day of glucocorticoids. A lack of consensus was the result of insufficient data to make evidence-based decisions and a disagreement among experts on the correct treatment.

The guidelines do not address the duration of treatment with bisphosphonates, a topic of importance because of concern for the potential long-term side effects of these medications.

THE BOTTOM LINE

The 2010 recommendations add a degree of complexity, with different medications recommended on the basis of glucocorticoid dose and duration as well as patient age, menopausal status, and childbearing potential. Guideline developers and clinicians face a difficult trade-off: easy-to-follow guidelines or more targeted guidelines that are more complex and therefore more difficult to use than previous guidelines.

This criticism is reasonable. The complexity is a result of insufficient evidence from clinical trials to make more exact and user-friendly recommendations, and also a result of the RAND/UCLA methodology. In cases that lack sufficient evidence on which to make a decision, the guideline development uses voting among experts in an attempt to develop consensus. This often results in complexity, lack of consensus, or inconsistencies.

The guidelines are straightforward for postmenopausal women and men age 50 and older on at least 7.5 mg prednisone for more than 3 months.

Since there is substantial evidence that many patients on glucocorticoid therapy go untreated, the risk of fracture in this population would be substantially reduced if clinicians would adhere to the recommendations.

Whenever a patient begins treatment with a glucocorticoid drug, we need to think about bone loss.

The American College of Rheumatology (ACR) issued recommendations for preventing and treating glucocorticoid-induced osteoporosis in 2010.¹ Compared with its previous guidelines,² the new ones are more tailored and nuanced but may be more difficult for physicians to follow. The guidelines call for assessing fracture risk using the computer-based Fracture Risk Assessment Tool, or FRAX (www/shef.ac.uk/FRAX), developed by the World Health Organization (WHO). For those without a computer or ready access to the Web, an application of FRAX is available for download on smartphones.

In this article, my purpose is to review the new recommendations and to offer my perspective, which does not necessarily reflect the opinions of the ACR.

DESPITE EVIDENCE, MANY PATIENTS RECEIVE NO INTERVENTION

Use of glucocorticoids is the most common cause of secondary osteoporosis. During the first 6 to 12 months of use, these drugs can cause a rapid loss of bone mass due to increased bone resorption; with continued use, they cause a slower but steady decline in bone mass due to reduced bone formation.³ Epidemiologic studies have found that the risk of fractures increases with dose, starting with doses as low as 2.5 mg per day of prednisone or its equivalent.⁴

Numerous clinical trials have evaluated the effect of bisphosphonates and teriparatide (Forteo) on bone mass and fracture risk in patients on glucocorticoid therapy. The bisphosphonates alendronate (Fosamax) and risedronate (Actonel) have both been shown to increase bone mass and reduce vertebral fracture risk in glucocorticoid recipients.^5–8 Zoledronic acid (Reclast), a parenteral bisphosphonate given in one annual dose, was shown to increase bone mass more than oral risedronate taken daily,⁹ and teriparatide, a formulation of parathyroid hormone, was better than alendronate.¹⁰

However, despite the known risk of fractures with glucocorticoid use and the demonstrated efficacy of available agents in preventing bone loss and fracture, many patients do not receive any intervention.^11,12

WHAT HAS HAPPENED SINCE 2001?

In the interval since 2001, several guidelines for managing glucocorticoid-induced osteoporosis have been published in other countries.^13–17 Broadly speaking, they recommend starting preventive drug therapy for patients at risk of fracture at the same time glucocorticoid drugs are started if the patient is expected to take glucocorticoids for more than 3 to 6 months in doses higher than 5 to 7.5 mg of prednisone or its equivalent daily.

Recommendations for patients who have been on glucocorticoids for longer than 3 to 6 months at initial evaluation have been based largely on T scores derived from dual-energy x-ray absorptiometry (DXA). Thresholds for initiating therapy have varied: the ACR in 2001 recommended preventive treatment if the T score is lower than −1.0, whereas British guidelines said −1.5 and Dutch guidelines said −2.5.

In the United States, since 2001 when the ACR published its last guidelines,² zoledronic acid and teriparatide have been approved for use in glucocorticoid-induced osteoporosis. In addition, guideline-development methodology has evolved and now is more scientifically rigorous. Finally, a risk-assessment tool has been developed that enables a more tailored approach (see below).

FRAX (www.shef.ac.uk/FRAX)

FRAX is a tool developed by the WHO to calculate the risk of fracture. If you go to the FRAX Web site and enter the required clinical information (race, age, sex, weight, height, previous fracture, family history of a fractured hip in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, consumption of three or more units of alcohol per day, and bone mineral density of the femoral neck), it will tell you the patient’s 10-year absolute (not relative) risk of major osteoporotic fracture and of hip fracture.

Since FRAX was unveiled in 2008, calculation of absolute fracture risk has become the standard method for making treatment decisions in patients with low bone mass who have not yet received any fracture-preventing treatment.¹⁸ The use of clinical risk factors in FRAX increases its ability to predict risk over and above the use of bone density by itself. And glucocorticoids are one of the clinical risk factors in FRAX.

But in which patients is treatment with a bisphosphonate or teriparatide cost-effective?

Thresholds for cost-effectiveness have been developed on the basis of economic assumptions that are country-specific. In the United States, the National Osteoporosis Foundation recommends drug therapy if the 10-year absolute risk of a major osteoporotic fracture of the hip, spine (clinical, not radiographic), wrist, or humerus is greater than 20% or if the risk of a hip fracture is greater than 3%.¹⁹

At equivalent bone densities, women taking glucocorticoids are at considerably higher risk of fracture than nonusers.²⁰ For example, consider a 65-year-old white woman, weight 59 kg, height 163 cm, no previous fractures, no parent with a fractured hip, no current smoking, no rheumatoid arthritis, no secondary osteoporosis, no excessive alcohol use, and a T score of −2.2 in the femoral neck. (Try this on the FRAX Web site.) If she does not use glucocorticoids, her 10-year risk of hip fracture is 2.0%; using glucocorticoids increases the risk to 3.6%. This is higher than the 3% National Osteoporosis Foundation guideline; thus, treatment would be recommended.

Also using FRAX, a 55-year-old white woman with a T score of −1.8 and on glucocorticoid therapy has a 67% higher risk of major osteoporotic fracture and an 80% higher risk of hip fracture.

For a third example, a white woman age 60, weight 70 kg, height 168 cm, negative for all the other risk factors but with a T score of −2.1 and on glucocorticoids has a calculated 10-year fracture risk of 2.1%, which is below the National Osteoporosis Foundation treatment threshold. However, most clinicians would probably recommend treatment for her, depending on the anticipated dose and duration of glucocorticoid therapy.

A caveat. In FRAX, glucocorticoid therapy is a categorical variable—a yes-or-no question—and yes is defined as having ever used a glucocorticoid in a dose greater than 5 mg for more than 3 months. Therefore, according to FRAX, a patient who took 5 mg of prednisone for 3 months 5 years ago has the same fracture risk as a patient on 60 mg of prednisone after a diagnosis of temporal arteritis. For this reason, the FRAX tool is likely to underestimate fracture risk, especially in patients currently taking glucocorticoids and those on higher doses of these drugs.

Kanis et al used the General Practice Research Database to adjust the fracture risk for glucocorticoid use in FRAX.²¹ At doses higher than 7.5 mg, the fracture risk had to be revised upward by 10% to 25% depending on the fracture site (hip vs any major osteoporotic fracture) and age (greater at age 40 than at age 90).

The underestimation of fracture risk led the ACR Expert Advisory Panel to create risk strata for major osteoporotic fractures, ie, low (< 10% risk per 10 years), medium (10%–20%), and high (> 20%) and uses these cut points to make treatment recommendations.

HOW THE 2010 GUIDELINES WERE DEVELOPED

Whereas the 2001 recommendations were based on a more informal consensus approach, the 2010 recommendations use a more scientifically rigorous methodology for guideline development, the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness Method. The RAND/UCLA method combines the best available scientific evidence with expert opinion to develop practice guidelines.

In drawing up the 2010 recommendations the ACR used three panels of experts. The Core Executive Panel conducted a systematic review of controlled clinical trials of therapies currently approved for treating glucocorticoid-induced osteoporosis in the United States, Canada, or the European Union. They found 53 articles meeting their inclusion criteria; an evidence report was produced that informed the development of the recommendations. This evidence report and guideline development process is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658. The Expert Advisory Panel framed the recommendations, and the Task Force Panel voted on them. The Core Executive Panel and Expert Advisory Panel constructed 48 patient-specific clinical scenarios using four variables: sex, age, race/ethnicity, and femoral neck T scores.

The members of the Task Force Panel were asked to use the evidence report and their expert judgment to vote on and rate the appropriateness of using a specific therapy in the context of each scenario on a 9-point Likert scale (1 = appropriate; 9 = not appropriate). Agreement occurred when 7 or more of the 10 panel members rated a scenario 1, 2, or 3. Disagreements were defined as 3 or more of the 10 members rating the scenario between 4 and 9 while the other members rated it lower.

Disagreements in voting were discussed in an attempt to achieve consensus, and a second vote was conducted which determined the final recommendations. If disagreement remained after the vote, no recommendation was made.

No attempt was made to assign priority of one drug over another when multiple drugs were deemed appropriate, although the final recommendations did differentiate drugs based on patient categories.

START WITH COUNSELING, ASSESSMENT

For patients starting or already on glucocorticoid therapy that is expected to last at least 3 months, the first step is to counsel them on lifestyle modifications (Table 1) and to assess their risk factors (Figure 1). Recommendations for monitoring patients receiving glucocorticoid therapy for at least 3 months are presented in Table 2.

These recommendations are based on literature review, and the strength of evidence is graded:

• Grade A—derived from multiple randomized controlled trials or a meta-analysis
• Grade B—derived from a single randomized controlled trial or nonrandomized study
• Grade C—derived from consensus, expert opinion, or case series.

This system is the same one used by the American College of Cardiology and is based on clinical trial data.²²

Recommendations for calcium intake and vitamin D supplementation were graded A; all other recommendations were graded C (Tables 1 and 2). It is important to note that practices that receive a grade of C may still be accepted as standard of care, such as fall assessment and smoking cessation.

FOR POSTMENOPAUSAL WOMEN AND FOR MEN AGE 50 AND OLDER

FRAX low-risk group

Recall that “low risk” based on the new ACR guidelines means that the 10-year absolute risk of a major osteoporotic fracture, as calculated with FRAX, is less than 10%.

• If glucocorticoid use is expected to last or has already lasted at least 3 months and the dose is less than 7.5 mg/day, no pharmacologic treatment is recommended.
• If glucocorticoid use is expected to last or has already lasted at least 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended.

Comment. These are the most straightforward of the recommendations. All three bisphosphonates are recommended as treatment options if the glucocorticoid dose is at least 7.5 mg/day and the duration at least 3 months. Ibandronate (Boniva) was not included because it has no data from clinical trials.

“Medium risk” means that the 10-year absolute fracture risk of major osteoporotic fractures is 10% to 20%.

• If glucocorticoid use is anticipated to last or has lasted at least 3 months and the dose is less than 7.5 mg/day, alendronate or risedronate is recommended.
• If glucocorticoid use is anticipated to last or has lasted at least 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended.

Comment. Treatment is recommended at all glucocorticoid doses for patients in the medium-risk category if the duration of glucocorticoid treatment is at least 3 months, with one difference: zoledronic acid is recommended only if the glucocorticoid dose is 7.5 mg/day or higher. This inconsistency persisted after a second round of voting by the Task Force Panel.

FRAX high-risk group

In this group, the 10-year risk of major osteoporotic fractures is higher than 20%.

• If the glucocorticoid dose is less than 5 mg/day for up to 1 month, alendronate, risedronate, or zoledronic acid is recommended.
• If the dose is 5 mg/day or more for up to 1 month, or any dose for more than 1 month, alendronate, risedronate, zoledronic acid or teriparatide is recommended.

Comment. Based on current National Osteoporosis Foundation guidelines, all patients with a 10-year risk greater than 20% are recommended for treatment for any duration and dose of glucocorticoid use. However, teriparatide is recommended only if the duration of glucocorticoid therapy is more than 1 month.

FOR PREMENOPAUSAL WOMEN AND FOR MEN YOUNGER THAN AGE 50

Use of FRAX is not appropriate in premenopausal women or in men younger than 50 years.

Younger patients with no prevalent fracture

For men younger than 50 and premenopausal women who have not had a previous fracture, data were considered inadequate to make a recommendation, and no votes were taken.

Prevalent fracture in premenopausal women of nonchildbearing potential

In premenopausal women of nonchildbearing potential who have had a fracture:

• If the glucocorticoid duration is 1 to 3 months and the dose is 5 mg/day or higher, alendronate or risedronate is recommended.
• If the duration is 1 to 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended
• If the duration is more than 3 months, alendronate, risedronate, zoledronic acid, or teriparatide is recommended.

Comment. Treatment is recommended with any of the four medications in patients with a fracture and treated with glucocorticoids for more than 3 months. For shorter-duration glucocorticoid use (1–3 months) at 5 mg/day or higher, only alendronate and risedronate are recommended. If the dose is 7.5 mg/day or higher, any bisphosphonate is recommended. Zoledronic acid was consistently differentiated by the expert panel on the basis of dose and duration of glucocorticoid use, in view of its 1-year duration of effect after one dose.

Prevalent fracture in women of childbearing potential

• If the glucocorticoid duration is 1 to 3 months, there was no consensus (ie, voting disagreements could not be resolved).
• If the glucocorticoid duration is more than 3 months and the dose is 7.5 mg/day or more, alendronate, risedronate, or teriparatide is recommended.
• If the glucocorticoid duration is more than 3 months and the dose is less than 7.5 mg/day, there was no consensus.

Comment. Childbearing potential creates further complexities because of concern about fetal toxicity with bisphosphonates. For short-term glucocorticoid therapy at any dose and for therapy longer than 3 months at less than 7.5 mg, no consensus could be reached. For therapy longer than 3 months and with 7.5 mg/day or higher, treatment is recommended but not with zoledronic acid, based on the long half-life of the drug and concern for fetal toxicity.

Additional risk stratification

The panel recommended that if the following were present, a shift to a higher fracture risk category should be considered (low to medium, or medium to high):

• High daily dose of glucocorticoid
• High cumulative glucocorticoid dose
• Declining bone mineral density on serial DXA.

These are known risk factors that increase fracture risk but would not affect fracture risk in the FRAX model.

WHAT IS NEW IN THE 2010 RECOMMENDATIONS?

Recommendations for counseling now include fall risk assessment, height measurement, 25-hydroxyvitamin D measurement, and evaluation of patients for prevalent and incident fractures using vertebral fracture assessment by DXA or radiographic imaging of the spine.

Recommended drugs now include teriparatide and zoledronic acid, while estrogen and testosterone are no longer recommended as therapies for glucocorticoid-induced osteoporosis. Ibandronate is not included, since there have been no randomized controlled trials of this bisphosphonate in glucocorticoid-induced osteoporosis.

Recommendations for treatment in 2001 were based on T scores alone, while the 2010 recommendations use an assessment of absolute fracture risk based on FRAX for postmenopausal women and for men age 50 and older.

A clinician’s guide that summarizes the ACR recommendations is available at www.rheumatology.org/practice/clinical/guidelines/.

RECOMMENDATIONS DO NOT REPLACE CLINICAL JUDGMENT

Although the 2010 recommendations were more rigorous in their development process than those of 2001, they have limitations and they should not replace clinical judgment. Rather, they are intended to provide an evidence-based approach to guide clinicians in making treatment choices in patients on glucocorticoid therapy.

CONSIDERING ABSOLUTE FRACTURE RISK IN TREATMENT DECISIONS

The 2001 ACR guidelines recommended fracture-preventing treatment in all patients starting glucocorticoid therapy at more than 5 mg/day if the planned duration of treatment was at least 3 months, and in patients on long-term glucocorticoid therapy if the T score was less than −1.0. While these guidelines were simple and easy to use, they were not specific enough to provide useful guidance in specific scenarios.

A model of absolute fracture risk was not available in 2001. A 55-year old white woman with a T score of −1.1 who smoked, who had been using 5 mg of prednisone for the last 12 months, and who had stable bone mass on serial DXA scans would have been recommended for treatment based on the 2001 recommendations. If this patient’s FRAX-calculated 10-year absolute risk of a major osteoporotic fracture is less than 10%, that would be well below the National Osteoporosis Foundation’s cost-effective treatment threshold of 20%. The new guidelines suggest no treatment is needed, since the risk category is low and the dose is less than 7.5 mg. However, if on serial DXA this patient had a significant decline in bone mass, the guidelines suggest shifting the patient to a higher risk category, ie, from low to medium risk, which would result in a recommendation in favor of treatment.

The 2010 recommendations are not as simple to use as those from 2001. They encourage using FRAX to calculate fracture risk; thus, knowledge of the strengths and limitations of FRAX is required. Access to the internet in the examination room or use of the FRAX tool on a smartphone as well as willingness to spend a minute to calculate fracture risk are needed. For those who cannot or choose not to use the FRAX tool, the ACR publication provides tables for patient risk assessment based on age and T score. However, the tables would have to be readily available in the clinic, which may not be practical.

The 2010 recommendation provide a more nuanced approach to treatment in patients on glucocorticoid therapy and are likely to change treatment decisions based on their use, just as FRAX has altered treatment decisions in patients with primary osteoporosis.²³

FRAX has limitations

FRAX underestimates the effect of glucocorticoids on fracture risk because steroid use is a yes-or-no question and its weight represents the average risk in a population that has ever used steroids, most of whom were using doses between 2.5 and 7.5 mg.

The WHO recognized this limitation and suggested an upward adjustment of risk for patients on 7.5 mg or more, ranging from 10% to 25%.²¹ For patients on high doses of steroids, this adjustment is still likely to result in underestimation of fracture risk and undertreatment of glucocorticoid-treated patients.

The 2010 recommendations adjust for this limitation, recommending treatment in the low-risk and medium-risk categories if the glucocorticoid dose is 7.5 mg or higher. If a patient is using high daily doses of steroids or has a declining bone density, the 2010 recommendations suggest increasing the risk category from low to medium or medium to high.

FRAX risk factors are dichotomous (yes/no) and are not adjusted for dose effects such as multiple fractures (vs a single fracture), heavy smoking (vs light smoking), heavy alcohol use (6 units per day vs 3 units), or severe rheumatoid arthritis (vs mild disease). Family history of osteoporosis in the FRAX is limited to parents with a hip fracture—vertebral fractures in a family member do not count.

Since FRAX uses the bone mineral density in the hip, it underestimates fracture risk in patients with low spine density but normal hip density. It may also underestimate fracture risk in patients with declining bone mass; the 2010 recommendations suggest the clinician should increase the risk category in this situation.

LIMITATIONS OF THE GUIDELINES

The 2010 recommendations do not include several important groups in which steroids are used, including transplant recipients, children, and patients on inhaled corticosteroids. The panel thought that there were insufficient data to make recommendations for these populations, as well as for premenopausal women and men younger than 50 years who did not have a prevalent fracture. The absence of a recommendation in these situations should not be considered a recommendation for no treatment; it is an acknowledgment of a lack of evidence, a lack of consensus among experts, and the need for additional clinical trials.

For premenopausal women and men under age 50 with a fracture, the recommendations are complicated and not intuitive. Zoledronic acid is not recommended for women of non-childbearing potential with a glucocorticoid duration of 1 to 3 months unless the steroid dose is at least 7.5 mg. This recommendation was based on panel voting and consensus that giving zoledronic acid, a medication with a 1-year duration of effect, in a patient on steroids for only 1 to 3 months was not warranted.

Teriparatide was recommended only if glucocorticoids are used for at least 3 months, although anyone who already has a fracture might be considered at high enough risk to warrant anabolic therapy regardless of steroid use or duration.

Zoledronic acid was excluded in women of childbearing potential, based on panel voting and consensus that drugs given in smaller amounts over 1 year might be less harmful to a fetus than one with a longer half-life given in a larger bolus once a year.

The panel could reach no consensus on women of childbearing potential with a prevalent fracture who were using less than 7.5 mg/day of glucocorticoids. A lack of consensus was the result of insufficient data to make evidence-based decisions and a disagreement among experts on the correct treatment.

The guidelines do not address the duration of treatment with bisphosphonates, a topic of importance because of concern for the potential long-term side effects of these medications.

THE BOTTOM LINE

The 2010 recommendations add a degree of complexity, with different medications recommended on the basis of glucocorticoid dose and duration as well as patient age, menopausal status, and childbearing potential. Guideline developers and clinicians face a difficult trade-off: easy-to-follow guidelines or more targeted guidelines that are more complex and therefore more difficult to use than previous guidelines.

This criticism is reasonable. The complexity is a result of insufficient evidence from clinical trials to make more exact and user-friendly recommendations, and also a result of the RAND/UCLA methodology. In cases that lack sufficient evidence on which to make a decision, the guideline development uses voting among experts in an attempt to develop consensus. This often results in complexity, lack of consensus, or inconsistencies.

The guidelines are straightforward for postmenopausal women and men age 50 and older on at least 7.5 mg prednisone for more than 3 months.

Since there is substantial evidence that many patients on glucocorticoid therapy go untreated, the risk of fracture in this population would be substantially reduced if clinicians would adhere to the recommendations.

Whenever a patient begins treatment with a glucocorticoid drug, we need to think about bone loss.

The American College of Rheumatology (ACR) issued recommendations for preventing and treating glucocorticoid-induced osteoporosis in 2010.¹ Compared with its previous guidelines,² the new ones are more tailored and nuanced but may be more difficult for physicians to follow. The guidelines call for assessing fracture risk using the computer-based Fracture Risk Assessment Tool, or FRAX (www/shef.ac.uk/FRAX), developed by the World Health Organization (WHO). For those without a computer or ready access to the Web, an application of FRAX is available for download on smartphones.

In this article, my purpose is to review the new recommendations and to offer my perspective, which does not necessarily reflect the opinions of the ACR.

DESPITE EVIDENCE, MANY PATIENTS RECEIVE NO INTERVENTION

Use of glucocorticoids is the most common cause of secondary osteoporosis. During the first 6 to 12 months of use, these drugs can cause a rapid loss of bone mass due to increased bone resorption; with continued use, they cause a slower but steady decline in bone mass due to reduced bone formation.³ Epidemiologic studies have found that the risk of fractures increases with dose, starting with doses as low as 2.5 mg per day of prednisone or its equivalent.⁴

Numerous clinical trials have evaluated the effect of bisphosphonates and teriparatide (Forteo) on bone mass and fracture risk in patients on glucocorticoid therapy. The bisphosphonates alendronate (Fosamax) and risedronate (Actonel) have both been shown to increase bone mass and reduce vertebral fracture risk in glucocorticoid recipients.^5–8 Zoledronic acid (Reclast), a parenteral bisphosphonate given in one annual dose, was shown to increase bone mass more than oral risedronate taken daily,⁹ and teriparatide, a formulation of parathyroid hormone, was better than alendronate.¹⁰

However, despite the known risk of fractures with glucocorticoid use and the demonstrated efficacy of available agents in preventing bone loss and fracture, many patients do not receive any intervention.^11,12

WHAT HAS HAPPENED SINCE 2001?

In the interval since 2001, several guidelines for managing glucocorticoid-induced osteoporosis have been published in other countries.^13–17 Broadly speaking, they recommend starting preventive drug therapy for patients at risk of fracture at the same time glucocorticoid drugs are started if the patient is expected to take glucocorticoids for more than 3 to 6 months in doses higher than 5 to 7.5 mg of prednisone or its equivalent daily.

Recommendations for patients who have been on glucocorticoids for longer than 3 to 6 months at initial evaluation have been based largely on T scores derived from dual-energy x-ray absorptiometry (DXA). Thresholds for initiating therapy have varied: the ACR in 2001 recommended preventive treatment if the T score is lower than −1.0, whereas British guidelines said −1.5 and Dutch guidelines said −2.5.

In the United States, since 2001 when the ACR published its last guidelines,² zoledronic acid and teriparatide have been approved for use in glucocorticoid-induced osteoporosis. In addition, guideline-development methodology has evolved and now is more scientifically rigorous. Finally, a risk-assessment tool has been developed that enables a more tailored approach (see below).

FRAX (www.shef.ac.uk/FRAX)

FRAX is a tool developed by the WHO to calculate the risk of fracture. If you go to the FRAX Web site and enter the required clinical information (race, age, sex, weight, height, previous fracture, family history of a fractured hip in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, consumption of three or more units of alcohol per day, and bone mineral density of the femoral neck), it will tell you the patient’s 10-year absolute (not relative) risk of major osteoporotic fracture and of hip fracture.

Since FRAX was unveiled in 2008, calculation of absolute fracture risk has become the standard method for making treatment decisions in patients with low bone mass who have not yet received any fracture-preventing treatment.¹⁸ The use of clinical risk factors in FRAX increases its ability to predict risk over and above the use of bone density by itself. And glucocorticoids are one of the clinical risk factors in FRAX.

But in which patients is treatment with a bisphosphonate or teriparatide cost-effective?

Thresholds for cost-effectiveness have been developed on the basis of economic assumptions that are country-specific. In the United States, the National Osteoporosis Foundation recommends drug therapy if the 10-year absolute risk of a major osteoporotic fracture of the hip, spine (clinical, not radiographic), wrist, or humerus is greater than 20% or if the risk of a hip fracture is greater than 3%.¹⁹

At equivalent bone densities, women taking glucocorticoids are at considerably higher risk of fracture than nonusers.²⁰ For example, consider a 65-year-old white woman, weight 59 kg, height 163 cm, no previous fractures, no parent with a fractured hip, no current smoking, no rheumatoid arthritis, no secondary osteoporosis, no excessive alcohol use, and a T score of −2.2 in the femoral neck. (Try this on the FRAX Web site.) If she does not use glucocorticoids, her 10-year risk of hip fracture is 2.0%; using glucocorticoids increases the risk to 3.6%. This is higher than the 3% National Osteoporosis Foundation guideline; thus, treatment would be recommended.

Also using FRAX, a 55-year-old white woman with a T score of −1.8 and on glucocorticoid therapy has a 67% higher risk of major osteoporotic fracture and an 80% higher risk of hip fracture.

For a third example, a white woman age 60, weight 70 kg, height 168 cm, negative for all the other risk factors but with a T score of −2.1 and on glucocorticoids has a calculated 10-year fracture risk of 2.1%, which is below the National Osteoporosis Foundation treatment threshold. However, most clinicians would probably recommend treatment for her, depending on the anticipated dose and duration of glucocorticoid therapy.

A caveat. In FRAX, glucocorticoid therapy is a categorical variable—a yes-or-no question—and yes is defined as having ever used a glucocorticoid in a dose greater than 5 mg for more than 3 months. Therefore, according to FRAX, a patient who took 5 mg of prednisone for 3 months 5 years ago has the same fracture risk as a patient on 60 mg of prednisone after a diagnosis of temporal arteritis. For this reason, the FRAX tool is likely to underestimate fracture risk, especially in patients currently taking glucocorticoids and those on higher doses of these drugs.

Kanis et al used the General Practice Research Database to adjust the fracture risk for glucocorticoid use in FRAX.²¹ At doses higher than 7.5 mg, the fracture risk had to be revised upward by 10% to 25% depending on the fracture site (hip vs any major osteoporotic fracture) and age (greater at age 40 than at age 90).

The underestimation of fracture risk led the ACR Expert Advisory Panel to create risk strata for major osteoporotic fractures, ie, low (< 10% risk per 10 years), medium (10%–20%), and high (> 20%) and uses these cut points to make treatment recommendations.

HOW THE 2010 GUIDELINES WERE DEVELOPED

Whereas the 2001 recommendations were based on a more informal consensus approach, the 2010 recommendations use a more scientifically rigorous methodology for guideline development, the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness Method. The RAND/UCLA method combines the best available scientific evidence with expert opinion to develop practice guidelines.

In drawing up the 2010 recommendations the ACR used three panels of experts. The Core Executive Panel conducted a systematic review of controlled clinical trials of therapies currently approved for treating glucocorticoid-induced osteoporosis in the United States, Canada, or the European Union. They found 53 articles meeting their inclusion criteria; an evidence report was produced that informed the development of the recommendations. This evidence report and guideline development process is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658. The Expert Advisory Panel framed the recommendations, and the Task Force Panel voted on them. The Core Executive Panel and Expert Advisory Panel constructed 48 patient-specific clinical scenarios using four variables: sex, age, race/ethnicity, and femoral neck T scores.

The members of the Task Force Panel were asked to use the evidence report and their expert judgment to vote on and rate the appropriateness of using a specific therapy in the context of each scenario on a 9-point Likert scale (1 = appropriate; 9 = not appropriate). Agreement occurred when 7 or more of the 10 panel members rated a scenario 1, 2, or 3. Disagreements were defined as 3 or more of the 10 members rating the scenario between 4 and 9 while the other members rated it lower.

Disagreements in voting were discussed in an attempt to achieve consensus, and a second vote was conducted which determined the final recommendations. If disagreement remained after the vote, no recommendation was made.

No attempt was made to assign priority of one drug over another when multiple drugs were deemed appropriate, although the final recommendations did differentiate drugs based on patient categories.

START WITH COUNSELING, ASSESSMENT

For patients starting or already on glucocorticoid therapy that is expected to last at least 3 months, the first step is to counsel them on lifestyle modifications (Table 1) and to assess their risk factors (Figure 1). Recommendations for monitoring patients receiving glucocorticoid therapy for at least 3 months are presented in Table 2.

These recommendations are based on literature review, and the strength of evidence is graded:

• Grade A—derived from multiple randomized controlled trials or a meta-analysis
• Grade B—derived from a single randomized controlled trial or nonrandomized study
• Grade C—derived from consensus, expert opinion, or case series.

This system is the same one used by the American College of Cardiology and is based on clinical trial data.²²

Recommendations for calcium intake and vitamin D supplementation were graded A; all other recommendations were graded C (Tables 1 and 2). It is important to note that practices that receive a grade of C may still be accepted as standard of care, such as fall assessment and smoking cessation.

FOR POSTMENOPAUSAL WOMEN AND FOR MEN AGE 50 AND OLDER

FRAX low-risk group

Recall that “low risk” based on the new ACR guidelines means that the 10-year absolute risk of a major osteoporotic fracture, as calculated with FRAX, is less than 10%.

• If glucocorticoid use is expected to last or has already lasted at least 3 months and the dose is less than 7.5 mg/day, no pharmacologic treatment is recommended.
• If glucocorticoid use is expected to last or has already lasted at least 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended.

Comment. These are the most straightforward of the recommendations. All three bisphosphonates are recommended as treatment options if the glucocorticoid dose is at least 7.5 mg/day and the duration at least 3 months. Ibandronate (Boniva) was not included because it has no data from clinical trials.

“Medium risk” means that the 10-year absolute fracture risk of major osteoporotic fractures is 10% to 20%.

• If glucocorticoid use is anticipated to last or has lasted at least 3 months and the dose is less than 7.5 mg/day, alendronate or risedronate is recommended.
• If glucocorticoid use is anticipated to last or has lasted at least 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended.

Comment. Treatment is recommended at all glucocorticoid doses for patients in the medium-risk category if the duration of glucocorticoid treatment is at least 3 months, with one difference: zoledronic acid is recommended only if the glucocorticoid dose is 7.5 mg/day or higher. This inconsistency persisted after a second round of voting by the Task Force Panel.

FRAX high-risk group

In this group, the 10-year risk of major osteoporotic fractures is higher than 20%.

• If the glucocorticoid dose is less than 5 mg/day for up to 1 month, alendronate, risedronate, or zoledronic acid is recommended.
• If the dose is 5 mg/day or more for up to 1 month, or any dose for more than 1 month, alendronate, risedronate, zoledronic acid or teriparatide is recommended.

Comment. Based on current National Osteoporosis Foundation guidelines, all patients with a 10-year risk greater than 20% are recommended for treatment for any duration and dose of glucocorticoid use. However, teriparatide is recommended only if the duration of glucocorticoid therapy is more than 1 month.

FOR PREMENOPAUSAL WOMEN AND FOR MEN YOUNGER THAN AGE 50

Use of FRAX is not appropriate in premenopausal women or in men younger than 50 years.

Younger patients with no prevalent fracture

For men younger than 50 and premenopausal women who have not had a previous fracture, data were considered inadequate to make a recommendation, and no votes were taken.

Prevalent fracture in premenopausal women of nonchildbearing potential

In premenopausal women of nonchildbearing potential who have had a fracture:

• If the glucocorticoid duration is 1 to 3 months and the dose is 5 mg/day or higher, alendronate or risedronate is recommended.
• If the duration is 1 to 3 months and the dose is 7.5 mg/day or higher, alendronate, risedronate, or zoledronic acid is recommended
• If the duration is more than 3 months, alendronate, risedronate, zoledronic acid, or teriparatide is recommended.

Comment. Treatment is recommended with any of the four medications in patients with a fracture and treated with glucocorticoids for more than 3 months. For shorter-duration glucocorticoid use (1–3 months) at 5 mg/day or higher, only alendronate and risedronate are recommended. If the dose is 7.5 mg/day or higher, any bisphosphonate is recommended. Zoledronic acid was consistently differentiated by the expert panel on the basis of dose and duration of glucocorticoid use, in view of its 1-year duration of effect after one dose.

Prevalent fracture in women of childbearing potential

• If the glucocorticoid duration is 1 to 3 months, there was no consensus (ie, voting disagreements could not be resolved).
• If the glucocorticoid duration is more than 3 months and the dose is 7.5 mg/day or more, alendronate, risedronate, or teriparatide is recommended.
• If the glucocorticoid duration is more than 3 months and the dose is less than 7.5 mg/day, there was no consensus.

Comment. Childbearing potential creates further complexities because of concern about fetal toxicity with bisphosphonates. For short-term glucocorticoid therapy at any dose and for therapy longer than 3 months at less than 7.5 mg, no consensus could be reached. For therapy longer than 3 months and with 7.5 mg/day or higher, treatment is recommended but not with zoledronic acid, based on the long half-life of the drug and concern for fetal toxicity.

Additional risk stratification

The panel recommended that if the following were present, a shift to a higher fracture risk category should be considered (low to medium, or medium to high):

• High daily dose of glucocorticoid
• High cumulative glucocorticoid dose
• Declining bone mineral density on serial DXA.

These are known risk factors that increase fracture risk but would not affect fracture risk in the FRAX model.

WHAT IS NEW IN THE 2010 RECOMMENDATIONS?

Recommendations for counseling now include fall risk assessment, height measurement, 25-hydroxyvitamin D measurement, and evaluation of patients for prevalent and incident fractures using vertebral fracture assessment by DXA or radiographic imaging of the spine.

Recommended drugs now include teriparatide and zoledronic acid, while estrogen and testosterone are no longer recommended as therapies for glucocorticoid-induced osteoporosis. Ibandronate is not included, since there have been no randomized controlled trials of this bisphosphonate in glucocorticoid-induced osteoporosis.

Recommendations for treatment in 2001 were based on T scores alone, while the 2010 recommendations use an assessment of absolute fracture risk based on FRAX for postmenopausal women and for men age 50 and older.

A clinician’s guide that summarizes the ACR recommendations is available at www.rheumatology.org/practice/clinical/guidelines/.

RECOMMENDATIONS DO NOT REPLACE CLINICAL JUDGMENT

Although the 2010 recommendations were more rigorous in their development process than those of 2001, they have limitations and they should not replace clinical judgment. Rather, they are intended to provide an evidence-based approach to guide clinicians in making treatment choices in patients on glucocorticoid therapy.

CONSIDERING ABSOLUTE FRACTURE RISK IN TREATMENT DECISIONS

The 2001 ACR guidelines recommended fracture-preventing treatment in all patients starting glucocorticoid therapy at more than 5 mg/day if the planned duration of treatment was at least 3 months, and in patients on long-term glucocorticoid therapy if the T score was less than −1.0. While these guidelines were simple and easy to use, they were not specific enough to provide useful guidance in specific scenarios.

A model of absolute fracture risk was not available in 2001. A 55-year old white woman with a T score of −1.1 who smoked, who had been using 5 mg of prednisone for the last 12 months, and who had stable bone mass on serial DXA scans would have been recommended for treatment based on the 2001 recommendations. If this patient’s FRAX-calculated 10-year absolute risk of a major osteoporotic fracture is less than 10%, that would be well below the National Osteoporosis Foundation’s cost-effective treatment threshold of 20%. The new guidelines suggest no treatment is needed, since the risk category is low and the dose is less than 7.5 mg. However, if on serial DXA this patient had a significant decline in bone mass, the guidelines suggest shifting the patient to a higher risk category, ie, from low to medium risk, which would result in a recommendation in favor of treatment.

The 2010 recommendations are not as simple to use as those from 2001. They encourage using FRAX to calculate fracture risk; thus, knowledge of the strengths and limitations of FRAX is required. Access to the internet in the examination room or use of the FRAX tool on a smartphone as well as willingness to spend a minute to calculate fracture risk are needed. For those who cannot or choose not to use the FRAX tool, the ACR publication provides tables for patient risk assessment based on age and T score. However, the tables would have to be readily available in the clinic, which may not be practical.

The 2010 recommendation provide a more nuanced approach to treatment in patients on glucocorticoid therapy and are likely to change treatment decisions based on their use, just as FRAX has altered treatment decisions in patients with primary osteoporosis.²³

FRAX has limitations

FRAX underestimates the effect of glucocorticoids on fracture risk because steroid use is a yes-or-no question and its weight represents the average risk in a population that has ever used steroids, most of whom were using doses between 2.5 and 7.5 mg.

The WHO recognized this limitation and suggested an upward adjustment of risk for patients on 7.5 mg or more, ranging from 10% to 25%.²¹ For patients on high doses of steroids, this adjustment is still likely to result in underestimation of fracture risk and undertreatment of glucocorticoid-treated patients.

The 2010 recommendations adjust for this limitation, recommending treatment in the low-risk and medium-risk categories if the glucocorticoid dose is 7.5 mg or higher. If a patient is using high daily doses of steroids or has a declining bone density, the 2010 recommendations suggest increasing the risk category from low to medium or medium to high.

FRAX risk factors are dichotomous (yes/no) and are not adjusted for dose effects such as multiple fractures (vs a single fracture), heavy smoking (vs light smoking), heavy alcohol use (6 units per day vs 3 units), or severe rheumatoid arthritis (vs mild disease). Family history of osteoporosis in the FRAX is limited to parents with a hip fracture—vertebral fractures in a family member do not count.

Since FRAX uses the bone mineral density in the hip, it underestimates fracture risk in patients with low spine density but normal hip density. It may also underestimate fracture risk in patients with declining bone mass; the 2010 recommendations suggest the clinician should increase the risk category in this situation.

LIMITATIONS OF THE GUIDELINES

The 2010 recommendations do not include several important groups in which steroids are used, including transplant recipients, children, and patients on inhaled corticosteroids. The panel thought that there were insufficient data to make recommendations for these populations, as well as for premenopausal women and men younger than 50 years who did not have a prevalent fracture. The absence of a recommendation in these situations should not be considered a recommendation for no treatment; it is an acknowledgment of a lack of evidence, a lack of consensus among experts, and the need for additional clinical trials.

For premenopausal women and men under age 50 with a fracture, the recommendations are complicated and not intuitive. Zoledronic acid is not recommended for women of non-childbearing potential with a glucocorticoid duration of 1 to 3 months unless the steroid dose is at least 7.5 mg. This recommendation was based on panel voting and consensus that giving zoledronic acid, a medication with a 1-year duration of effect, in a patient on steroids for only 1 to 3 months was not warranted.

Teriparatide was recommended only if glucocorticoids are used for at least 3 months, although anyone who already has a fracture might be considered at high enough risk to warrant anabolic therapy regardless of steroid use or duration.

Zoledronic acid was excluded in women of childbearing potential, based on panel voting and consensus that drugs given in smaller amounts over 1 year might be less harmful to a fetus than one with a longer half-life given in a larger bolus once a year.

The panel could reach no consensus on women of childbearing potential with a prevalent fracture who were using less than 7.5 mg/day of glucocorticoids. A lack of consensus was the result of insufficient data to make evidence-based decisions and a disagreement among experts on the correct treatment.

The guidelines do not address the duration of treatment with bisphosphonates, a topic of importance because of concern for the potential long-term side effects of these medications.

THE BOTTOM LINE

The 2010 recommendations add a degree of complexity, with different medications recommended on the basis of glucocorticoid dose and duration as well as patient age, menopausal status, and childbearing potential. Guideline developers and clinicians face a difficult trade-off: easy-to-follow guidelines or more targeted guidelines that are more complex and therefore more difficult to use than previous guidelines.

This criticism is reasonable. The complexity is a result of insufficient evidence from clinical trials to make more exact and user-friendly recommendations, and also a result of the RAND/UCLA methodology. In cases that lack sufficient evidence on which to make a decision, the guideline development uses voting among experts in an attempt to develop consensus. This often results in complexity, lack of consensus, or inconsistencies.

The guidelines are straightforward for postmenopausal women and men age 50 and older on at least 7.5 mg prednisone for more than 3 months.

Since there is substantial evidence that many patients on glucocorticoid therapy go untreated, the risk of fracture in this population would be substantially reduced if clinicians would adhere to the recommendations.

Cardiac tamponade is a life-threatening condition that can be palliated or cured, depending on its cause and on the timeliness of treatment. Making a timely diagnosis and providing the appropriate treatment can be gratifying for both patient and physician.

Cardiac tamponade occurs when fluid in the pericardial space reaches a pressure exceeding central venous pressure. This leads to jugular venous distention, visceral organ engorgement, edema, and elevated pulmonary venous pressure that causes dyspnea. Despite compensatory tachycardia, the decrease in cardiac filling leads to a fall in cardiac output and to arterial hypoperfusion of vital organs.

PEARL 1: SLOW ACCUMULATION LEADS TO EDEMA

The rate at which pericardial fluid accumulates influences the clinical presentation of cardiac tamponade, in particular whether or not there is edema. Whereas rapid accumulation is characterized more by hypotension than by edema, the slow accumulation of pericardial fluid affords the patient time to drink enough liquid to keep the central venous pressure higher than the rising pericardial pressure. Thus, edema and dyspnea are more prominent features of cardiac tamponade when there is a slow rise in pericardial pressure.

PEARL 2: EDEMA IS NOT ALWAYS TREATED WITH A DIURETIC

Edema is not always treated with a diuretic. In a patient who has a pericardial effusion that has developed slowly and who has been drinking enough fluid to keep the central venous pressure higher than the pericardial pressure, a diuretic can remove enough volume from the circulation to lower the central venous pressure below the intrapericardial pressure and thus convert a benign pericardial effusion to potentially lethal cardiac tamponade.

One must understand the cause of edema or low urine output before treating it. This underscores the importance of the history and the physical examination. All of the following must be assessed:

• Symptoms and time course of the illness
• Concurrent medical illnesses
• Neck veins
• Blood pressure and its response to inspiration
• Heart sounds
• Heart rate and rhythm
• Abdominal organ engorgement
• Edema (or its absence).

PEARL 3: UNDERSTANDING THE CAUSE IS ESSENTIAL

Understanding the cause of cardiac tamponade is essential.

A trauma patient first encountered in the emergency department may have an underlying disease, but the focus is squarely on the effects of trauma or violent injury. In a patient with multiple trauma, hypotension and tachycardia that do not respond to intravenous volume replacement when there is an obvious rise in central venous pressure should be clues to cardiac tamponade.¹

If the patient has recently undergone a cardiac procedure (for example, cardiac surgery, myocardial biopsy, coronary intervention, electrophysiologic study with intracardiac electrodes, transvenous pacemaker placement, pacemaker lead extraction, or radiofrequency ablation), knowing about the procedure narrows the differential diagnosis when hypotension, tachycardia, and jugular venous distention develop.

PEARL 4: CARDIAC OR AORTIC RUPTURE REQUIRES SURGERY

When the etiology of cardiac tamponade is cardiac or aortic rupture, the treatment is surgical.

Painful sudden causes of cardiac tamponade include hemopericardium due to rupture of the free wall after myocardial infarction, and spontaneous or posttraumatic dissection and rupture of the ascending aorta. Prompt diagnosis is necessary, but since these lesions will not close and heal spontaneously, the definitive treatment should be surgery. Moreover, needle removal of intrapericardial blood that has been opposing further bleeding is sure to permit bleeding to recur, often with lethal consequences.²

Causes of cardiac tamponade that have a less-acute onset are likely to be complications of medical problems. Medical illnesses known to be associated with cardiac tamponade include:

• Infectious disease (idiopathic or viral, associated with smallpox vaccination, mycobacterial, purulent bacterial, fungal)
• Metastatic cancer (lung, breast, esophagus, lymphoma, pancreas, liver, leukemia, stomach, melanoma)³
• Connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, Wegener granulomatosis, acute rheumatic fever)
• Endocrine disease (hypothyroidism)
• Drug side effects (procainamide, isoniazid, hydralazine, minoxidil, phenytoin, anticoagulants, methysergide)
• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Congestive heart failure
• Uremia
• Radiation therapy
• Postmyocardial infarction syndrome (Dressler syndrome)
• Postpericardiotomy syndrome.

PEARL 5: REVIEW IMAGING BEFORE DIAGNOSING

What often brings a patient with cardiac tamponade to the attention of the physician is a finding on echocardiography, computed tomography, or magnetic resonance imaging of the chest.

Always review the imaging studies before making the diagnosis of cardiac tamponade. These tests must be reviewed to assess the anatomy and the size and location of the effusion. Particularly, one must look for atrial and right ventricular collapse and inferior vena caval plethora, which are echocardiographic signs of cardiac tamponade.⁴ Figures 1, 2, and 3 show imaging studies in a patient who presented with worsening cough 2 weeks after undergoing a cardiac procedure and who was found to have cardiac tamponade.

When the history and these imaging studies place cardiac tamponade high in the differential diagnosis as the cause of edema or dyspnea, it is time to reexamine the patient. The best first step is to measure pulsus paradoxus.

HOW PULSUS PARADOXUS OCCURS

To fully appreciate the subtleties of the next pearls, it is necessary to understand the pathophysiology of cardiac tamponade.

When pericardial fluid accumulation raises the pericardial pressure above the central venous pressure and pulmonary venous pressure (intravascular pressure), blood will not passively return to the right side of the heart from the venae cavae nor to the left side of the heart from the pulmonary veins unless it is influenced by the effects of respiration on intrathoracic pressure. During respiration, the right and left sides of the heart are alternately filled and deprived of their respective venous return.

During inspiration, as the intrathoracic pressure decreases, blood in the venae cavae empties into the right side of the heart, while blood in the pulmonary veins preferentially remains in the pulmonary veins, underfilling the left side of the heart. Since the right ventricle is more filled than the left ventricle during inspiration, the ventricular septum shifts from right to left, further opposing pulmonary venous return. As a result, during cardiac tamponade, the systemic blood pressure falls with inspiration.

During expiration the opposite occurs. Expiration decreases the intrathoracic volume, so the intrathoracic pressure rises. This tends to oppose vena caval return to the right side of the heart and to favor pulmonary venous return to the left side of the heart. The ventricular septum shifts from left to right, further accommodating left ventricular filling, raising stroke volume, and increasing blood pressure. This exaggerated alternate filling of the right and left sides of the heart during cardiac tamponade is what accounts for pulsus paradoxus, an inspiratory fall in systolic blood pressure of greater than 10 mm Hg.

If intravascular pressure is low (due to hemorrhage, dehydration, or diuretic therapy), the pressure in the pericardial space needed to oppose venous return is much less. In this low-pressure scenario, the results are low cardiac output and hypotension, which are treated by giving intravenous fluids to maintain intravascular volume.

PEARL 6: MEASURE PULSUS PARADOXUS

When cardiac tamponade is considered, one must always measure the pulsus paradoxus.

The term pulsus paradoxus was coined by Adolph Kussmaul in 1873, before physicians could even measure blood pressure. All they could do at that time was palpate the pulse and listen to the heart. Kussmaul described his observation as a conspicuous discrepancy between the cardiac action and the arterial pulse.

Although not described by Kussmaul, another explanation for this finding might be more suited to the use of the word “paradoxical.” When the pulse is palpated in a normal patient, with inspiration the pulse rate will increase via the Bainbridge reflex, and with expiration it will decrease. But in a patient with cardiac tamponade, there is a paradoxical inspiratory slowing of the pulse (because the decreased magnitude of the pulse at times makes it imperceptible) and an expiratory increase in pulse rate as the magnitude of the pulse again makes it palpable.

The magnitude of the fall in systolic blood pressure during inspiration has been used to estimate the level of hemodynamic impairment resulting from pericardial effusion.⁵ A rapidly accumulating pericardial effusion can have more hemodynamic impact than a much larger one that accumulates slowly. Thus, the intrapericardial pressure must be considered more than the volume of pericardial fluid.

When there is severe cardiac tamponade and overt pulsus paradoxus, simple palpation of a proximal arterial pulse can detect a marked inspiratory decrease or loss of the pulse, which returns with expiration. Tachycardia is almost always present, unless the cause is hypothyroidism.⁶

How to measure pulsus paradoxus with a manual sphygmomanometer

A stethoscope and manual sphygmomanometer are all that is needed to measure pulsus paradoxus. A noninvasive blood pressure monitor that averages multiple measurements cannot detect or quantify pulsus paradoxus.

The patient should be supine with the head elevated 30° to 45°, and the examiner should be seated comfortably at the patient’s side. The manometer should be on the opposite side of the patient in plain view of the examiner. Position the cuff on the arm above the elbow and place your stethoscope on the antecubital fossa. Then:

• Inflate the cuff 20 mm Hg above the highest systolic pressure previously auscultated.
• Slowly decrease the manometer pressure by 5 mm Hg and hold it there through two or three respiratory cycles while listening for the first Korotkoff (systolic) sound. Repeat this until you can hear the systolic sound (but only during expiration) and mentally note the pressure.
• Continue to decrease the manometer pressure by 5-mm Hg increments while listening. When the Korotkoff sounds no longer disappear with inspiration, mentally note this second value as well. The pulsus paradoxus is the difference between these values.
• When the Korotkoff sounds disappear as the manometer pressure is decreased, note this final value. This is the diastolic blood pressure.

PEARL 7: THE PLETHYSMOGRAM WAVE-FORM PARALLELS PULSUS PARADOXUS

Manual measurement of blood pressure and pulsus paradoxus can be difficult, especially in an obese patient or one with a fat-distorted arm on which the cuff does not maintain its position. In such patients, increased girth of the neck and abdomen also make it difficult to assess the jugular venous distention and visceral organ engorgement that characterize cardiac tamponade.

When the use of a sphygmomanometer is not possible, an arterial catheter can be inserted to demonstrate pulsus paradoxus. Simpler, however, is the novel use of another noninvasive instrument to detect and coarsely quantify pulsus paradoxus.⁷ The waveform on finger pulse oximetry can demonstrate pulsus paradoxus. The plethysmogram of the finger pulse oximeter can demonstrate the decrease in magnitude of the waveform with each inspiration (Figure 4).

Caution must be taken when interpreting this waveform, as with any measurement of pulsus paradoxus, to exclude a concomitant arrhythmia.

PEARL 8: PULSUS PARADOXUS WITHOUT CARDIAC TAMPONADE

Pulsus paradoxus can be present in the absence of cardiac tamponade. Once pulsus paradoxus of more than 10 mm Hg is measured, one must be sure the patient does not have a condition that can cause pulsus paradoxus without cardiac tamponade. Most of these are pulmonary conditions that necessitate an exaggerated inspiratory effort that can lower intrathoracic pressure sufficiently to oppose pulmonary venous return and cause a fall in systemic blood pressure:

• Chronic bronchitis
• Emphysema
• Mucus plug
• Pneumothorax
• Pulmonary embolism
• Stridor.

In these, there may be pulsus paradoxus, but not due to cardiac tamponade.

PEARL 9: CARDIAC TAMPONADE CAN BE PRESENT WITHOUT PULSUS PARADOXUS

Cardiac tamponade can be present without pulsus paradoxus. This occurs when certain conditions prevent inspiratory underfilling of the left ventricle relative to the filling of the right ventricle.⁸

How does this work? In cardiac tamponade, factors that drive the exaggerated fall in arterial pressure with inspiration (pulsus paradoxus) are the augmented right ventricular filling and the decreased left ventricular filling, both due to the lowering of the intrathoracic pressure. As the vena caval emptying is augmented, the right ventricular filling is increased, the ventricular septum shifts to the left, and pulmonary venous return to the heart is decreased.

Factors that can oppose pulsus paradoxus:

• Positive pressure ventilation prevents pulsus paradoxus by preventing the fall in intrathoracic pressure.
• Severe aortic regurgitation does not permit underfilling of the left ventricle during inspiration.
• An atrial septal defect will always equalize the right and left atrial pressures, preventing differential right ventricular and left ventricular filling with inspiration.
• Severe left ventricular hypertrophy does not permit the inspiratory shift of the ventricular septum from right to left that would otherwise lead to decreased left ventricular filling.
• Severe left ventricular dysfunction, with its low stroke volume and severe elevation of left ventricular end-diastolic pressure, never permits underfilling of the left ventricle, despite cardiac tamponade and an inspiratory decrease in intrathoracic pressure.
• Intravascular volume depletion due to hemorrhage, hemodialysis, or mistaken use of diuretics to treat edema can cause marked hypotension, making pulsus paradoxus impossible to detect.

Knowledge of underlying medical conditions, the likelihood of their causing cardiac tamponade, and the appearance of the echocardiogram prompt the physician to look further when the presence or absence of pulsus paradoxus does not fit with the working diagnosis.

The echocardiogram can give hints to the etiology of a pericardial effusion, such as clotted blood after trauma or a cardiac-perforating procedure, tumor studding of the epicardium,⁹ or fibrin strands indicating chronicity or an inflammatory process.¹⁰ Diastolic collapse of the right ventricle, more than collapse of the right atrium or left atrium, speaks for the severity of cardiac tamponade. With hemodynamically significant pericardial effusion and cardiac tamponade, the inferior vena cava is distended and does not decrease in size with inspiration unless there is severe intravascular volume depletion, at which time the inferior vena cava is underfilled throughout the respiratory cycle.

PEARL 10: PLAN HOW TO DRAIN

The size and location of the pericardial effusion and the patient’s hemodynamics must be integrated when deciding how to relieve cardiac tamponade. When cardiac tamponade is indeed severe and the patient and physician agree that it must be drained, the options are percutaneous needle aspiration (pericardiocentesis) and surgical pericardiostomy (creation of a pericardial window). Here again, as assessed by echocardiography, the access to the pericardial fluid should influence the choice.

Pericardiocentesis can be safely done if certain criteria are met. The patient must be able to lie still in the supine position, perhaps with the head of the bed elevated 30 degrees. Anticoagulation must be reversed or allowed time to resolve if drainage is not an emergency.

Pericardiocentesis can be risky or unsuccessful if there is not enough pericardial fluid to permit respiratory cardiac motion without perforating the heart with the needle; if the effusion is loculated (confined to a pocket) posteriorly; or if it is too far from the skin to permit precise control and placement of a spinal needle into the pericardial space. In cases of cardiac tamponade in which the anatomy indicates surgical pericardiostomy but severe hypotension prevents the induction of anesthesia and positive-pressure ventilation—which can result in profound, irreversible hypotension—percutaneous needle drainage (pericardiocentesis) should be performed in the operating room to relieve the tamponade before the induction of anesthesia and the surgical drainage.¹¹

To reiterate, a suspected cardiac or aortic rupture that causes cardiac tamponade is usually large and not apt to self-seal. In such cases, the halt in the accumulation of pericardial blood is due to hypotension and not due to spontaneous resolution. Open surgical drainage is required from the outset because an initial success of pericardiocentesis yields to the recurrence of cardiac tamponade.

PEARL 11: ANTICIPATE WHAT THE FLUID SHOULD LOOK LIKE

Before performing pericardiocentesis, anticipate the appearance of the pericardial fluid on the basis of the presumed etiology, ie:

• Sanguinous—trauma, heart surgery, cardiac perforation from a procedure, anticoagulation, uremia, or malignancy
• Serous—congestive heart failure, acute radiation therapy
• Purulent—infections (natural or postoperative)
• Turbid (like gold paint)—mycobacterial infection, rheumatoid arthritis, myxedema
• Chylous—pericardium fistulized to the thoracic duct by a natural or postsurgical cause.

Sanguinous pericardial effusion encountered during a pericardiocentesis, if not anticipated, can be daunting and can cause the operator to question if it is the result of inadvertent needle placement in a cardiac chamber. If the needle is indeed in the heart, blood often surges out under pressure in pulses, which strongly suggests that the needle is not in the pericardial space and should be removed; but if confirmation of the location is needed before removing the needle, it can be done by injecting 2 mL of agitated sterile saline through the pericardiocentesis needle during echocardiographic imaging.¹²

Before inserting the needle, the ideal access location and needle angle must be determined by the operator with echocardiographic transducer in hand. The distance from skin to a point just through the parietal pericardium can also be measured at this time.

Once the needle is in the pericardial fluid (and you are confident of its placement), removal of 50 to 100 mL of the fluid with a large syringe can be enough to afford the patient easier breathing, higher blood pressure, and lower pulsus paradoxus—and even the physician will breathe easier. The same syringe can be filled and emptied multiple times. Less traumatic and more complete removal of pericardial fluid requires insertion of a multihole pigtail catheter over a J-tipped guidewire that is introduced through the needle.

PEARL 12: DRAIN SLOWLY TO AVOID PULMONARY EDEMA

Pulmonary edema is an uncommon complication of pericardiocentesis that might be avoidable. Heralded by sudden coughing and pink, frothy sputum, it can rapidly deteriorate into respiratory failure. The mechanism has been attributed to a sudden increase in right ventricular stroke volume and resultant left ventricular filling after the excess pericardial fluid has been removed, before the systemic arteries, which constrict to keep the systemic blood pressure up during cardiac tamponade, have had time to relax.¹³

To avoid this complication, if the volume of pericardial fluid responsible for cardiac tamponade is large, it should be removed slowly,¹⁴ stopping for a several-minute rest after each 250 mL. Catheter removal of pericardial fluid by gravity drainage over 24 hours has been suggested.¹⁵ A drawback to this approach is catheter clotting or sludging before all the fluid has been removed. It is helpful to keep the drainage catheter close to the patient’s body temperature to make the fluid less viscous. Output should be monitored hourly.

When the pericardial fluid has been completely drained, one must decide how long to leave the catheter in. One reason to remove the catheter at this time is that it causes pleuritic pain; another is to avoid introducing infection. A reason to leave the catheter in is to observe the effect of medical treatment on the hourly pericardial fluid output. Nonsteroidal anti-inflammatory drugs are the drugs of first choice when treating pericardial inflammation and suppressing production of pericardial fluid.¹⁶ In most cases the catheter should not be left in place for more than 3 days.

Laboratory analysis of the pericardial fluid should shed light on its suspected cause. Analysis usually involves chemistry testing, microscopic inspection of blood cell smears, cytology, microbiologic stains and cultures, and immunologic tests. Results often take days. Meyers and colleagues¹⁷ expound on this subject.

Cardiac tamponade is a life-threatening condition that can be palliated or cured, depending on its cause and on the timeliness of treatment. Making a timely diagnosis and providing the appropriate treatment can be gratifying for both patient and physician.

Cardiac tamponade occurs when fluid in the pericardial space reaches a pressure exceeding central venous pressure. This leads to jugular venous distention, visceral organ engorgement, edema, and elevated pulmonary venous pressure that causes dyspnea. Despite compensatory tachycardia, the decrease in cardiac filling leads to a fall in cardiac output and to arterial hypoperfusion of vital organs.

PEARL 1: SLOW ACCUMULATION LEADS TO EDEMA

The rate at which pericardial fluid accumulates influences the clinical presentation of cardiac tamponade, in particular whether or not there is edema. Whereas rapid accumulation is characterized more by hypotension than by edema, the slow accumulation of pericardial fluid affords the patient time to drink enough liquid to keep the central venous pressure higher than the rising pericardial pressure. Thus, edema and dyspnea are more prominent features of cardiac tamponade when there is a slow rise in pericardial pressure.

PEARL 2: EDEMA IS NOT ALWAYS TREATED WITH A DIURETIC

Edema is not always treated with a diuretic. In a patient who has a pericardial effusion that has developed slowly and who has been drinking enough fluid to keep the central venous pressure higher than the pericardial pressure, a diuretic can remove enough volume from the circulation to lower the central venous pressure below the intrapericardial pressure and thus convert a benign pericardial effusion to potentially lethal cardiac tamponade.

One must understand the cause of edema or low urine output before treating it. This underscores the importance of the history and the physical examination. All of the following must be assessed:

• Symptoms and time course of the illness
• Concurrent medical illnesses
• Neck veins
• Blood pressure and its response to inspiration
• Heart sounds
• Heart rate and rhythm
• Abdominal organ engorgement
• Edema (or its absence).

PEARL 3: UNDERSTANDING THE CAUSE IS ESSENTIAL

Understanding the cause of cardiac tamponade is essential.

A trauma patient first encountered in the emergency department may have an underlying disease, but the focus is squarely on the effects of trauma or violent injury. In a patient with multiple trauma, hypotension and tachycardia that do not respond to intravenous volume replacement when there is an obvious rise in central venous pressure should be clues to cardiac tamponade.¹

If the patient has recently undergone a cardiac procedure (for example, cardiac surgery, myocardial biopsy, coronary intervention, electrophysiologic study with intracardiac electrodes, transvenous pacemaker placement, pacemaker lead extraction, or radiofrequency ablation), knowing about the procedure narrows the differential diagnosis when hypotension, tachycardia, and jugular venous distention develop.

PEARL 4: CARDIAC OR AORTIC RUPTURE REQUIRES SURGERY

When the etiology of cardiac tamponade is cardiac or aortic rupture, the treatment is surgical.

Painful sudden causes of cardiac tamponade include hemopericardium due to rupture of the free wall after myocardial infarction, and spontaneous or posttraumatic dissection and rupture of the ascending aorta. Prompt diagnosis is necessary, but since these lesions will not close and heal spontaneously, the definitive treatment should be surgery. Moreover, needle removal of intrapericardial blood that has been opposing further bleeding is sure to permit bleeding to recur, often with lethal consequences.²

Causes of cardiac tamponade that have a less-acute onset are likely to be complications of medical problems. Medical illnesses known to be associated with cardiac tamponade include:

• Infectious disease (idiopathic or viral, associated with smallpox vaccination, mycobacterial, purulent bacterial, fungal)
• Metastatic cancer (lung, breast, esophagus, lymphoma, pancreas, liver, leukemia, stomach, melanoma)³
• Connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, Wegener granulomatosis, acute rheumatic fever)
• Endocrine disease (hypothyroidism)
• Drug side effects (procainamide, isoniazid, hydralazine, minoxidil, phenytoin, anticoagulants, methysergide)
• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Congestive heart failure
• Uremia
• Radiation therapy
• Postmyocardial infarction syndrome (Dressler syndrome)
• Postpericardiotomy syndrome.

PEARL 5: REVIEW IMAGING BEFORE DIAGNOSING

What often brings a patient with cardiac tamponade to the attention of the physician is a finding on echocardiography, computed tomography, or magnetic resonance imaging of the chest.

Always review the imaging studies before making the diagnosis of cardiac tamponade. These tests must be reviewed to assess the anatomy and the size and location of the effusion. Particularly, one must look for atrial and right ventricular collapse and inferior vena caval plethora, which are echocardiographic signs of cardiac tamponade.⁴ Figures 1, 2, and 3 show imaging studies in a patient who presented with worsening cough 2 weeks after undergoing a cardiac procedure and who was found to have cardiac tamponade.

When the history and these imaging studies place cardiac tamponade high in the differential diagnosis as the cause of edema or dyspnea, it is time to reexamine the patient. The best first step is to measure pulsus paradoxus.

HOW PULSUS PARADOXUS OCCURS

To fully appreciate the subtleties of the next pearls, it is necessary to understand the pathophysiology of cardiac tamponade.

When pericardial fluid accumulation raises the pericardial pressure above the central venous pressure and pulmonary venous pressure (intravascular pressure), blood will not passively return to the right side of the heart from the venae cavae nor to the left side of the heart from the pulmonary veins unless it is influenced by the effects of respiration on intrathoracic pressure. During respiration, the right and left sides of the heart are alternately filled and deprived of their respective venous return.

During inspiration, as the intrathoracic pressure decreases, blood in the venae cavae empties into the right side of the heart, while blood in the pulmonary veins preferentially remains in the pulmonary veins, underfilling the left side of the heart. Since the right ventricle is more filled than the left ventricle during inspiration, the ventricular septum shifts from right to left, further opposing pulmonary venous return. As a result, during cardiac tamponade, the systemic blood pressure falls with inspiration.

During expiration the opposite occurs. Expiration decreases the intrathoracic volume, so the intrathoracic pressure rises. This tends to oppose vena caval return to the right side of the heart and to favor pulmonary venous return to the left side of the heart. The ventricular septum shifts from left to right, further accommodating left ventricular filling, raising stroke volume, and increasing blood pressure. This exaggerated alternate filling of the right and left sides of the heart during cardiac tamponade is what accounts for pulsus paradoxus, an inspiratory fall in systolic blood pressure of greater than 10 mm Hg.

If intravascular pressure is low (due to hemorrhage, dehydration, or diuretic therapy), the pressure in the pericardial space needed to oppose venous return is much less. In this low-pressure scenario, the results are low cardiac output and hypotension, which are treated by giving intravenous fluids to maintain intravascular volume.

PEARL 6: MEASURE PULSUS PARADOXUS

When cardiac tamponade is considered, one must always measure the pulsus paradoxus.

The term pulsus paradoxus was coined by Adolph Kussmaul in 1873, before physicians could even measure blood pressure. All they could do at that time was palpate the pulse and listen to the heart. Kussmaul described his observation as a conspicuous discrepancy between the cardiac action and the arterial pulse.

Although not described by Kussmaul, another explanation for this finding might be more suited to the use of the word “paradoxical.” When the pulse is palpated in a normal patient, with inspiration the pulse rate will increase via the Bainbridge reflex, and with expiration it will decrease. But in a patient with cardiac tamponade, there is a paradoxical inspiratory slowing of the pulse (because the decreased magnitude of the pulse at times makes it imperceptible) and an expiratory increase in pulse rate as the magnitude of the pulse again makes it palpable.

The magnitude of the fall in systolic blood pressure during inspiration has been used to estimate the level of hemodynamic impairment resulting from pericardial effusion.⁵ A rapidly accumulating pericardial effusion can have more hemodynamic impact than a much larger one that accumulates slowly. Thus, the intrapericardial pressure must be considered more than the volume of pericardial fluid.

When there is severe cardiac tamponade and overt pulsus paradoxus, simple palpation of a proximal arterial pulse can detect a marked inspiratory decrease or loss of the pulse, which returns with expiration. Tachycardia is almost always present, unless the cause is hypothyroidism.⁶

How to measure pulsus paradoxus with a manual sphygmomanometer

A stethoscope and manual sphygmomanometer are all that is needed to measure pulsus paradoxus. A noninvasive blood pressure monitor that averages multiple measurements cannot detect or quantify pulsus paradoxus.

The patient should be supine with the head elevated 30° to 45°, and the examiner should be seated comfortably at the patient’s side. The manometer should be on the opposite side of the patient in plain view of the examiner. Position the cuff on the arm above the elbow and place your stethoscope on the antecubital fossa. Then:

• Inflate the cuff 20 mm Hg above the highest systolic pressure previously auscultated.
• Slowly decrease the manometer pressure by 5 mm Hg and hold it there through two or three respiratory cycles while listening for the first Korotkoff (systolic) sound. Repeat this until you can hear the systolic sound (but only during expiration) and mentally note the pressure.
• Continue to decrease the manometer pressure by 5-mm Hg increments while listening. When the Korotkoff sounds no longer disappear with inspiration, mentally note this second value as well. The pulsus paradoxus is the difference between these values.
• When the Korotkoff sounds disappear as the manometer pressure is decreased, note this final value. This is the diastolic blood pressure.

PEARL 7: THE PLETHYSMOGRAM WAVE-FORM PARALLELS PULSUS PARADOXUS

Manual measurement of blood pressure and pulsus paradoxus can be difficult, especially in an obese patient or one with a fat-distorted arm on which the cuff does not maintain its position. In such patients, increased girth of the neck and abdomen also make it difficult to assess the jugular venous distention and visceral organ engorgement that characterize cardiac tamponade.

When the use of a sphygmomanometer is not possible, an arterial catheter can be inserted to demonstrate pulsus paradoxus. Simpler, however, is the novel use of another noninvasive instrument to detect and coarsely quantify pulsus paradoxus.⁷ The waveform on finger pulse oximetry can demonstrate pulsus paradoxus. The plethysmogram of the finger pulse oximeter can demonstrate the decrease in magnitude of the waveform with each inspiration (Figure 4).

Caution must be taken when interpreting this waveform, as with any measurement of pulsus paradoxus, to exclude a concomitant arrhythmia.

PEARL 8: PULSUS PARADOXUS WITHOUT CARDIAC TAMPONADE

Pulsus paradoxus can be present in the absence of cardiac tamponade. Once pulsus paradoxus of more than 10 mm Hg is measured, one must be sure the patient does not have a condition that can cause pulsus paradoxus without cardiac tamponade. Most of these are pulmonary conditions that necessitate an exaggerated inspiratory effort that can lower intrathoracic pressure sufficiently to oppose pulmonary venous return and cause a fall in systemic blood pressure:

• Chronic bronchitis
• Emphysema
• Mucus plug
• Pneumothorax
• Pulmonary embolism
• Stridor.

In these, there may be pulsus paradoxus, but not due to cardiac tamponade.

PEARL 9: CARDIAC TAMPONADE CAN BE PRESENT WITHOUT PULSUS PARADOXUS

Cardiac tamponade can be present without pulsus paradoxus. This occurs when certain conditions prevent inspiratory underfilling of the left ventricle relative to the filling of the right ventricle.⁸

How does this work? In cardiac tamponade, factors that drive the exaggerated fall in arterial pressure with inspiration (pulsus paradoxus) are the augmented right ventricular filling and the decreased left ventricular filling, both due to the lowering of the intrathoracic pressure. As the vena caval emptying is augmented, the right ventricular filling is increased, the ventricular septum shifts to the left, and pulmonary venous return to the heart is decreased.

Factors that can oppose pulsus paradoxus:

• Positive pressure ventilation prevents pulsus paradoxus by preventing the fall in intrathoracic pressure.
• Severe aortic regurgitation does not permit underfilling of the left ventricle during inspiration.
• An atrial septal defect will always equalize the right and left atrial pressures, preventing differential right ventricular and left ventricular filling with inspiration.
• Severe left ventricular hypertrophy does not permit the inspiratory shift of the ventricular septum from right to left that would otherwise lead to decreased left ventricular filling.
• Severe left ventricular dysfunction, with its low stroke volume and severe elevation of left ventricular end-diastolic pressure, never permits underfilling of the left ventricle, despite cardiac tamponade and an inspiratory decrease in intrathoracic pressure.
• Intravascular volume depletion due to hemorrhage, hemodialysis, or mistaken use of diuretics to treat edema can cause marked hypotension, making pulsus paradoxus impossible to detect.

Knowledge of underlying medical conditions, the likelihood of their causing cardiac tamponade, and the appearance of the echocardiogram prompt the physician to look further when the presence or absence of pulsus paradoxus does not fit with the working diagnosis.

The echocardiogram can give hints to the etiology of a pericardial effusion, such as clotted blood after trauma or a cardiac-perforating procedure, tumor studding of the epicardium,⁹ or fibrin strands indicating chronicity or an inflammatory process.¹⁰ Diastolic collapse of the right ventricle, more than collapse of the right atrium or left atrium, speaks for the severity of cardiac tamponade. With hemodynamically significant pericardial effusion and cardiac tamponade, the inferior vena cava is distended and does not decrease in size with inspiration unless there is severe intravascular volume depletion, at which time the inferior vena cava is underfilled throughout the respiratory cycle.

PEARL 10: PLAN HOW TO DRAIN

The size and location of the pericardial effusion and the patient’s hemodynamics must be integrated when deciding how to relieve cardiac tamponade. When cardiac tamponade is indeed severe and the patient and physician agree that it must be drained, the options are percutaneous needle aspiration (pericardiocentesis) and surgical pericardiostomy (creation of a pericardial window). Here again, as assessed by echocardiography, the access to the pericardial fluid should influence the choice.

Pericardiocentesis can be safely done if certain criteria are met. The patient must be able to lie still in the supine position, perhaps with the head of the bed elevated 30 degrees. Anticoagulation must be reversed or allowed time to resolve if drainage is not an emergency.

Pericardiocentesis can be risky or unsuccessful if there is not enough pericardial fluid to permit respiratory cardiac motion without perforating the heart with the needle; if the effusion is loculated (confined to a pocket) posteriorly; or if it is too far from the skin to permit precise control and placement of a spinal needle into the pericardial space. In cases of cardiac tamponade in which the anatomy indicates surgical pericardiostomy but severe hypotension prevents the induction of anesthesia and positive-pressure ventilation—which can result in profound, irreversible hypotension—percutaneous needle drainage (pericardiocentesis) should be performed in the operating room to relieve the tamponade before the induction of anesthesia and the surgical drainage.¹¹

To reiterate, a suspected cardiac or aortic rupture that causes cardiac tamponade is usually large and not apt to self-seal. In such cases, the halt in the accumulation of pericardial blood is due to hypotension and not due to spontaneous resolution. Open surgical drainage is required from the outset because an initial success of pericardiocentesis yields to the recurrence of cardiac tamponade.

PEARL 11: ANTICIPATE WHAT THE FLUID SHOULD LOOK LIKE

Before performing pericardiocentesis, anticipate the appearance of the pericardial fluid on the basis of the presumed etiology, ie:

• Sanguinous—trauma, heart surgery, cardiac perforation from a procedure, anticoagulation, uremia, or malignancy
• Serous—congestive heart failure, acute radiation therapy
• Purulent—infections (natural or postoperative)
• Turbid (like gold paint)—mycobacterial infection, rheumatoid arthritis, myxedema
• Chylous—pericardium fistulized to the thoracic duct by a natural or postsurgical cause.

Sanguinous pericardial effusion encountered during a pericardiocentesis, if not anticipated, can be daunting and can cause the operator to question if it is the result of inadvertent needle placement in a cardiac chamber. If the needle is indeed in the heart, blood often surges out under pressure in pulses, which strongly suggests that the needle is not in the pericardial space and should be removed; but if confirmation of the location is needed before removing the needle, it can be done by injecting 2 mL of agitated sterile saline through the pericardiocentesis needle during echocardiographic imaging.¹²

Before inserting the needle, the ideal access location and needle angle must be determined by the operator with echocardiographic transducer in hand. The distance from skin to a point just through the parietal pericardium can also be measured at this time.

Once the needle is in the pericardial fluid (and you are confident of its placement), removal of 50 to 100 mL of the fluid with a large syringe can be enough to afford the patient easier breathing, higher blood pressure, and lower pulsus paradoxus—and even the physician will breathe easier. The same syringe can be filled and emptied multiple times. Less traumatic and more complete removal of pericardial fluid requires insertion of a multihole pigtail catheter over a J-tipped guidewire that is introduced through the needle.

PEARL 12: DRAIN SLOWLY TO AVOID PULMONARY EDEMA

Pulmonary edema is an uncommon complication of pericardiocentesis that might be avoidable. Heralded by sudden coughing and pink, frothy sputum, it can rapidly deteriorate into respiratory failure. The mechanism has been attributed to a sudden increase in right ventricular stroke volume and resultant left ventricular filling after the excess pericardial fluid has been removed, before the systemic arteries, which constrict to keep the systemic blood pressure up during cardiac tamponade, have had time to relax.¹³

To avoid this complication, if the volume of pericardial fluid responsible for cardiac tamponade is large, it should be removed slowly,¹⁴ stopping for a several-minute rest after each 250 mL. Catheter removal of pericardial fluid by gravity drainage over 24 hours has been suggested.¹⁵ A drawback to this approach is catheter clotting or sludging before all the fluid has been removed. It is helpful to keep the drainage catheter close to the patient’s body temperature to make the fluid less viscous. Output should be monitored hourly.

When the pericardial fluid has been completely drained, one must decide how long to leave the catheter in. One reason to remove the catheter at this time is that it causes pleuritic pain; another is to avoid introducing infection. A reason to leave the catheter in is to observe the effect of medical treatment on the hourly pericardial fluid output. Nonsteroidal anti-inflammatory drugs are the drugs of first choice when treating pericardial inflammation and suppressing production of pericardial fluid.¹⁶ In most cases the catheter should not be left in place for more than 3 days.

Laboratory analysis of the pericardial fluid should shed light on its suspected cause. Analysis usually involves chemistry testing, microscopic inspection of blood cell smears, cytology, microbiologic stains and cultures, and immunologic tests. Results often take days. Meyers and colleagues¹⁷ expound on this subject.

Cardiac tamponade is a life-threatening condition that can be palliated or cured, depending on its cause and on the timeliness of treatment. Making a timely diagnosis and providing the appropriate treatment can be gratifying for both patient and physician.

Cardiac tamponade occurs when fluid in the pericardial space reaches a pressure exceeding central venous pressure. This leads to jugular venous distention, visceral organ engorgement, edema, and elevated pulmonary venous pressure that causes dyspnea. Despite compensatory tachycardia, the decrease in cardiac filling leads to a fall in cardiac output and to arterial hypoperfusion of vital organs.

PEARL 1: SLOW ACCUMULATION LEADS TO EDEMA

The rate at which pericardial fluid accumulates influences the clinical presentation of cardiac tamponade, in particular whether or not there is edema. Whereas rapid accumulation is characterized more by hypotension than by edema, the slow accumulation of pericardial fluid affords the patient time to drink enough liquid to keep the central venous pressure higher than the rising pericardial pressure. Thus, edema and dyspnea are more prominent features of cardiac tamponade when there is a slow rise in pericardial pressure.

PEARL 2: EDEMA IS NOT ALWAYS TREATED WITH A DIURETIC

Edema is not always treated with a diuretic. In a patient who has a pericardial effusion that has developed slowly and who has been drinking enough fluid to keep the central venous pressure higher than the pericardial pressure, a diuretic can remove enough volume from the circulation to lower the central venous pressure below the intrapericardial pressure and thus convert a benign pericardial effusion to potentially lethal cardiac tamponade.

One must understand the cause of edema or low urine output before treating it. This underscores the importance of the history and the physical examination. All of the following must be assessed:

• Symptoms and time course of the illness
• Concurrent medical illnesses
• Neck veins
• Blood pressure and its response to inspiration
• Heart sounds
• Heart rate and rhythm
• Abdominal organ engorgement
• Edema (or its absence).

PEARL 3: UNDERSTANDING THE CAUSE IS ESSENTIAL

Understanding the cause of cardiac tamponade is essential.

A trauma patient first encountered in the emergency department may have an underlying disease, but the focus is squarely on the effects of trauma or violent injury. In a patient with multiple trauma, hypotension and tachycardia that do not respond to intravenous volume replacement when there is an obvious rise in central venous pressure should be clues to cardiac tamponade.¹

If the patient has recently undergone a cardiac procedure (for example, cardiac surgery, myocardial biopsy, coronary intervention, electrophysiologic study with intracardiac electrodes, transvenous pacemaker placement, pacemaker lead extraction, or radiofrequency ablation), knowing about the procedure narrows the differential diagnosis when hypotension, tachycardia, and jugular venous distention develop.

PEARL 4: CARDIAC OR AORTIC RUPTURE REQUIRES SURGERY

When the etiology of cardiac tamponade is cardiac or aortic rupture, the treatment is surgical.

Painful sudden causes of cardiac tamponade include hemopericardium due to rupture of the free wall after myocardial infarction, and spontaneous or posttraumatic dissection and rupture of the ascending aorta. Prompt diagnosis is necessary, but since these lesions will not close and heal spontaneously, the definitive treatment should be surgery. Moreover, needle removal of intrapericardial blood that has been opposing further bleeding is sure to permit bleeding to recur, often with lethal consequences.²

Causes of cardiac tamponade that have a less-acute onset are likely to be complications of medical problems. Medical illnesses known to be associated with cardiac tamponade include:

• Infectious disease (idiopathic or viral, associated with smallpox vaccination, mycobacterial, purulent bacterial, fungal)
• Metastatic cancer (lung, breast, esophagus, lymphoma, pancreas, liver, leukemia, stomach, melanoma)³
• Connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, Wegener granulomatosis, acute rheumatic fever)
• Endocrine disease (hypothyroidism)
• Drug side effects (procainamide, isoniazid, hydralazine, minoxidil, phenytoin, anticoagulants, methysergide)
• Inflammatory bowel disease (Crohn disease, ulcerative colitis)
• Congestive heart failure
• Uremia
• Radiation therapy
• Postmyocardial infarction syndrome (Dressler syndrome)
• Postpericardiotomy syndrome.

PEARL 5: REVIEW IMAGING BEFORE DIAGNOSING

What often brings a patient with cardiac tamponade to the attention of the physician is a finding on echocardiography, computed tomography, or magnetic resonance imaging of the chest.

Always review the imaging studies before making the diagnosis of cardiac tamponade. These tests must be reviewed to assess the anatomy and the size and location of the effusion. Particularly, one must look for atrial and right ventricular collapse and inferior vena caval plethora, which are echocardiographic signs of cardiac tamponade.⁴ Figures 1, 2, and 3 show imaging studies in a patient who presented with worsening cough 2 weeks after undergoing a cardiac procedure and who was found to have cardiac tamponade.

When the history and these imaging studies place cardiac tamponade high in the differential diagnosis as the cause of edema or dyspnea, it is time to reexamine the patient. The best first step is to measure pulsus paradoxus.

HOW PULSUS PARADOXUS OCCURS

To fully appreciate the subtleties of the next pearls, it is necessary to understand the pathophysiology of cardiac tamponade.

When pericardial fluid accumulation raises the pericardial pressure above the central venous pressure and pulmonary venous pressure (intravascular pressure), blood will not passively return to the right side of the heart from the venae cavae nor to the left side of the heart from the pulmonary veins unless it is influenced by the effects of respiration on intrathoracic pressure. During respiration, the right and left sides of the heart are alternately filled and deprived of their respective venous return.

During inspiration, as the intrathoracic pressure decreases, blood in the venae cavae empties into the right side of the heart, while blood in the pulmonary veins preferentially remains in the pulmonary veins, underfilling the left side of the heart. Since the right ventricle is more filled than the left ventricle during inspiration, the ventricular septum shifts from right to left, further opposing pulmonary venous return. As a result, during cardiac tamponade, the systemic blood pressure falls with inspiration.

During expiration the opposite occurs. Expiration decreases the intrathoracic volume, so the intrathoracic pressure rises. This tends to oppose vena caval return to the right side of the heart and to favor pulmonary venous return to the left side of the heart. The ventricular septum shifts from left to right, further accommodating left ventricular filling, raising stroke volume, and increasing blood pressure. This exaggerated alternate filling of the right and left sides of the heart during cardiac tamponade is what accounts for pulsus paradoxus, an inspiratory fall in systolic blood pressure of greater than 10 mm Hg.

If intravascular pressure is low (due to hemorrhage, dehydration, or diuretic therapy), the pressure in the pericardial space needed to oppose venous return is much less. In this low-pressure scenario, the results are low cardiac output and hypotension, which are treated by giving intravenous fluids to maintain intravascular volume.

PEARL 6: MEASURE PULSUS PARADOXUS

When cardiac tamponade is considered, one must always measure the pulsus paradoxus.

The term pulsus paradoxus was coined by Adolph Kussmaul in 1873, before physicians could even measure blood pressure. All they could do at that time was palpate the pulse and listen to the heart. Kussmaul described his observation as a conspicuous discrepancy between the cardiac action and the arterial pulse.

Although not described by Kussmaul, another explanation for this finding might be more suited to the use of the word “paradoxical.” When the pulse is palpated in a normal patient, with inspiration the pulse rate will increase via the Bainbridge reflex, and with expiration it will decrease. But in a patient with cardiac tamponade, there is a paradoxical inspiratory slowing of the pulse (because the decreased magnitude of the pulse at times makes it imperceptible) and an expiratory increase in pulse rate as the magnitude of the pulse again makes it palpable.

The magnitude of the fall in systolic blood pressure during inspiration has been used to estimate the level of hemodynamic impairment resulting from pericardial effusion.⁵ A rapidly accumulating pericardial effusion can have more hemodynamic impact than a much larger one that accumulates slowly. Thus, the intrapericardial pressure must be considered more than the volume of pericardial fluid.

When there is severe cardiac tamponade and overt pulsus paradoxus, simple palpation of a proximal arterial pulse can detect a marked inspiratory decrease or loss of the pulse, which returns with expiration. Tachycardia is almost always present, unless the cause is hypothyroidism.⁶

How to measure pulsus paradoxus with a manual sphygmomanometer

A stethoscope and manual sphygmomanometer are all that is needed to measure pulsus paradoxus. A noninvasive blood pressure monitor that averages multiple measurements cannot detect or quantify pulsus paradoxus.

The patient should be supine with the head elevated 30° to 45°, and the examiner should be seated comfortably at the patient’s side. The manometer should be on the opposite side of the patient in plain view of the examiner. Position the cuff on the arm above the elbow and place your stethoscope on the antecubital fossa. Then:

• Inflate the cuff 20 mm Hg above the highest systolic pressure previously auscultated.
• Slowly decrease the manometer pressure by 5 mm Hg and hold it there through two or three respiratory cycles while listening for the first Korotkoff (systolic) sound. Repeat this until you can hear the systolic sound (but only during expiration) and mentally note the pressure.
• Continue to decrease the manometer pressure by 5-mm Hg increments while listening. When the Korotkoff sounds no longer disappear with inspiration, mentally note this second value as well. The pulsus paradoxus is the difference between these values.
• When the Korotkoff sounds disappear as the manometer pressure is decreased, note this final value. This is the diastolic blood pressure.

PEARL 7: THE PLETHYSMOGRAM WAVE-FORM PARALLELS PULSUS PARADOXUS

Manual measurement of blood pressure and pulsus paradoxus can be difficult, especially in an obese patient or one with a fat-distorted arm on which the cuff does not maintain its position. In such patients, increased girth of the neck and abdomen also make it difficult to assess the jugular venous distention and visceral organ engorgement that characterize cardiac tamponade.

When the use of a sphygmomanometer is not possible, an arterial catheter can be inserted to demonstrate pulsus paradoxus. Simpler, however, is the novel use of another noninvasive instrument to detect and coarsely quantify pulsus paradoxus.⁷ The waveform on finger pulse oximetry can demonstrate pulsus paradoxus. The plethysmogram of the finger pulse oximeter can demonstrate the decrease in magnitude of the waveform with each inspiration (Figure 4).

Caution must be taken when interpreting this waveform, as with any measurement of pulsus paradoxus, to exclude a concomitant arrhythmia.

PEARL 8: PULSUS PARADOXUS WITHOUT CARDIAC TAMPONADE

Pulsus paradoxus can be present in the absence of cardiac tamponade. Once pulsus paradoxus of more than 10 mm Hg is measured, one must be sure the patient does not have a condition that can cause pulsus paradoxus without cardiac tamponade. Most of these are pulmonary conditions that necessitate an exaggerated inspiratory effort that can lower intrathoracic pressure sufficiently to oppose pulmonary venous return and cause a fall in systemic blood pressure:

• Chronic bronchitis
• Emphysema
• Mucus plug
• Pneumothorax
• Pulmonary embolism
• Stridor.

In these, there may be pulsus paradoxus, but not due to cardiac tamponade.

PEARL 9: CARDIAC TAMPONADE CAN BE PRESENT WITHOUT PULSUS PARADOXUS

Cardiac tamponade can be present without pulsus paradoxus. This occurs when certain conditions prevent inspiratory underfilling of the left ventricle relative to the filling of the right ventricle.⁸

How does this work? In cardiac tamponade, factors that drive the exaggerated fall in arterial pressure with inspiration (pulsus paradoxus) are the augmented right ventricular filling and the decreased left ventricular filling, both due to the lowering of the intrathoracic pressure. As the vena caval emptying is augmented, the right ventricular filling is increased, the ventricular septum shifts to the left, and pulmonary venous return to the heart is decreased.

Factors that can oppose pulsus paradoxus:

• Positive pressure ventilation prevents pulsus paradoxus by preventing the fall in intrathoracic pressure.
• Severe aortic regurgitation does not permit underfilling of the left ventricle during inspiration.
• An atrial septal defect will always equalize the right and left atrial pressures, preventing differential right ventricular and left ventricular filling with inspiration.
• Severe left ventricular hypertrophy does not permit the inspiratory shift of the ventricular septum from right to left that would otherwise lead to decreased left ventricular filling.
• Severe left ventricular dysfunction, with its low stroke volume and severe elevation of left ventricular end-diastolic pressure, never permits underfilling of the left ventricle, despite cardiac tamponade and an inspiratory decrease in intrathoracic pressure.
• Intravascular volume depletion due to hemorrhage, hemodialysis, or mistaken use of diuretics to treat edema can cause marked hypotension, making pulsus paradoxus impossible to detect.

Knowledge of underlying medical conditions, the likelihood of their causing cardiac tamponade, and the appearance of the echocardiogram prompt the physician to look further when the presence or absence of pulsus paradoxus does not fit with the working diagnosis.

The echocardiogram can give hints to the etiology of a pericardial effusion, such as clotted blood after trauma or a cardiac-perforating procedure, tumor studding of the epicardium,⁹ or fibrin strands indicating chronicity or an inflammatory process.¹⁰ Diastolic collapse of the right ventricle, more than collapse of the right atrium or left atrium, speaks for the severity of cardiac tamponade. With hemodynamically significant pericardial effusion and cardiac tamponade, the inferior vena cava is distended and does not decrease in size with inspiration unless there is severe intravascular volume depletion, at which time the inferior vena cava is underfilled throughout the respiratory cycle.

PEARL 10: PLAN HOW TO DRAIN

The size and location of the pericardial effusion and the patient’s hemodynamics must be integrated when deciding how to relieve cardiac tamponade. When cardiac tamponade is indeed severe and the patient and physician agree that it must be drained, the options are percutaneous needle aspiration (pericardiocentesis) and surgical pericardiostomy (creation of a pericardial window). Here again, as assessed by echocardiography, the access to the pericardial fluid should influence the choice.

Pericardiocentesis can be safely done if certain criteria are met. The patient must be able to lie still in the supine position, perhaps with the head of the bed elevated 30 degrees. Anticoagulation must be reversed or allowed time to resolve if drainage is not an emergency.

Pericardiocentesis can be risky or unsuccessful if there is not enough pericardial fluid to permit respiratory cardiac motion without perforating the heart with the needle; if the effusion is loculated (confined to a pocket) posteriorly; or if it is too far from the skin to permit precise control and placement of a spinal needle into the pericardial space. In cases of cardiac tamponade in which the anatomy indicates surgical pericardiostomy but severe hypotension prevents the induction of anesthesia and positive-pressure ventilation—which can result in profound, irreversible hypotension—percutaneous needle drainage (pericardiocentesis) should be performed in the operating room to relieve the tamponade before the induction of anesthesia and the surgical drainage.¹¹

To reiterate, a suspected cardiac or aortic rupture that causes cardiac tamponade is usually large and not apt to self-seal. In such cases, the halt in the accumulation of pericardial blood is due to hypotension and not due to spontaneous resolution. Open surgical drainage is required from the outset because an initial success of pericardiocentesis yields to the recurrence of cardiac tamponade.

PEARL 11: ANTICIPATE WHAT THE FLUID SHOULD LOOK LIKE

Before performing pericardiocentesis, anticipate the appearance of the pericardial fluid on the basis of the presumed etiology, ie:

• Sanguinous—trauma, heart surgery, cardiac perforation from a procedure, anticoagulation, uremia, or malignancy
• Serous—congestive heart failure, acute radiation therapy
• Purulent—infections (natural or postoperative)
• Turbid (like gold paint)—mycobacterial infection, rheumatoid arthritis, myxedema
• Chylous—pericardium fistulized to the thoracic duct by a natural or postsurgical cause.

Sanguinous pericardial effusion encountered during a pericardiocentesis, if not anticipated, can be daunting and can cause the operator to question if it is the result of inadvertent needle placement in a cardiac chamber. If the needle is indeed in the heart, blood often surges out under pressure in pulses, which strongly suggests that the needle is not in the pericardial space and should be removed; but if confirmation of the location is needed before removing the needle, it can be done by injecting 2 mL of agitated sterile saline through the pericardiocentesis needle during echocardiographic imaging.¹²

Before inserting the needle, the ideal access location and needle angle must be determined by the operator with echocardiographic transducer in hand. The distance from skin to a point just through the parietal pericardium can also be measured at this time.

Once the needle is in the pericardial fluid (and you are confident of its placement), removal of 50 to 100 mL of the fluid with a large syringe can be enough to afford the patient easier breathing, higher blood pressure, and lower pulsus paradoxus—and even the physician will breathe easier. The same syringe can be filled and emptied multiple times. Less traumatic and more complete removal of pericardial fluid requires insertion of a multihole pigtail catheter over a J-tipped guidewire that is introduced through the needle.

PEARL 12: DRAIN SLOWLY TO AVOID PULMONARY EDEMA

Pulmonary edema is an uncommon complication of pericardiocentesis that might be avoidable. Heralded by sudden coughing and pink, frothy sputum, it can rapidly deteriorate into respiratory failure. The mechanism has been attributed to a sudden increase in right ventricular stroke volume and resultant left ventricular filling after the excess pericardial fluid has been removed, before the systemic arteries, which constrict to keep the systemic blood pressure up during cardiac tamponade, have had time to relax.¹³

To avoid this complication, if the volume of pericardial fluid responsible for cardiac tamponade is large, it should be removed slowly,¹⁴ stopping for a several-minute rest after each 250 mL. Catheter removal of pericardial fluid by gravity drainage over 24 hours has been suggested.¹⁵ A drawback to this approach is catheter clotting or sludging before all the fluid has been removed. It is helpful to keep the drainage catheter close to the patient’s body temperature to make the fluid less viscous. Output should be monitored hourly.

When the pericardial fluid has been completely drained, one must decide how long to leave the catheter in. One reason to remove the catheter at this time is that it causes pleuritic pain; another is to avoid introducing infection. A reason to leave the catheter in is to observe the effect of medical treatment on the hourly pericardial fluid output. Nonsteroidal anti-inflammatory drugs are the drugs of first choice when treating pericardial inflammation and suppressing production of pericardial fluid.¹⁶ In most cases the catheter should not be left in place for more than 3 days.

Laboratory analysis of the pericardial fluid should shed light on its suspected cause. Analysis usually involves chemistry testing, microscopic inspection of blood cell smears, cytology, microbiologic stains and cultures, and immunologic tests. Results often take days. Meyers and colleagues¹⁷ expound on this subject.

Yes. Acute pericarditis has a unique clinical presentation, physical findings, and electrocardiographic (ECG) changes. ECG is always ordered to look for ischemic changes in patients with chest pain. Acute pericarditis develops in stages, which makes it easy to differentiate from early repolarization and, more significantly, myocardial infarction. The ECG changes, along with the clinical presentation and physical findings, can make the diagnosis of pericarditis.

In atypical and complicated cases, advanced imaging studies (ie, echocardiography and cardiac magnetic resonance imaging) have been used to confirm the diagnosis and to follow the course of the disease. However, ECG remains a useful, cost-effective test.

PERICARDIAL DISEASE IS DIVERSE

The pericardium is a thin layer that covers the heart and separates it from other structures in the mediastinum.

Pericardial syndromes include acute, recurrent, constrictive, and effusive-constrictive pericarditis, as well as pericardial effusion with or without tamponade. Causes include viral or bacterial infection, postpericardiotomy syndrome (Dressler syndrome), postmyocardial infarction, primary and metastatic tumors, trauma, uremia, radiation, and autoimmune disease, but pericardial syndromes can also be idiopathic.¹

Acute pericarditis is the most common pericardial syndrome and occurs in all age groups. Once diagnosed, it can easily be treated with antiinflammatory drugs. However, recurrent pericarditis, reported in 30% of patients experiencing a first attack of pericarditis, can be difficult to manage, can have a significant impact on the patient’s health, and can be life-threatening.²

CHANGES OF ACUTE PERICARDITIS DEVELOP IN STAGES

Pericarditis can be diagnosed on the basis of ECG changes, clinical signs and symptoms, and laboratory and imaging findings.³ ECG criteria of acute pericarditis have been published.^4,5

The characteristic chest pain in acute pericarditis is usually sudden in onset and sharp and occurs over the anterior chest wall. The pain is exacerbated by inspiration and decreases when the patient sits up and leans forward.⁴

ECG classically shows a widespread saddle-shaped (upward concave) ST-segment elevation in the precordial and limb leads, reflecting subepicardial inflammation. PR-segment depression (with PR-segment elevation in lead aVR) can accompany or precede the ST changes and is known as the “discordant ST-PR segment sign” (Figures 1 and 2). These changes are seen in 60% of patients.

The ECG changes develop in stages, making them easy to differentiate from early repolarization and, more significantly, from myocardial infarction. Four stages are apparent^1,4,6–9:

• Stage I occurs in a few hours to days, with diffuse, up-sloping ST-segment elevation and upright T waves, the result of an alteration in ventricular repolarization caused by pericardial inflammation. Because of alteration in repolarization of the atrium secondary to inflammation, the PR segment is elevated in aVR and depressed in the rest of the limb and chest leads.
• Stage II—the ST and PR segments normalize.
• Stage III—widespread T-wave inversion.
• Stage IV—normalization of the T waves.

There is no pathologic Q-wave formation or loss of R-wave progression in acute pericarditis.

The ECG changes of pericarditis vary widely from one patient to another, depending on the extent and severity of pericardial inflammation and the timing of the patient’s presentation. Changes vary in duration. In some cases, ST elevation returns to baseline within a few days without T-wave inversions; in other cases, T-wave inversions can persist for weeks to months. Sometimes the abnormalities resolve by the time symptoms develop.

ASSOCIATED CONDITIONS

Myocardial involvement

In acute myocarditis, findings on ECG can be normal unless the pericardium is involved. Changes that can be seen in myocarditis and that indicate a deeper involvement of inflammation include ST-segment abnormalities, arrhythmias (eg, premature ventricular or atrial contractions), pathologic Q waves, intraventricular conduction delay, and right or left bundle branch block.^1,10–12

Elevated troponin and new focal or global left ventricular dysfunction on cardiac imaging indicates myocarditis, especially in a patient with a normal coronary angiogram.^10–13

Pericardial effusion: Tachycardia and low QRS voltage

Pericardial effusion is often a complication of pericarditis, but it can also develop from other conditions, such as myxedema, uremia, malignancy, connective tissue disease, aortic dissection, and postpericardiotomy syndrome, and it can also be iatrogenic.

The most common ECG sign of pericardial effusion is tachycardia and low voltage of the QRS complexes. Low voltage is defined as a total amplitude of the QRS complexes in each of the six limb leads less than or equal to 5 mm, and less than or equal to 10 mm in V₁ through V₆. However, low voltage is not always present in the chest leads.

Mechanisms proposed to explain low QRS voltage associated with pericardial effusion include internal short-circuiting of the electrical currents by accumulated fluids within the pericardial sac, greater distance of the heart from body surface electrodes, reduced cardiac size caused by effusion, and change in the generation and propagation of electrical current in the myocardium.14,15

Cardiac tamponade: Tachycardia, electrical alternans, low QRS voltage

Sinus tachycardia and electrical alternans are specific but not sensitive signs of pericardial tamponade (Figure 3).^16,17 Electrical alternans is characterized by beat-to-beat alterations in the axis of QRS complexes in the limb and precordial leads as a result of the mechanical swinging of the heart in a large pericardial effusion.¹⁷ There is evidence to suggest that low QRS voltage is more the result of the tamponade than the effusion.¹⁸

Treating tamponade with pericardiocentesis, surgical creation of a fistula (“window”) between the pericardial space and the pleural cavity, or anti-inflammatory drugs can resolve low QRS voltage within 1 week.

DIFFERENTIAL DIAGNOSIS OF ACUTE PERICARDITIS

Acute myocardial infarction

ECG changes in acute pericarditis differ from those in acute myocardial infarction in many ways.

ST-segment elevation in pericarditis rarely exceeds 5 mm, in contrast to acute myocardial infarction, in which ST elevation at the J point has to be more than 2 mm and in two anatomically contiguous leads.¹⁹

In pericarditis, the changes occur more slowly and in stages, reflecting the evolving inflammation of different areas of the pericardium.

The ST segment is elevated diffusely in the precordial and limb leads in pericarditis, indicating involvement of more than one coronary vascular territory, differentiating it from characteristic regional changes in myocardial infarction.^19,20

If concomitant atrial injury is present with acute pericarditis, then PR elevation in aVR with PR depression in other leads may be seen.

Finally, pathologic Q waves or high-grade heart block reflects acute myocardial infarction.

Early repolarization: Elevation of the J point

Early repolarization is sometimes seen in healthy young people, especially in black men.

Early repolarization is characterized by elevation of the J point (ie, the junction between the end of the QRS complex and the beginning of the ST segment). Elevation of the J point causes elevation of the ST segment in the mid to lateral precordial leads (V₃–V₆) with an up-right T wave.²¹

Acute pericarditis tends to cause ST-segment elevation in both the limb and precordial leads, whereas ST elevation in early repolarization mainly involves the lateral chest leads.

The PR segment is more prominent in acute pericarditis, especially in lead aVR.

Another finding that strongly favors acute pericarditis is the ratio of the height of the ST-segment junction to the height of the apex of the T wave of more than 0.25 in leads I, V₄, V₅, and V₆ (Figure 4).^5,8,22

Yes. Acute pericarditis has a unique clinical presentation, physical findings, and electrocardiographic (ECG) changes. ECG is always ordered to look for ischemic changes in patients with chest pain. Acute pericarditis develops in stages, which makes it easy to differentiate from early repolarization and, more significantly, myocardial infarction. The ECG changes, along with the clinical presentation and physical findings, can make the diagnosis of pericarditis.

In atypical and complicated cases, advanced imaging studies (ie, echocardiography and cardiac magnetic resonance imaging) have been used to confirm the diagnosis and to follow the course of the disease. However, ECG remains a useful, cost-effective test.

PERICARDIAL DISEASE IS DIVERSE

The pericardium is a thin layer that covers the heart and separates it from other structures in the mediastinum.

Pericardial syndromes include acute, recurrent, constrictive, and effusive-constrictive pericarditis, as well as pericardial effusion with or without tamponade. Causes include viral or bacterial infection, postpericardiotomy syndrome (Dressler syndrome), postmyocardial infarction, primary and metastatic tumors, trauma, uremia, radiation, and autoimmune disease, but pericardial syndromes can also be idiopathic.¹

Acute pericarditis is the most common pericardial syndrome and occurs in all age groups. Once diagnosed, it can easily be treated with antiinflammatory drugs. However, recurrent pericarditis, reported in 30% of patients experiencing a first attack of pericarditis, can be difficult to manage, can have a significant impact on the patient’s health, and can be life-threatening.²

CHANGES OF ACUTE PERICARDITIS DEVELOP IN STAGES

Pericarditis can be diagnosed on the basis of ECG changes, clinical signs and symptoms, and laboratory and imaging findings.³ ECG criteria of acute pericarditis have been published.^4,5

The characteristic chest pain in acute pericarditis is usually sudden in onset and sharp and occurs over the anterior chest wall. The pain is exacerbated by inspiration and decreases when the patient sits up and leans forward.⁴

ECG classically shows a widespread saddle-shaped (upward concave) ST-segment elevation in the precordial and limb leads, reflecting subepicardial inflammation. PR-segment depression (with PR-segment elevation in lead aVR) can accompany or precede the ST changes and is known as the “discordant ST-PR segment sign” (Figures 1 and 2). These changes are seen in 60% of patients.

The ECG changes develop in stages, making them easy to differentiate from early repolarization and, more significantly, from myocardial infarction. Four stages are apparent^1,4,6–9:

• Stage I occurs in a few hours to days, with diffuse, up-sloping ST-segment elevation and upright T waves, the result of an alteration in ventricular repolarization caused by pericardial inflammation. Because of alteration in repolarization of the atrium secondary to inflammation, the PR segment is elevated in aVR and depressed in the rest of the limb and chest leads.
• Stage II—the ST and PR segments normalize.
• Stage III—widespread T-wave inversion.
• Stage IV—normalization of the T waves.

There is no pathologic Q-wave formation or loss of R-wave progression in acute pericarditis.

The ECG changes of pericarditis vary widely from one patient to another, depending on the extent and severity of pericardial inflammation and the timing of the patient’s presentation. Changes vary in duration. In some cases, ST elevation returns to baseline within a few days without T-wave inversions; in other cases, T-wave inversions can persist for weeks to months. Sometimes the abnormalities resolve by the time symptoms develop.

ASSOCIATED CONDITIONS

Myocardial involvement

In acute myocarditis, findings on ECG can be normal unless the pericardium is involved. Changes that can be seen in myocarditis and that indicate a deeper involvement of inflammation include ST-segment abnormalities, arrhythmias (eg, premature ventricular or atrial contractions), pathologic Q waves, intraventricular conduction delay, and right or left bundle branch block.^1,10–12

Elevated troponin and new focal or global left ventricular dysfunction on cardiac imaging indicates myocarditis, especially in a patient with a normal coronary angiogram.^10–13

Pericardial effusion: Tachycardia and low QRS voltage

Pericardial effusion is often a complication of pericarditis, but it can also develop from other conditions, such as myxedema, uremia, malignancy, connective tissue disease, aortic dissection, and postpericardiotomy syndrome, and it can also be iatrogenic.

The most common ECG sign of pericardial effusion is tachycardia and low voltage of the QRS complexes. Low voltage is defined as a total amplitude of the QRS complexes in each of the six limb leads less than or equal to 5 mm, and less than or equal to 10 mm in V₁ through V₆. However, low voltage is not always present in the chest leads.

Mechanisms proposed to explain low QRS voltage associated with pericardial effusion include internal short-circuiting of the electrical currents by accumulated fluids within the pericardial sac, greater distance of the heart from body surface electrodes, reduced cardiac size caused by effusion, and change in the generation and propagation of electrical current in the myocardium.14,15

Cardiac tamponade: Tachycardia, electrical alternans, low QRS voltage

Sinus tachycardia and electrical alternans are specific but not sensitive signs of pericardial tamponade (Figure 3).^16,17 Electrical alternans is characterized by beat-to-beat alterations in the axis of QRS complexes in the limb and precordial leads as a result of the mechanical swinging of the heart in a large pericardial effusion.¹⁷ There is evidence to suggest that low QRS voltage is more the result of the tamponade than the effusion.¹⁸

Treating tamponade with pericardiocentesis, surgical creation of a fistula (“window”) between the pericardial space and the pleural cavity, or anti-inflammatory drugs can resolve low QRS voltage within 1 week.

DIFFERENTIAL DIAGNOSIS OF ACUTE PERICARDITIS

Acute myocardial infarction

ECG changes in acute pericarditis differ from those in acute myocardial infarction in many ways.

ST-segment elevation in pericarditis rarely exceeds 5 mm, in contrast to acute myocardial infarction, in which ST elevation at the J point has to be more than 2 mm and in two anatomically contiguous leads.¹⁹

In pericarditis, the changes occur more slowly and in stages, reflecting the evolving inflammation of different areas of the pericardium.

The ST segment is elevated diffusely in the precordial and limb leads in pericarditis, indicating involvement of more than one coronary vascular territory, differentiating it from characteristic regional changes in myocardial infarction.^19,20

If concomitant atrial injury is present with acute pericarditis, then PR elevation in aVR with PR depression in other leads may be seen.

Finally, pathologic Q waves or high-grade heart block reflects acute myocardial infarction.

Early repolarization: Elevation of the J point

Early repolarization is sometimes seen in healthy young people, especially in black men.

Early repolarization is characterized by elevation of the J point (ie, the junction between the end of the QRS complex and the beginning of the ST segment). Elevation of the J point causes elevation of the ST segment in the mid to lateral precordial leads (V₃–V₆) with an up-right T wave.²¹

Acute pericarditis tends to cause ST-segment elevation in both the limb and precordial leads, whereas ST elevation in early repolarization mainly involves the lateral chest leads.

The PR segment is more prominent in acute pericarditis, especially in lead aVR.

Another finding that strongly favors acute pericarditis is the ratio of the height of the ST-segment junction to the height of the apex of the T wave of more than 0.25 in leads I, V₄, V₅, and V₆ (Figure 4).^5,8,22

Yes. Acute pericarditis has a unique clinical presentation, physical findings, and electrocardiographic (ECG) changes. ECG is always ordered to look for ischemic changes in patients with chest pain. Acute pericarditis develops in stages, which makes it easy to differentiate from early repolarization and, more significantly, myocardial infarction. The ECG changes, along with the clinical presentation and physical findings, can make the diagnosis of pericarditis.

In atypical and complicated cases, advanced imaging studies (ie, echocardiography and cardiac magnetic resonance imaging) have been used to confirm the diagnosis and to follow the course of the disease. However, ECG remains a useful, cost-effective test.

PERICARDIAL DISEASE IS DIVERSE

The pericardium is a thin layer that covers the heart and separates it from other structures in the mediastinum.

Pericardial syndromes include acute, recurrent, constrictive, and effusive-constrictive pericarditis, as well as pericardial effusion with or without tamponade. Causes include viral or bacterial infection, postpericardiotomy syndrome (Dressler syndrome), postmyocardial infarction, primary and metastatic tumors, trauma, uremia, radiation, and autoimmune disease, but pericardial syndromes can also be idiopathic.¹

Acute pericarditis is the most common pericardial syndrome and occurs in all age groups. Once diagnosed, it can easily be treated with antiinflammatory drugs. However, recurrent pericarditis, reported in 30% of patients experiencing a first attack of pericarditis, can be difficult to manage, can have a significant impact on the patient’s health, and can be life-threatening.²

CHANGES OF ACUTE PERICARDITIS DEVELOP IN STAGES

Pericarditis can be diagnosed on the basis of ECG changes, clinical signs and symptoms, and laboratory and imaging findings.³ ECG criteria of acute pericarditis have been published.^4,5

The characteristic chest pain in acute pericarditis is usually sudden in onset and sharp and occurs over the anterior chest wall. The pain is exacerbated by inspiration and decreases when the patient sits up and leans forward.⁴

ECG classically shows a widespread saddle-shaped (upward concave) ST-segment elevation in the precordial and limb leads, reflecting subepicardial inflammation. PR-segment depression (with PR-segment elevation in lead aVR) can accompany or precede the ST changes and is known as the “discordant ST-PR segment sign” (Figures 1 and 2). These changes are seen in 60% of patients.

The ECG changes develop in stages, making them easy to differentiate from early repolarization and, more significantly, from myocardial infarction. Four stages are apparent^1,4,6–9:

• Stage I occurs in a few hours to days, with diffuse, up-sloping ST-segment elevation and upright T waves, the result of an alteration in ventricular repolarization caused by pericardial inflammation. Because of alteration in repolarization of the atrium secondary to inflammation, the PR segment is elevated in aVR and depressed in the rest of the limb and chest leads.
• Stage II—the ST and PR segments normalize.
• Stage III—widespread T-wave inversion.
• Stage IV—normalization of the T waves.

There is no pathologic Q-wave formation or loss of R-wave progression in acute pericarditis.

The ECG changes of pericarditis vary widely from one patient to another, depending on the extent and severity of pericardial inflammation and the timing of the patient’s presentation. Changes vary in duration. In some cases, ST elevation returns to baseline within a few days without T-wave inversions; in other cases, T-wave inversions can persist for weeks to months. Sometimes the abnormalities resolve by the time symptoms develop.

ASSOCIATED CONDITIONS

Myocardial involvement

In acute myocarditis, findings on ECG can be normal unless the pericardium is involved. Changes that can be seen in myocarditis and that indicate a deeper involvement of inflammation include ST-segment abnormalities, arrhythmias (eg, premature ventricular or atrial contractions), pathologic Q waves, intraventricular conduction delay, and right or left bundle branch block.^1,10–12

Elevated troponin and new focal or global left ventricular dysfunction on cardiac imaging indicates myocarditis, especially in a patient with a normal coronary angiogram.^10–13

Pericardial effusion: Tachycardia and low QRS voltage

Pericardial effusion is often a complication of pericarditis, but it can also develop from other conditions, such as myxedema, uremia, malignancy, connective tissue disease, aortic dissection, and postpericardiotomy syndrome, and it can also be iatrogenic.

The most common ECG sign of pericardial effusion is tachycardia and low voltage of the QRS complexes. Low voltage is defined as a total amplitude of the QRS complexes in each of the six limb leads less than or equal to 5 mm, and less than or equal to 10 mm in V₁ through V₆. However, low voltage is not always present in the chest leads.

Mechanisms proposed to explain low QRS voltage associated with pericardial effusion include internal short-circuiting of the electrical currents by accumulated fluids within the pericardial sac, greater distance of the heart from body surface electrodes, reduced cardiac size caused by effusion, and change in the generation and propagation of electrical current in the myocardium.14,15

Cardiac tamponade: Tachycardia, electrical alternans, low QRS voltage

Sinus tachycardia and electrical alternans are specific but not sensitive signs of pericardial tamponade (Figure 3).^16,17 Electrical alternans is characterized by beat-to-beat alterations in the axis of QRS complexes in the limb and precordial leads as a result of the mechanical swinging of the heart in a large pericardial effusion.¹⁷ There is evidence to suggest that low QRS voltage is more the result of the tamponade than the effusion.¹⁸

Treating tamponade with pericardiocentesis, surgical creation of a fistula (“window”) between the pericardial space and the pleural cavity, or anti-inflammatory drugs can resolve low QRS voltage within 1 week.

DIFFERENTIAL DIAGNOSIS OF ACUTE PERICARDITIS

Acute myocardial infarction

ECG changes in acute pericarditis differ from those in acute myocardial infarction in many ways.

ST-segment elevation in pericarditis rarely exceeds 5 mm, in contrast to acute myocardial infarction, in which ST elevation at the J point has to be more than 2 mm and in two anatomically contiguous leads.¹⁹

In pericarditis, the changes occur more slowly and in stages, reflecting the evolving inflammation of different areas of the pericardium.

The ST segment is elevated diffusely in the precordial and limb leads in pericarditis, indicating involvement of more than one coronary vascular territory, differentiating it from characteristic regional changes in myocardial infarction.^19,20

If concomitant atrial injury is present with acute pericarditis, then PR elevation in aVR with PR depression in other leads may be seen.

Finally, pathologic Q waves or high-grade heart block reflects acute myocardial infarction.

Early repolarization: Elevation of the J point

Early repolarization is sometimes seen in healthy young people, especially in black men.

Early repolarization is characterized by elevation of the J point (ie, the junction between the end of the QRS complex and the beginning of the ST segment). Elevation of the J point causes elevation of the ST segment in the mid to lateral precordial leads (V₃–V₆) with an up-right T wave.²¹

Acute pericarditis tends to cause ST-segment elevation in both the limb and precordial leads, whereas ST elevation in early repolarization mainly involves the lateral chest leads.

The PR segment is more prominent in acute pericarditis, especially in lead aVR.

Another finding that strongly favors acute pericarditis is the ratio of the height of the ST-segment junction to the height of the apex of the T wave of more than 0.25 in leads I, V₄, V₅, and V₆ (Figure 4).^5,8,22

Poor control of blood pressure is one of the most common risk factors for death worldwide, responsible for 62% of cases of cerebral vascular disease and 49% of cases of ischemic heart disease as well as 7.1 million deaths annually. As our population ages and the prevalence of obesity, diabetes, and chronic kidney disease increases, resistant hypertension will be seen more often in general practice.

Using a case study, this article will provide a strategy for diagnosing and treating resistant hypertension.

CASE: A WOMAN WITH LONG-STANDING HIGH BLOOD PRESSURE

A 37-year-old woman was referred for help with managing difficult-to-control hypertension. She had been diagnosed with hypertension at age 32, and it was well controlled until about 2 years ago. Various combinations of antihypertensive drugs had been tried, and a search for a cause of secondary hypertension revealed no clues.

On examination, her blood pressure averaged 212/124 mm Hg, and her heart rate was 109 beats per minute. Her medications were:

• Amlodipine (Norvasc), a calcium channel blocker, 10 mg once daily
• Valsartan (Diovan), an angiotensin II receptor antagonist, 160 mg once daily
• Carvedilol (Coreg), a beta-blocker, 25 mg twice daily
• Labetalol (Normodyne), a beta-blocker, 400 mg three times daily
• Clonidine (Catapres), a sympatholytic agent, 0.05 mg three times daily
• Doxazosin (Cardura), a peripheral alpha-blocker, 16 mg once daily
• Xylometazoline (Xylomet), an alpha agonist nasal spray for nasal congestion.

She had previously been taking spironolactone (Aldactone), hydralazine (Apresoline), and hydrochlorothiazide, but they were discontinued because of adverse effects.

Does this patient have resistant hypertension? How should her condition be managed?

RESISTANT HYPERTENSION DEFINED

The seventh Joint National Committee and the American Heart Association define resistant hypertension as an office blood pressure above the appropriate goal of therapy (< 140/90 mm Hg for most patients, and < 130/80 mm Hg for those with ischemic heart disease, diabetes, or renal insufficiency) despite the use of three or more antihypertensive drugs from different classes at full dosages, one of which is a diuretic.^1,2

In this definition, the number of antihypertensive drugs required is arbitrary. More importantly, the concept of resistant hypertension is focused on identifying patients who may have a reversible cause of hypertension, as well as those who could benefit from special diagnostic or therapeutic intervention because of persistently high blood pressure.

This definition does not apply to patients who have recently been diagnosed with hypertension.

Resistant hypertension is not synonymous with uncontrolled hypertension, which includes all cases of hypertension that is not optimally controlled despite treatment, including apparent resistance (ie, pseudoresistance) and true resistance (defined below).

COMMON, BUT ITS PREVALENCE IS HARD TO PINPOINT

The prevalence of resistant hypertension is unknown because of inadequate sample sizes in published studies. However, it is common and is likely to become more common with the aging of the population and with the increasing prevalence of obesity, diabetes mellitus, and chronic kidney disease.

In small studies, the prevalence of resistance in hypertensive patients ranged from 5% in general medical practice to more than 50% in nephrology clinics. In the National Health and Nutrition Examination Survey in 2003 to 2004, only 58% of people being treated for hypertension had achieved blood pressure levels lower than 140/90 mm Hg,³ and the control rate in those with diabetes mellitus or chronic kidney disease was less than 40%.⁴

Isolated systolic hypertension—elevated systolic pressure with normal diastolic pressure—increases in prevalence with age in those with treated, uncontrolled hypertension. It accounted for 29.1% of cases of treated, uncontrolled hypertension in patients ages 25 to 44, 66.1% of cases in patients ages 45 to 64, and 87.6% of cases in patients age 65 and older.⁵

Even in clinical trials, in which one would expect excellent control of hypertension, rates of control ranged from 45% to 82%.^6–10

APPARENT RESISTANCE VS TRUE RESISTANCE

Resistant hypertension can be divided arbitrarily into two broad categories: apparent resistance and true resistance, with the prevalence of apparent resistance being considerably higher. Each broad category has a long list of possible causes; most are readily identifiable in the course of a thorough history and physical examination and routine laboratory testing. If resistance to therapy persists, referral to a hypertension specialist is a logical next step.

Detecting pseudoresistance

Causes of apparent resistance include improper technique in measuring blood pressure, such as not having the patient rest before measurement, allowing the patient to have coffee or to smoke just before measurement, or not positioning the patient’s arm at the level of the heart during measurement.

Many elderly patients have calcified arteries that are hard to compress, leading to erroneously high systolic blood pressure measurements, a situation called pseudohypertension and a cause of pseudoresistance. The only way to measure blood pressure accurately in such cases is intra-arterially. These patients often do not have target-organ disease, which would be expected with high systolic pressure.

The white-coat phenomenon is another common cause of apparent resistance. It is defined as persistently elevated clinic or office blood pressure (> 140/90 mm Hg), together with normal daytime ambulatory blood pressure (the “white-coat effect” is the difference between those blood pressures).

Finally, poor patient adherence to treatment is estimated to account for 40% of cases of resistant hypertension.^4,5,11 Poor adherence is difficult to prove because patients often claim they are compliant, but certain clues are indicative. For example, patients taking a diuretic should have increased uric acid levels, so normal uric acid levels in a patient on a diuretic could be a clue that he or she is not taking the medication. If poor adherence is suspected, patients should be admitted to the hospital to take the medications under close observation.

Many cases of resistant hypertension are drug-induced, particularly in patients taking a nonsteroidal anti-inflammatory drug or a cyclooxygenase II inhibitor. Use of ginseng, ma huang, and bitter lemon should also be suspected. Drugs or herbal preparations contributing to high blood pressure should be discontinued or minimized.

Alcohol intake in excess of two drinks (1 oz of alcohol) per day for men and half that amount for women can also contribute to hypertension.

Volume overload is common and has many causes, including a compensatory response to vasodilators, excessive salt intake, or an undetected reduction in the glomerular filtration rate causing retention of salt and water.

Drug considerations

A common cause of apparent resistant hypertension is physicians not following blood pressure treatment guidelines by not increasing the dosage when needed or by prescribing inappropriate drug combinations.

We commonly see furosemide (Lasix) being misused, ie, being prescribed once daily for hypertension. (It has a shorter duration of action than thiazide diuretics, the usual class of diuretics used for hypertension.)

For a patient who is already on many medications but whose hypertension is not responding, the first step should be to give a diuretic of an appropriate class in an appropriate dosage.

Diuretics are often inappropriately stopped if a patient develops hypokalemia. Potassium supplementation should always be an adjunct to diuretic therapy. Potassium itself is a potent vasodilator and, given as a supplement, has been shown to reduce stroke risk in rats.

The combination of an angiotensin receptor blocker and an angiotensin-converting enzyme inhibitor should not be used for patients with true resistant hypertension. The direct renin inhibitor aliskiren (Tekturna) should not be used in combination with these drugs, and the combination of aliskiren and valsartan (Valturna) has now been taken off the market.

Spironolactone (Aldactone) is sometimes used for resistant hypertension in the belief that in some cases primary aldosteronism is the underlying cause. A study in 1,400 participants confirms that it lowers blood pressure,⁹ but the reason is unclear: the blood pressure response was unrelated to levels of renin, angiotensin, or the plasma aldosterone-to-renin ratio.

Identify secondary causes of hypertension

Patients should be evaluated for kidney disease, which is the most common secondary medical reason for resistant hypertension. For patients with poor renal function (estimated glomerular filtration rate < 50 mL/minute), hydrochlorothiazide is not effective against hypertension, but chlorthalidone is. In addition, patients with poor renal function should be given loop diuretics such as furosemide two or three times daily, or the long-acting drug torsemide (Demadex) should be used instead.

Genetic variation can cause different rates of metabolism of drugs, contributing to resistant hypertension. Certain people metabolize hydralazine very fast, making it less effective. The same is true for some beta-blockers.

Obesity and diabetes can also contribute to resistant hypertension.

Ancillary neurohumoral studies are occasionally indicated to rule out identifiable causes of secondary hypertension that may be correctable. There are many identifiable causes of hypertension, but detailing each is beyond the scope of this article.

Patients should be tested for thyroid disease. Hypothyroidism can cause high blood pressure, although usually diastolic rather than systolic hypertension. Hyperthyroidism can cause marked systolic hypertension.

Table 1 provides a step-by-step guide for evaluating and managing patients with resistant hypertension.

EXPERIMENTAL DRUG THERAPY

Endothelin receptor antagonists are currently under investigation for the treatment of resistant hypertension. The protein endothelin-1 (ET-1) is a potent vasoconstrictor (30–50 times more potent than angiotensin II and norepinephrine) and has a long duration of action. ET-1 binds to two receptors with opposing effects: ET-A promotes vasoconstriction, and ET-B promotes vasodilation and clears ET-1.

Darusentan, a selective blocker of ET-A, was tested in the phase III DORADO trial, which was discontinued because the initial results did not meet primary outcome measures. Initial findings had indicated that it might not be as useful as hoped. Side effects included headache, flushing, and edema.

EXPERIMENTAL NONPHARMACOLOGIC THERAPIES

Electrical stimulation of carotid sinus baroreceptors is being tried under the assumption that a high sympathoexcitatory state contributes to resistant hypertension. Devices are placed around the carotid artery bifurcation, and stimulation is believed to increase the depressor influences that modulate blood pressure. Large-scale trials are under way, but it is too early to tell if the approach will be useful. Patients complain of neck pain from the device.

Renal denervation is another experimental approach.¹² The kidney has a central role in blood pressure regulation: efferent nerves regulate renal vascular resistance, renal blood flow, and renin release from the juxtaglomerular apparatus; afferent nerves modulate sympathetic output from the central nervous system. The results of the Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN) trials 1 and 2 have been encouraging. The Symplicity HTN-3 trial will begin soon in the United States.

OUR PATIENT UNDERGOES ADDITIONAL STUDIES

To rule out the white-coat effect in our patient, we measured her blood pressure with an automated device that takes several readings without the clinician in the room. (This topic has been reviewed by Vidt et al in this journal¹³). The average of the automated readings was 183/113 mm Hg, and her average pulse was 109 beats per minute, arguing against a white-coat effect.

Her blood pressure was also markedly elevated (average 198/129) during 24-hour ambulatory blood pressure monitoring.

Findings on physical examination were unremarkable except for grade III hypertensive retinopathy. She had no carotid or abdominal bruits. Her peripheral pulses were strong and synchronous bilaterally.

Laboratory testing found the patient had normal serum electrolyte levels and good renal function but relatively low urinary sodium, 90 mmol/day (normal 40–220), and very low renin activity, 0.7 μg/L/h (normal up-right 0.8–5.8 μg/L/h, supine 0.5–1.8 μg/L/h), calling into question the wisdom of treatment with an angiotensin receptor blocker.

Hemodynamic studies were performed using impedance cardiography and found very high systemic vascular resistance with normal cardiac output, indicating that the patient had a high preload, which could be from hypervolemia or intense venous constriction. It is especially interesting that her vascular resistance was high despite her treatment regimen that included an angiotensin receptor blocker and a vasodilator, perhaps an indication of nonadherence with her medications.

Diuresis reduces her blood pressure

The patient was admitted to the hospital, and because her laboratory results indicated that plasma renin activity was suppressed, the angiotensin receptor blocker valsartan was discontinued.

On day 1, her weight was 162 lb and average blood pressure was 194/128 mm Hg. After 4 days of diuresis with escalating doses of furosemide, her weight was 153 lb and blood pressures ranged from 140 to 158 over 82 to 98 mm Hg. Her heart rate was 90 beats per minute. The hospital stay showed that volume overload was one of the factors maintaining her hypertension. She was discharged on metoprolol succinate (Toprol-XL) 100 mg twice daily and furosemide 80 mg twice daily.

Her blood pressure fluctuates widely after discharge

Over the next 5 days after discharge, the patient’s blood pressure rose steadily to 180/122 mm Hg, her heart rate was in excess of 100 beats per minute, and her weight increased to 158 lb. Blood screening found that the level of metoprolol was undetectable, and a diuretic screen showed no furosemide in the urine. Both the patient and her husband were adamant that she was taking her medications.

Hydrochlorothiazide 25 mg daily was added, and nadolol (Corgard) 80 mg once daily was started in place of metoprolol. On a return visit, her blood pressure and heart rate were finally good at 138/86 mm Hg and 60 beats per minute (sitting) and 134/92 and 63 (standing).

On 24-hour monitoring, some fluctuations of elevated blood pressure were still evident, with an average of 142/91 mm Hg, so nifedipine (Procardia) 60 mg daily was added.

Her final list of medications is hydrochlorothiazide 25 mg, nadolol 80 mg, and nifedipine XL 60 mg, all taken once daily.

Volume overload complicated by nonadherence

In summary, the main pathogenetic mechanism that sustained this patient’s hypertension was volume overload. Her urinary sodium level indicated that she was not taking excessive amounts of sodium. The volume overload may have been a compensatory response to the concomitant use of peripheral vasodilators plus sympatholytic agents.

In addition, she was not adherent to her antihypertensive regimen. The fact that her heart rate was 109 beats per minute despite having a drug regimen that included five sympathetic blocking agents was a strong clue. She eventually admitted that she did not like taking diuretics because they made her skin wrinkle.

In general, in a case like this, I try to minimize the number of drugs and give a diuretic as well as different classes of appropriate drugs.

Poor control of blood pressure is one of the most common risk factors for death worldwide, responsible for 62% of cases of cerebral vascular disease and 49% of cases of ischemic heart disease as well as 7.1 million deaths annually. As our population ages and the prevalence of obesity, diabetes, and chronic kidney disease increases, resistant hypertension will be seen more often in general practice.

Using a case study, this article will provide a strategy for diagnosing and treating resistant hypertension.

CASE: A WOMAN WITH LONG-STANDING HIGH BLOOD PRESSURE

A 37-year-old woman was referred for help with managing difficult-to-control hypertension. She had been diagnosed with hypertension at age 32, and it was well controlled until about 2 years ago. Various combinations of antihypertensive drugs had been tried, and a search for a cause of secondary hypertension revealed no clues.

On examination, her blood pressure averaged 212/124 mm Hg, and her heart rate was 109 beats per minute. Her medications were:

• Amlodipine (Norvasc), a calcium channel blocker, 10 mg once daily
• Valsartan (Diovan), an angiotensin II receptor antagonist, 160 mg once daily
• Carvedilol (Coreg), a beta-blocker, 25 mg twice daily
• Labetalol (Normodyne), a beta-blocker, 400 mg three times daily
• Clonidine (Catapres), a sympatholytic agent, 0.05 mg three times daily
• Doxazosin (Cardura), a peripheral alpha-blocker, 16 mg once daily
• Xylometazoline (Xylomet), an alpha agonist nasal spray for nasal congestion.

She had previously been taking spironolactone (Aldactone), hydralazine (Apresoline), and hydrochlorothiazide, but they were discontinued because of adverse effects.

Does this patient have resistant hypertension? How should her condition be managed?

RESISTANT HYPERTENSION DEFINED

The seventh Joint National Committee and the American Heart Association define resistant hypertension as an office blood pressure above the appropriate goal of therapy (< 140/90 mm Hg for most patients, and < 130/80 mm Hg for those with ischemic heart disease, diabetes, or renal insufficiency) despite the use of three or more antihypertensive drugs from different classes at full dosages, one of which is a diuretic.^1,2

In this definition, the number of antihypertensive drugs required is arbitrary. More importantly, the concept of resistant hypertension is focused on identifying patients who may have a reversible cause of hypertension, as well as those who could benefit from special diagnostic or therapeutic intervention because of persistently high blood pressure.

This definition does not apply to patients who have recently been diagnosed with hypertension.

Resistant hypertension is not synonymous with uncontrolled hypertension, which includes all cases of hypertension that is not optimally controlled despite treatment, including apparent resistance (ie, pseudoresistance) and true resistance (defined below).

COMMON, BUT ITS PREVALENCE IS HARD TO PINPOINT

The prevalence of resistant hypertension is unknown because of inadequate sample sizes in published studies. However, it is common and is likely to become more common with the aging of the population and with the increasing prevalence of obesity, diabetes mellitus, and chronic kidney disease.

In small studies, the prevalence of resistance in hypertensive patients ranged from 5% in general medical practice to more than 50% in nephrology clinics. In the National Health and Nutrition Examination Survey in 2003 to 2004, only 58% of people being treated for hypertension had achieved blood pressure levels lower than 140/90 mm Hg,³ and the control rate in those with diabetes mellitus or chronic kidney disease was less than 40%.⁴

Isolated systolic hypertension—elevated systolic pressure with normal diastolic pressure—increases in prevalence with age in those with treated, uncontrolled hypertension. It accounted for 29.1% of cases of treated, uncontrolled hypertension in patients ages 25 to 44, 66.1% of cases in patients ages 45 to 64, and 87.6% of cases in patients age 65 and older.⁵

Even in clinical trials, in which one would expect excellent control of hypertension, rates of control ranged from 45% to 82%.^6–10

APPARENT RESISTANCE VS TRUE RESISTANCE

Resistant hypertension can be divided arbitrarily into two broad categories: apparent resistance and true resistance, with the prevalence of apparent resistance being considerably higher. Each broad category has a long list of possible causes; most are readily identifiable in the course of a thorough history and physical examination and routine laboratory testing. If resistance to therapy persists, referral to a hypertension specialist is a logical next step.

Detecting pseudoresistance

Causes of apparent resistance include improper technique in measuring blood pressure, such as not having the patient rest before measurement, allowing the patient to have coffee or to smoke just before measurement, or not positioning the patient’s arm at the level of the heart during measurement.

Many elderly patients have calcified arteries that are hard to compress, leading to erroneously high systolic blood pressure measurements, a situation called pseudohypertension and a cause of pseudoresistance. The only way to measure blood pressure accurately in such cases is intra-arterially. These patients often do not have target-organ disease, which would be expected with high systolic pressure.

The white-coat phenomenon is another common cause of apparent resistance. It is defined as persistently elevated clinic or office blood pressure (> 140/90 mm Hg), together with normal daytime ambulatory blood pressure (the “white-coat effect” is the difference between those blood pressures).

Finally, poor patient adherence to treatment is estimated to account for 40% of cases of resistant hypertension.^4,5,11 Poor adherence is difficult to prove because patients often claim they are compliant, but certain clues are indicative. For example, patients taking a diuretic should have increased uric acid levels, so normal uric acid levels in a patient on a diuretic could be a clue that he or she is not taking the medication. If poor adherence is suspected, patients should be admitted to the hospital to take the medications under close observation.

Many cases of resistant hypertension are drug-induced, particularly in patients taking a nonsteroidal anti-inflammatory drug or a cyclooxygenase II inhibitor. Use of ginseng, ma huang, and bitter lemon should also be suspected. Drugs or herbal preparations contributing to high blood pressure should be discontinued or minimized.

Alcohol intake in excess of two drinks (1 oz of alcohol) per day for men and half that amount for women can also contribute to hypertension.

Volume overload is common and has many causes, including a compensatory response to vasodilators, excessive salt intake, or an undetected reduction in the glomerular filtration rate causing retention of salt and water.

Drug considerations

A common cause of apparent resistant hypertension is physicians not following blood pressure treatment guidelines by not increasing the dosage when needed or by prescribing inappropriate drug combinations.

We commonly see furosemide (Lasix) being misused, ie, being prescribed once daily for hypertension. (It has a shorter duration of action than thiazide diuretics, the usual class of diuretics used for hypertension.)

For a patient who is already on many medications but whose hypertension is not responding, the first step should be to give a diuretic of an appropriate class in an appropriate dosage.

Diuretics are often inappropriately stopped if a patient develops hypokalemia. Potassium supplementation should always be an adjunct to diuretic therapy. Potassium itself is a potent vasodilator and, given as a supplement, has been shown to reduce stroke risk in rats.

The combination of an angiotensin receptor blocker and an angiotensin-converting enzyme inhibitor should not be used for patients with true resistant hypertension. The direct renin inhibitor aliskiren (Tekturna) should not be used in combination with these drugs, and the combination of aliskiren and valsartan (Valturna) has now been taken off the market.

Spironolactone (Aldactone) is sometimes used for resistant hypertension in the belief that in some cases primary aldosteronism is the underlying cause. A study in 1,400 participants confirms that it lowers blood pressure,⁹ but the reason is unclear: the blood pressure response was unrelated to levels of renin, angiotensin, or the plasma aldosterone-to-renin ratio.

Identify secondary causes of hypertension

Patients should be evaluated for kidney disease, which is the most common secondary medical reason for resistant hypertension. For patients with poor renal function (estimated glomerular filtration rate < 50 mL/minute), hydrochlorothiazide is not effective against hypertension, but chlorthalidone is. In addition, patients with poor renal function should be given loop diuretics such as furosemide two or three times daily, or the long-acting drug torsemide (Demadex) should be used instead.

Genetic variation can cause different rates of metabolism of drugs, contributing to resistant hypertension. Certain people metabolize hydralazine very fast, making it less effective. The same is true for some beta-blockers.

Obesity and diabetes can also contribute to resistant hypertension.

Ancillary neurohumoral studies are occasionally indicated to rule out identifiable causes of secondary hypertension that may be correctable. There are many identifiable causes of hypertension, but detailing each is beyond the scope of this article.

Patients should be tested for thyroid disease. Hypothyroidism can cause high blood pressure, although usually diastolic rather than systolic hypertension. Hyperthyroidism can cause marked systolic hypertension.

Table 1 provides a step-by-step guide for evaluating and managing patients with resistant hypertension.

EXPERIMENTAL DRUG THERAPY

Endothelin receptor antagonists are currently under investigation for the treatment of resistant hypertension. The protein endothelin-1 (ET-1) is a potent vasoconstrictor (30–50 times more potent than angiotensin II and norepinephrine) and has a long duration of action. ET-1 binds to two receptors with opposing effects: ET-A promotes vasoconstriction, and ET-B promotes vasodilation and clears ET-1.

Darusentan, a selective blocker of ET-A, was tested in the phase III DORADO trial, which was discontinued because the initial results did not meet primary outcome measures. Initial findings had indicated that it might not be as useful as hoped. Side effects included headache, flushing, and edema.

EXPERIMENTAL NONPHARMACOLOGIC THERAPIES

Electrical stimulation of carotid sinus baroreceptors is being tried under the assumption that a high sympathoexcitatory state contributes to resistant hypertension. Devices are placed around the carotid artery bifurcation, and stimulation is believed to increase the depressor influences that modulate blood pressure. Large-scale trials are under way, but it is too early to tell if the approach will be useful. Patients complain of neck pain from the device.

Renal denervation is another experimental approach.¹² The kidney has a central role in blood pressure regulation: efferent nerves regulate renal vascular resistance, renal blood flow, and renin release from the juxtaglomerular apparatus; afferent nerves modulate sympathetic output from the central nervous system. The results of the Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN) trials 1 and 2 have been encouraging. The Symplicity HTN-3 trial will begin soon in the United States.

OUR PATIENT UNDERGOES ADDITIONAL STUDIES

To rule out the white-coat effect in our patient, we measured her blood pressure with an automated device that takes several readings without the clinician in the room. (This topic has been reviewed by Vidt et al in this journal¹³). The average of the automated readings was 183/113 mm Hg, and her average pulse was 109 beats per minute, arguing against a white-coat effect.

Her blood pressure was also markedly elevated (average 198/129) during 24-hour ambulatory blood pressure monitoring.

Findings on physical examination were unremarkable except for grade III hypertensive retinopathy. She had no carotid or abdominal bruits. Her peripheral pulses were strong and synchronous bilaterally.

Laboratory testing found the patient had normal serum electrolyte levels and good renal function but relatively low urinary sodium, 90 mmol/day (normal 40–220), and very low renin activity, 0.7 μg/L/h (normal up-right 0.8–5.8 μg/L/h, supine 0.5–1.8 μg/L/h), calling into question the wisdom of treatment with an angiotensin receptor blocker.

Hemodynamic studies were performed using impedance cardiography and found very high systemic vascular resistance with normal cardiac output, indicating that the patient had a high preload, which could be from hypervolemia or intense venous constriction. It is especially interesting that her vascular resistance was high despite her treatment regimen that included an angiotensin receptor blocker and a vasodilator, perhaps an indication of nonadherence with her medications.

Diuresis reduces her blood pressure

The patient was admitted to the hospital, and because her laboratory results indicated that plasma renin activity was suppressed, the angiotensin receptor blocker valsartan was discontinued.

On day 1, her weight was 162 lb and average blood pressure was 194/128 mm Hg. After 4 days of diuresis with escalating doses of furosemide, her weight was 153 lb and blood pressures ranged from 140 to 158 over 82 to 98 mm Hg. Her heart rate was 90 beats per minute. The hospital stay showed that volume overload was one of the factors maintaining her hypertension. She was discharged on metoprolol succinate (Toprol-XL) 100 mg twice daily and furosemide 80 mg twice daily.

Her blood pressure fluctuates widely after discharge

Over the next 5 days after discharge, the patient’s blood pressure rose steadily to 180/122 mm Hg, her heart rate was in excess of 100 beats per minute, and her weight increased to 158 lb. Blood screening found that the level of metoprolol was undetectable, and a diuretic screen showed no furosemide in the urine. Both the patient and her husband were adamant that she was taking her medications.

Hydrochlorothiazide 25 mg daily was added, and nadolol (Corgard) 80 mg once daily was started in place of metoprolol. On a return visit, her blood pressure and heart rate were finally good at 138/86 mm Hg and 60 beats per minute (sitting) and 134/92 and 63 (standing).

On 24-hour monitoring, some fluctuations of elevated blood pressure were still evident, with an average of 142/91 mm Hg, so nifedipine (Procardia) 60 mg daily was added.

Her final list of medications is hydrochlorothiazide 25 mg, nadolol 80 mg, and nifedipine XL 60 mg, all taken once daily.

Volume overload complicated by nonadherence

In summary, the main pathogenetic mechanism that sustained this patient’s hypertension was volume overload. Her urinary sodium level indicated that she was not taking excessive amounts of sodium. The volume overload may have been a compensatory response to the concomitant use of peripheral vasodilators plus sympatholytic agents.

In addition, she was not adherent to her antihypertensive regimen. The fact that her heart rate was 109 beats per minute despite having a drug regimen that included five sympathetic blocking agents was a strong clue. She eventually admitted that she did not like taking diuretics because they made her skin wrinkle.

In general, in a case like this, I try to minimize the number of drugs and give a diuretic as well as different classes of appropriate drugs.

Poor control of blood pressure is one of the most common risk factors for death worldwide, responsible for 62% of cases of cerebral vascular disease and 49% of cases of ischemic heart disease as well as 7.1 million deaths annually. As our population ages and the prevalence of obesity, diabetes, and chronic kidney disease increases, resistant hypertension will be seen more often in general practice.

Using a case study, this article will provide a strategy for diagnosing and treating resistant hypertension.

CASE: A WOMAN WITH LONG-STANDING HIGH BLOOD PRESSURE

A 37-year-old woman was referred for help with managing difficult-to-control hypertension. She had been diagnosed with hypertension at age 32, and it was well controlled until about 2 years ago. Various combinations of antihypertensive drugs had been tried, and a search for a cause of secondary hypertension revealed no clues.

On examination, her blood pressure averaged 212/124 mm Hg, and her heart rate was 109 beats per minute. Her medications were:

• Amlodipine (Norvasc), a calcium channel blocker, 10 mg once daily
• Valsartan (Diovan), an angiotensin II receptor antagonist, 160 mg once daily
• Carvedilol (Coreg), a beta-blocker, 25 mg twice daily
• Labetalol (Normodyne), a beta-blocker, 400 mg three times daily
• Clonidine (Catapres), a sympatholytic agent, 0.05 mg three times daily
• Doxazosin (Cardura), a peripheral alpha-blocker, 16 mg once daily
• Xylometazoline (Xylomet), an alpha agonist nasal spray for nasal congestion.

She had previously been taking spironolactone (Aldactone), hydralazine (Apresoline), and hydrochlorothiazide, but they were discontinued because of adverse effects.

Does this patient have resistant hypertension? How should her condition be managed?

RESISTANT HYPERTENSION DEFINED

The seventh Joint National Committee and the American Heart Association define resistant hypertension as an office blood pressure above the appropriate goal of therapy (< 140/90 mm Hg for most patients, and < 130/80 mm Hg for those with ischemic heart disease, diabetes, or renal insufficiency) despite the use of three or more antihypertensive drugs from different classes at full dosages, one of which is a diuretic.^1,2

In this definition, the number of antihypertensive drugs required is arbitrary. More importantly, the concept of resistant hypertension is focused on identifying patients who may have a reversible cause of hypertension, as well as those who could benefit from special diagnostic or therapeutic intervention because of persistently high blood pressure.

This definition does not apply to patients who have recently been diagnosed with hypertension.

Resistant hypertension is not synonymous with uncontrolled hypertension, which includes all cases of hypertension that is not optimally controlled despite treatment, including apparent resistance (ie, pseudoresistance) and true resistance (defined below).

COMMON, BUT ITS PREVALENCE IS HARD TO PINPOINT

The prevalence of resistant hypertension is unknown because of inadequate sample sizes in published studies. However, it is common and is likely to become more common with the aging of the population and with the increasing prevalence of obesity, diabetes mellitus, and chronic kidney disease.

In small studies, the prevalence of resistance in hypertensive patients ranged from 5% in general medical practice to more than 50% in nephrology clinics. In the National Health and Nutrition Examination Survey in 2003 to 2004, only 58% of people being treated for hypertension had achieved blood pressure levels lower than 140/90 mm Hg,³ and the control rate in those with diabetes mellitus or chronic kidney disease was less than 40%.⁴

Isolated systolic hypertension—elevated systolic pressure with normal diastolic pressure—increases in prevalence with age in those with treated, uncontrolled hypertension. It accounted for 29.1% of cases of treated, uncontrolled hypertension in patients ages 25 to 44, 66.1% of cases in patients ages 45 to 64, and 87.6% of cases in patients age 65 and older.⁵

Even in clinical trials, in which one would expect excellent control of hypertension, rates of control ranged from 45% to 82%.^6–10

APPARENT RESISTANCE VS TRUE RESISTANCE

Resistant hypertension can be divided arbitrarily into two broad categories: apparent resistance and true resistance, with the prevalence of apparent resistance being considerably higher. Each broad category has a long list of possible causes; most are readily identifiable in the course of a thorough history and physical examination and routine laboratory testing. If resistance to therapy persists, referral to a hypertension specialist is a logical next step.

Detecting pseudoresistance

Causes of apparent resistance include improper technique in measuring blood pressure, such as not having the patient rest before measurement, allowing the patient to have coffee or to smoke just before measurement, or not positioning the patient’s arm at the level of the heart during measurement.

Many elderly patients have calcified arteries that are hard to compress, leading to erroneously high systolic blood pressure measurements, a situation called pseudohypertension and a cause of pseudoresistance. The only way to measure blood pressure accurately in such cases is intra-arterially. These patients often do not have target-organ disease, which would be expected with high systolic pressure.

The white-coat phenomenon is another common cause of apparent resistance. It is defined as persistently elevated clinic or office blood pressure (> 140/90 mm Hg), together with normal daytime ambulatory blood pressure (the “white-coat effect” is the difference between those blood pressures).

Finally, poor patient adherence to treatment is estimated to account for 40% of cases of resistant hypertension.^4,5,11 Poor adherence is difficult to prove because patients often claim they are compliant, but certain clues are indicative. For example, patients taking a diuretic should have increased uric acid levels, so normal uric acid levels in a patient on a diuretic could be a clue that he or she is not taking the medication. If poor adherence is suspected, patients should be admitted to the hospital to take the medications under close observation.

Many cases of resistant hypertension are drug-induced, particularly in patients taking a nonsteroidal anti-inflammatory drug or a cyclooxygenase II inhibitor. Use of ginseng, ma huang, and bitter lemon should also be suspected. Drugs or herbal preparations contributing to high blood pressure should be discontinued or minimized.

Alcohol intake in excess of two drinks (1 oz of alcohol) per day for men and half that amount for women can also contribute to hypertension.

Volume overload is common and has many causes, including a compensatory response to vasodilators, excessive salt intake, or an undetected reduction in the glomerular filtration rate causing retention of salt and water.

Drug considerations

A common cause of apparent resistant hypertension is physicians not following blood pressure treatment guidelines by not increasing the dosage when needed or by prescribing inappropriate drug combinations.

We commonly see furosemide (Lasix) being misused, ie, being prescribed once daily for hypertension. (It has a shorter duration of action than thiazide diuretics, the usual class of diuretics used for hypertension.)

For a patient who is already on many medications but whose hypertension is not responding, the first step should be to give a diuretic of an appropriate class in an appropriate dosage.

Diuretics are often inappropriately stopped if a patient develops hypokalemia. Potassium supplementation should always be an adjunct to diuretic therapy. Potassium itself is a potent vasodilator and, given as a supplement, has been shown to reduce stroke risk in rats.

The combination of an angiotensin receptor blocker and an angiotensin-converting enzyme inhibitor should not be used for patients with true resistant hypertension. The direct renin inhibitor aliskiren (Tekturna) should not be used in combination with these drugs, and the combination of aliskiren and valsartan (Valturna) has now been taken off the market.

Spironolactone (Aldactone) is sometimes used for resistant hypertension in the belief that in some cases primary aldosteronism is the underlying cause. A study in 1,400 participants confirms that it lowers blood pressure,⁹ but the reason is unclear: the blood pressure response was unrelated to levels of renin, angiotensin, or the plasma aldosterone-to-renin ratio.

Identify secondary causes of hypertension

Patients should be evaluated for kidney disease, which is the most common secondary medical reason for resistant hypertension. For patients with poor renal function (estimated glomerular filtration rate < 50 mL/minute), hydrochlorothiazide is not effective against hypertension, but chlorthalidone is. In addition, patients with poor renal function should be given loop diuretics such as furosemide two or three times daily, or the long-acting drug torsemide (Demadex) should be used instead.

Genetic variation can cause different rates of metabolism of drugs, contributing to resistant hypertension. Certain people metabolize hydralazine very fast, making it less effective. The same is true for some beta-blockers.

Obesity and diabetes can also contribute to resistant hypertension.

Ancillary neurohumoral studies are occasionally indicated to rule out identifiable causes of secondary hypertension that may be correctable. There are many identifiable causes of hypertension, but detailing each is beyond the scope of this article.

Patients should be tested for thyroid disease. Hypothyroidism can cause high blood pressure, although usually diastolic rather than systolic hypertension. Hyperthyroidism can cause marked systolic hypertension.

Table 1 provides a step-by-step guide for evaluating and managing patients with resistant hypertension.

EXPERIMENTAL DRUG THERAPY

Endothelin receptor antagonists are currently under investigation for the treatment of resistant hypertension. The protein endothelin-1 (ET-1) is a potent vasoconstrictor (30–50 times more potent than angiotensin II and norepinephrine) and has a long duration of action. ET-1 binds to two receptors with opposing effects: ET-A promotes vasoconstriction, and ET-B promotes vasodilation and clears ET-1.

Darusentan, a selective blocker of ET-A, was tested in the phase III DORADO trial, which was discontinued because the initial results did not meet primary outcome measures. Initial findings had indicated that it might not be as useful as hoped. Side effects included headache, flushing, and edema.

EXPERIMENTAL NONPHARMACOLOGIC THERAPIES

Electrical stimulation of carotid sinus baroreceptors is being tried under the assumption that a high sympathoexcitatory state contributes to resistant hypertension. Devices are placed around the carotid artery bifurcation, and stimulation is believed to increase the depressor influences that modulate blood pressure. Large-scale trials are under way, but it is too early to tell if the approach will be useful. Patients complain of neck pain from the device.

Renal denervation is another experimental approach.¹² The kidney has a central role in blood pressure regulation: efferent nerves regulate renal vascular resistance, renal blood flow, and renin release from the juxtaglomerular apparatus; afferent nerves modulate sympathetic output from the central nervous system. The results of the Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN) trials 1 and 2 have been encouraging. The Symplicity HTN-3 trial will begin soon in the United States.

OUR PATIENT UNDERGOES ADDITIONAL STUDIES

To rule out the white-coat effect in our patient, we measured her blood pressure with an automated device that takes several readings without the clinician in the room. (This topic has been reviewed by Vidt et al in this journal¹³). The average of the automated readings was 183/113 mm Hg, and her average pulse was 109 beats per minute, arguing against a white-coat effect.

Her blood pressure was also markedly elevated (average 198/129) during 24-hour ambulatory blood pressure monitoring.

Findings on physical examination were unremarkable except for grade III hypertensive retinopathy. She had no carotid or abdominal bruits. Her peripheral pulses were strong and synchronous bilaterally.

Laboratory testing found the patient had normal serum electrolyte levels and good renal function but relatively low urinary sodium, 90 mmol/day (normal 40–220), and very low renin activity, 0.7 μg/L/h (normal up-right 0.8–5.8 μg/L/h, supine 0.5–1.8 μg/L/h), calling into question the wisdom of treatment with an angiotensin receptor blocker.

Hemodynamic studies were performed using impedance cardiography and found very high systemic vascular resistance with normal cardiac output, indicating that the patient had a high preload, which could be from hypervolemia or intense venous constriction. It is especially interesting that her vascular resistance was high despite her treatment regimen that included an angiotensin receptor blocker and a vasodilator, perhaps an indication of nonadherence with her medications.

Diuresis reduces her blood pressure

The patient was admitted to the hospital, and because her laboratory results indicated that plasma renin activity was suppressed, the angiotensin receptor blocker valsartan was discontinued.

On day 1, her weight was 162 lb and average blood pressure was 194/128 mm Hg. After 4 days of diuresis with escalating doses of furosemide, her weight was 153 lb and blood pressures ranged from 140 to 158 over 82 to 98 mm Hg. Her heart rate was 90 beats per minute. The hospital stay showed that volume overload was one of the factors maintaining her hypertension. She was discharged on metoprolol succinate (Toprol-XL) 100 mg twice daily and furosemide 80 mg twice daily.

Her blood pressure fluctuates widely after discharge

Over the next 5 days after discharge, the patient’s blood pressure rose steadily to 180/122 mm Hg, her heart rate was in excess of 100 beats per minute, and her weight increased to 158 lb. Blood screening found that the level of metoprolol was undetectable, and a diuretic screen showed no furosemide in the urine. Both the patient and her husband were adamant that she was taking her medications.

Hydrochlorothiazide 25 mg daily was added, and nadolol (Corgard) 80 mg once daily was started in place of metoprolol. On a return visit, her blood pressure and heart rate were finally good at 138/86 mm Hg and 60 beats per minute (sitting) and 134/92 and 63 (standing).

On 24-hour monitoring, some fluctuations of elevated blood pressure were still evident, with an average of 142/91 mm Hg, so nifedipine (Procardia) 60 mg daily was added.

Her final list of medications is hydrochlorothiazide 25 mg, nadolol 80 mg, and nifedipine XL 60 mg, all taken once daily.

Volume overload complicated by nonadherence

In summary, the main pathogenetic mechanism that sustained this patient’s hypertension was volume overload. Her urinary sodium level indicated that she was not taking excessive amounts of sodium. The volume overload may have been a compensatory response to the concomitant use of peripheral vasodilators plus sympatholytic agents.

In addition, she was not adherent to her antihypertensive regimen. The fact that her heart rate was 109 beats per minute despite having a drug regimen that included five sympathetic blocking agents was a strong clue. She eventually admitted that she did not like taking diuretics because they made her skin wrinkle.

In general, in a case like this, I try to minimize the number of drugs and give a diuretic as well as different classes of appropriate drugs.

A 36-year-old woman on total parenteral nutrition because of short-bowel syndrome presented with a 2-week history of skin lesions on the face, arms, and legs, but no fever. Examination revealed prominent vesicular lesions on the left arm (Figure 1), face, palms, and soles. Cultures of biopsy specimens were negative for viral, bacterial, and fungal organisms.

Q: Which is the most likely diagnosis?

• Herpes simplex infection
• Varicella zoster infection
• Coxsackievirus infection
• Micronutrient deficiency
• Pemphigus vulgaris

A: Micronutrient deficiency is most likely the cause of her lesions—specifically, severe zinc deficiency, as she was found to have a serum zinc concentration of 12 μg/dL (reference range 55–150). Biopsy specimens showed characteristic intraepidermal blistering with necrosis and minimal inflammation. Serum levels of other micronutrients (iron, copper, selenium) were normal.

Her total parenteral nutrition regimen contained no zinc. Zinc supplementation was started, and a few days later the lesions began to resolve.

Herpes viral infections can cause similar blistering lesions, but this diagnosis was unlikely given the negative viral culture and direct fluorescence antibody test. Coxsackievirus infection is most often seen in children and typically causes fever and mouth sores, which this patient did not have. Lesions of pemphigus vulgaris typically exhibit the Nikolsky sign, ie, they are flaccid, they rupture easily, and the surrounding superficial skin separates from the deeper layers with rubbing or minor trauma. Our patient’s blisters were tense, with a negative Nikolsky sign, and skin biopsy was not consistent with pemphigus vulgaris.

Dermatitis can result from zinc deficiency, which can occur in conditions that cause severe malnutrition due to malabsorption or reduced dietary intake—eg, inflammatory bowel disease, anorexia nervosa, chronic alcoholism, and cystic fibrosis. The lesions can be complicated by secondary bacterial infection, which can cause significant morbidity. Zinc deficiency can also suppress cell-mediated and humoral immunity.

Zinc deficiency can be diagnosed on the basis of clinical findings, skin biopsy, and serum zinc levels. Other micronutrient deficiencies can coexist and should be ruled out. Perioral and acral skin lesions are typically more prominent. Zinc supplementation usually produces rapid resolution of the lesions.

Our patient’s presentation highlights the importance of monitoring micronutrient levels, including zinc, in patients on long-term total parenteral nutrition. Nutritional deficiencies should be considered as a possible cause of dermatitis in such patients.

A 36-year-old woman on total parenteral nutrition because of short-bowel syndrome presented with a 2-week history of skin lesions on the face, arms, and legs, but no fever. Examination revealed prominent vesicular lesions on the left arm (Figure 1), face, palms, and soles. Cultures of biopsy specimens were negative for viral, bacterial, and fungal organisms.

Q: Which is the most likely diagnosis?

• Herpes simplex infection
• Varicella zoster infection
• Coxsackievirus infection
• Micronutrient deficiency
• Pemphigus vulgaris

A: Micronutrient deficiency is most likely the cause of her lesions—specifically, severe zinc deficiency, as she was found to have a serum zinc concentration of 12 μg/dL (reference range 55–150). Biopsy specimens showed characteristic intraepidermal blistering with necrosis and minimal inflammation. Serum levels of other micronutrients (iron, copper, selenium) were normal.

Her total parenteral nutrition regimen contained no zinc. Zinc supplementation was started, and a few days later the lesions began to resolve.

Herpes viral infections can cause similar blistering lesions, but this diagnosis was unlikely given the negative viral culture and direct fluorescence antibody test. Coxsackievirus infection is most often seen in children and typically causes fever and mouth sores, which this patient did not have. Lesions of pemphigus vulgaris typically exhibit the Nikolsky sign, ie, they are flaccid, they rupture easily, and the surrounding superficial skin separates from the deeper layers with rubbing or minor trauma. Our patient’s blisters were tense, with a negative Nikolsky sign, and skin biopsy was not consistent with pemphigus vulgaris.

Dermatitis can result from zinc deficiency, which can occur in conditions that cause severe malnutrition due to malabsorption or reduced dietary intake—eg, inflammatory bowel disease, anorexia nervosa, chronic alcoholism, and cystic fibrosis. The lesions can be complicated by secondary bacterial infection, which can cause significant morbidity. Zinc deficiency can also suppress cell-mediated and humoral immunity.

Zinc deficiency can be diagnosed on the basis of clinical findings, skin biopsy, and serum zinc levels. Other micronutrient deficiencies can coexist and should be ruled out. Perioral and acral skin lesions are typically more prominent. Zinc supplementation usually produces rapid resolution of the lesions.

Our patient’s presentation highlights the importance of monitoring micronutrient levels, including zinc, in patients on long-term total parenteral nutrition. Nutritional deficiencies should be considered as a possible cause of dermatitis in such patients.

A 36-year-old woman on total parenteral nutrition because of short-bowel syndrome presented with a 2-week history of skin lesions on the face, arms, and legs, but no fever. Examination revealed prominent vesicular lesions on the left arm (Figure 1), face, palms, and soles. Cultures of biopsy specimens were negative for viral, bacterial, and fungal organisms.

Q: Which is the most likely diagnosis?

• Herpes simplex infection
• Varicella zoster infection
• Coxsackievirus infection
• Micronutrient deficiency
• Pemphigus vulgaris

A: Micronutrient deficiency is most likely the cause of her lesions—specifically, severe zinc deficiency, as she was found to have a serum zinc concentration of 12 μg/dL (reference range 55–150). Biopsy specimens showed characteristic intraepidermal blistering with necrosis and minimal inflammation. Serum levels of other micronutrients (iron, copper, selenium) were normal.

Her total parenteral nutrition regimen contained no zinc. Zinc supplementation was started, and a few days later the lesions began to resolve.

Herpes viral infections can cause similar blistering lesions, but this diagnosis was unlikely given the negative viral culture and direct fluorescence antibody test. Coxsackievirus infection is most often seen in children and typically causes fever and mouth sores, which this patient did not have. Lesions of pemphigus vulgaris typically exhibit the Nikolsky sign, ie, they are flaccid, they rupture easily, and the surrounding superficial skin separates from the deeper layers with rubbing or minor trauma. Our patient’s blisters were tense, with a negative Nikolsky sign, and skin biopsy was not consistent with pemphigus vulgaris.

Dermatitis can result from zinc deficiency, which can occur in conditions that cause severe malnutrition due to malabsorption or reduced dietary intake—eg, inflammatory bowel disease, anorexia nervosa, chronic alcoholism, and cystic fibrosis. The lesions can be complicated by secondary bacterial infection, which can cause significant morbidity. Zinc deficiency can also suppress cell-mediated and humoral immunity.

Zinc deficiency can be diagnosed on the basis of clinical findings, skin biopsy, and serum zinc levels. Other micronutrient deficiencies can coexist and should be ruled out. Perioral and acral skin lesions are typically more prominent. Zinc supplementation usually produces rapid resolution of the lesions.

Our patient’s presentation highlights the importance of monitoring micronutrient levels, including zinc, in patients on long-term total parenteral nutrition. Nutritional deficiencies should be considered as a possible cause of dermatitis in such patients.

A 49-year-old man with rheumatic mitral valve stenosis, which had been diagnosed 3 years previously, presented to the outpatient department with worsening exertional dyspnea, fatigue, and cough.

At rest, he appeared comfortable; his pulse rate was 94 bpm and his blood pressure was 117/82 mm Hg. Cardiac auscultation revealed a loud first heart sound, a mid-diastolic murmur with presystolic accentuation at the cardiac apex, and a pansystolic murmur at the left lower sternal border that increased in intensity with inspiration. A prominent left parasternal heave was present.

His 12-lead electrocardiogram is shown in Figure 1.

Transthoracic echocardiography confirmed severe mitral stenosis with an estimated mitral valve area of 0.7 cm² without significant mitral regurgitation. In addition, right ventricular dilatation with moderately severe systolic dysfunction and 4+ (severe) tricuspid regurgitation were present. On the basis of the peak tricuspid regurgitant velocity, the right ventricular systolic pressure was calculated to be 80 mm Hg, consistent with severe pulmonary hypertension. The left ventricular end-diastolic volume was reduced and the ejection fraction was normal.

On right heart catheterization, the pulmonary artery pressure was 92/51 mm Hg.

Q: Electrocardiographic findings that support a diagnosis of pulmonary hypertension include which of the following?

• QRS complex axis of +110°
• R/S (QRS complex) ratio greater than 1 in lead V₁
• Sum of the amplitudes of the R wave in lead V₁ and the S wave in lead V₆ greater than 1.0 mV
• All of the above

A: The correct answer is all of the above. Regardless of the cause, patients with long-standing pulmonary hypertension possess varying degrees of right ventricular hypertrophy that may be accompanied by right ventricular enlargement and systolic dysfunction. A QRS complex axis of 110° or more, an R/S (QRS complex) ratio greater than 1 in lead V₁, and the sum of the amplitudes of the R wave in lead V₁ and the S wave in lead V₆ greater than 1.0 mV all support right ventricular hypertrophy.¹

As noted in this electrocardiogram, T-wave inversion in leads V₁ and V₂ supports a right ventricular repolarization abnormality secondary to the hypertrophy.²

Q: Important electrocardiographic findings in this patient that support secondary pulmonary hypertension due to mitral stenosis include which of the following?

• Tall peaked P waves in lead II of at least 0.25 mV and positive P waves in V₁ greater than 0.15 mV
• Prolonged P waves of at least 120 ms in lead II and terminal negative P waves in V₁ greater than 40 ms
• Right ventricular hypertrophy
• All of the above

A: The correct answer is prolonged P waves of at least 120 ms in lead II and terminal negative P waves in V₁ greater than 40 ms.

Abnormal surface electrocardiographic findings reflecting atrial enlargement or slowed atrial conduction are difficult to differentiate and are best characterized as “atrial abnormalities.” On surface electrocardiography, an atrial abnormality is represented by a P wave morphology that is best studied in leads II and V₁. In lead II, a tall peaked P wave of at least 0.25 mV supports right atrial abnormality, and a prolonged P wave (≥ 120 ms) supports left atrial abnormality. In lead V₁, right atrial abnormality is suggested by a positive P wave in V₁ greater than 0.15 mV, and a terminally negative P wave greater than 40 ms in duration and greater than 0.1 mV deep supports left atrial abnormality.³

It is well recognized that the pathophysiology of pulmonary hypertension involves both the right ventricle and the right atrium.^4,5 Therefore, irrespective of the cause of pulmonary hypertension, electrocardiography may additionally reveal right atrial abnormality.⁶

When the findings suggest pulmonary hypertension (ie, right ventricular hypertrophy with or without right atrial abnormality), it is also important to evaluate for concurrent left atrial abnormality. If present, concomitant left atrial abnormality is a valuable, more specific clue that may help characterize secondary pulmonary hypertension from left-sided heart disease, as illustrated in this example with long-standing severe mitral stenosis.²

A 49-year-old man with rheumatic mitral valve stenosis, which had been diagnosed 3 years previously, presented to the outpatient department with worsening exertional dyspnea, fatigue, and cough.

At rest, he appeared comfortable; his pulse rate was 94 bpm and his blood pressure was 117/82 mm Hg. Cardiac auscultation revealed a loud first heart sound, a mid-diastolic murmur with presystolic accentuation at the cardiac apex, and a pansystolic murmur at the left lower sternal border that increased in intensity with inspiration. A prominent left parasternal heave was present.

His 12-lead electrocardiogram is shown in Figure 1.

Transthoracic echocardiography confirmed severe mitral stenosis with an estimated mitral valve area of 0.7 cm² without significant mitral regurgitation. In addition, right ventricular dilatation with moderately severe systolic dysfunction and 4+ (severe) tricuspid regurgitation were present. On the basis of the peak tricuspid regurgitant velocity, the right ventricular systolic pressure was calculated to be 80 mm Hg, consistent with severe pulmonary hypertension. The left ventricular end-diastolic volume was reduced and the ejection fraction was normal.

On right heart catheterization, the pulmonary artery pressure was 92/51 mm Hg.

Q: Electrocardiographic findings that support a diagnosis of pulmonary hypertension include which of the following?

• QRS complex axis of +110°
• R/S (QRS complex) ratio greater than 1 in lead V₁
• Sum of the amplitudes of the R wave in lead V₁ and the S wave in lead V₆ greater than 1.0 mV
• All of the above

A: The correct answer is all of the above. Regardless of the cause, patients with long-standing pulmonary hypertension possess varying degrees of right ventricular hypertrophy that may be accompanied by right ventricular enlargement and systolic dysfunction. A QRS complex axis of 110° or more, an R/S (QRS complex) ratio greater than 1 in lead V₁, and the sum of the amplitudes of the R wave in lead V₁ and the S wave in lead V₆ greater than 1.0 mV all support right ventricular hypertrophy.¹

As noted in this electrocardiogram, T-wave inversion in leads V₁ and V₂ supports a right ventricular repolarization abnormality secondary to the hypertrophy.²

Q: Important electrocardiographic findings in this patient that support secondary pulmonary hypertension due to mitral stenosis include which of the following?

• Tall peaked P waves in lead II of at least 0.25 mV and positive P waves in V₁ greater than 0.15 mV
• Prolonged P waves of at least 120 ms in lead II and terminal negative P waves in V₁ greater than 40 ms
• Right ventricular hypertrophy
• All of the above

A: The correct answer is prolonged P waves of at least 120 ms in lead II and terminal negative P waves in V₁ greater than 40 ms.

Abnormal surface electrocardiographic findings reflecting atrial enlargement or slowed atrial conduction are difficult to differentiate and are best characterized as “atrial abnormalities.” On surface electrocardiography, an atrial abnormality is represented by a P wave morphology that is best studied in leads II and V₁. In lead II, a tall peaked P wave of at least 0.25 mV supports right atrial abnormality, and a prolonged P wave (≥ 120 ms) supports left atrial abnormality. In lead V₁, right atrial abnormality is suggested by a positive P wave in V₁ greater than 0.15 mV, and a terminally negative P wave greater than 40 ms in duration and greater than 0.1 mV deep supports left atrial abnormality.³

It is well recognized that the pathophysiology of pulmonary hypertension involves both the right ventricle and the right atrium.^4,5 Therefore, irrespective of the cause of pulmonary hypertension, electrocardiography may additionally reveal right atrial abnormality.⁶

When the findings suggest pulmonary hypertension (ie, right ventricular hypertrophy with or without right atrial abnormality), it is also important to evaluate for concurrent left atrial abnormality. If present, concomitant left atrial abnormality is a valuable, more specific clue that may help characterize secondary pulmonary hypertension from left-sided heart disease, as illustrated in this example with long-standing severe mitral stenosis.²

A 49-year-old man with rheumatic mitral valve stenosis, which had been diagnosed 3 years previously, presented to the outpatient department with worsening exertional dyspnea, fatigue, and cough.

At rest, he appeared comfortable; his pulse rate was 94 bpm and his blood pressure was 117/82 mm Hg. Cardiac auscultation revealed a loud first heart sound, a mid-diastolic murmur with presystolic accentuation at the cardiac apex, and a pansystolic murmur at the left lower sternal border that increased in intensity with inspiration. A prominent left parasternal heave was present.

His 12-lead electrocardiogram is shown in Figure 1.

Transthoracic echocardiography confirmed severe mitral stenosis with an estimated mitral valve area of 0.7 cm² without significant mitral regurgitation. In addition, right ventricular dilatation with moderately severe systolic dysfunction and 4+ (severe) tricuspid regurgitation were present. On the basis of the peak tricuspid regurgitant velocity, the right ventricular systolic pressure was calculated to be 80 mm Hg, consistent with severe pulmonary hypertension. The left ventricular end-diastolic volume was reduced and the ejection fraction was normal.

On right heart catheterization, the pulmonary artery pressure was 92/51 mm Hg.

Q: Electrocardiographic findings that support a diagnosis of pulmonary hypertension include which of the following?

• QRS complex axis of +110°
• R/S (QRS complex) ratio greater than 1 in lead V₁
• Sum of the amplitudes of the R wave in lead V₁ and the S wave in lead V₆ greater than 1.0 mV
• All of the above

A: The correct answer is all of the above. Regardless of the cause, patients with long-standing pulmonary hypertension possess varying degrees of right ventricular hypertrophy that may be accompanied by right ventricular enlargement and systolic dysfunction. A QRS complex axis of 110° or more, an R/S (QRS complex) ratio greater than 1 in lead V₁, and the sum of the amplitudes of the R wave in lead V₁ and the S wave in lead V₆ greater than 1.0 mV all support right ventricular hypertrophy.¹

As noted in this electrocardiogram, T-wave inversion in leads V₁ and V₂ supports a right ventricular repolarization abnormality secondary to the hypertrophy.²

Q: Important electrocardiographic findings in this patient that support secondary pulmonary hypertension due to mitral stenosis include which of the following?

• Tall peaked P waves in lead II of at least 0.25 mV and positive P waves in V₁ greater than 0.15 mV
• Prolonged P waves of at least 120 ms in lead II and terminal negative P waves in V₁ greater than 40 ms
• Right ventricular hypertrophy
• All of the above

A: The correct answer is prolonged P waves of at least 120 ms in lead II and terminal negative P waves in V₁ greater than 40 ms.

Abnormal surface electrocardiographic findings reflecting atrial enlargement or slowed atrial conduction are difficult to differentiate and are best characterized as “atrial abnormalities.” On surface electrocardiography, an atrial abnormality is represented by a P wave morphology that is best studied in leads II and V₁. In lead II, a tall peaked P wave of at least 0.25 mV supports right atrial abnormality, and a prolonged P wave (≥ 120 ms) supports left atrial abnormality. In lead V₁, right atrial abnormality is suggested by a positive P wave in V₁ greater than 0.15 mV, and a terminally negative P wave greater than 40 ms in duration and greater than 0.1 mV deep supports left atrial abnormality.³

It is well recognized that the pathophysiology of pulmonary hypertension involves both the right ventricle and the right atrium.^4,5 Therefore, irrespective of the cause of pulmonary hypertension, electrocardiography may additionally reveal right atrial abnormality.⁶

When the findings suggest pulmonary hypertension (ie, right ventricular hypertrophy with or without right atrial abnormality), it is also important to evaluate for concurrent left atrial abnormality. If present, concomitant left atrial abnormality is a valuable, more specific clue that may help characterize secondary pulmonary hypertension from left-sided heart disease, as illustrated in this example with long-standing severe mitral stenosis.²

A 54-year-old woman presented with a 7-day history of odynophagia, pharyngeal swelling, and painful skin lesions on her left ear. She had been on antiretroviral therapy for human immunodeficiency virus infection but had not been fully compliant with the treatment.

See editorial

On examination, she had painful erythematous vesicles and pustules on the left auricle and in the external auditory canal (Figure 1), as well as small vesicles and circumscribed erosions on the left anterior twothirds of her tongue (Figure 2) and left palate. Facial sensory function was normal; however, she had lagophthalmos, a flattened nasolabial fold, ptosis of the oral commissure, and a loss of the forehead wrinkles on the left side of her face—all signs of peripheral facial nerve paralysis.

Q: Which is the most likely diagnosis?

• Ramsay Hunt syndrome
• Herpes simplex
• Contact dermatitis
• Malignant external otitis
• Erysipelas

A: This patient had Ramsay Hunt syndrome, also known as herpes zoster oticus. It is a rare complication of herpes zoster in which the reactivation of latent varicella-zoster virus infection in the geniculate ganglion causes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Taste perception, hearing (eg, tinnitus, hyperacusis), and lacrimation can be affected.¹

Ramsay Hunt syndrome is generally considered a polycranial neuropathy of cranial nerves VII (facial) and VIII (acoustic). In some cases other cranial neuropathies may be present and may involve cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus). Vestibular disturbances such as vertigo are also often reported. It is more severe in patients with immune deficiency. Because the classic symptoms are not always present at the onset, the syndrome can be misdiagnosed.

DIAGNOSIS

Once the vesicular rash caused by herpes zoster has appeared, the diagnosis is usually readily apparent. The other main disease to consider in the differential diagnosis is herpes simplex. Herpes zoster infection is characterized by a painful sensory prodrome, dermatomal distribution, and lack of a history of a similar rash. However, if the patient has had a similar vesicular rash in the same location, then recurrent zosteriform herpes simplex should be considered. A noninfectious cause to consider is contact dermatitis. However, contact dermatitis usually produces intense itch rather than pain.

If the clinical presentation is uncertain, then viral culture, direct immunofluorescence testing, and a polymerase chain reaction assay is indicated to confirm the diagnosis. Polymerase chain reaction testing is the most sensitive test.³

TREATMENT

The rapid start of antiviral therapy is particularly critical in immunocompromised patients,⁴ even if the vesicles have been present for 72 hours. Immunocompromised patients with Ramsay Hunt syndrome and other forms of complicated herpes zoster infection should be hospitalized for intravenous acyclovir therapy.

Corticosteroids and oral acyclovir (10 mg/kg three times daily for 7 days) are commonly used in Ramsay Hunt syndrome. In a recent review,⁵ combination therapy with a corticosteroid and intravenous acyclovir did not show a benefit over corticosteroids alone in promoting resolution of facial neuropathy after 6 months.⁵ However, randomized clinical trials are needed to evaluate both therapies.

Although antiviral therapy reduces pain associated with acute neuritis, pain syndromes associated with herpes zoster can still be severe. Nonsteroidal antiinflammatory drugs and acetaminophen are useful for mild pain, either alone or in combination with a weak opioid analgesic (eg, tramadol, codeine). For moderate to severe pain that disturbs sleep, a stronger opioid analgesic (eg, oxycodone, morphine) may be necessary.⁶

Vestibular suppressants may be helpful if vestibular symptoms are severe. Temporary relief of otalgia may be achieved by applying a local anesthetic to the trigger point, if in the external auditory canal. Carbamazepine may be helpful, especially in cases of idiopathic geniculate neuralgia.⁷

OTHER CONSIDERATIONS

Once drug therapy is started, the patient should be seen at 2 weeks, 6 weeks, and 3 months to monitor the evolution of nerve paralysis.⁸

A 54-year-old woman presented with a 7-day history of odynophagia, pharyngeal swelling, and painful skin lesions on her left ear. She had been on antiretroviral therapy for human immunodeficiency virus infection but had not been fully compliant with the treatment.

See editorial

On examination, she had painful erythematous vesicles and pustules on the left auricle and in the external auditory canal (Figure 1), as well as small vesicles and circumscribed erosions on the left anterior twothirds of her tongue (Figure 2) and left palate. Facial sensory function was normal; however, she had lagophthalmos, a flattened nasolabial fold, ptosis of the oral commissure, and a loss of the forehead wrinkles on the left side of her face—all signs of peripheral facial nerve paralysis.

Q: Which is the most likely diagnosis?

• Ramsay Hunt syndrome
• Herpes simplex
• Contact dermatitis
• Malignant external otitis
• Erysipelas

A: This patient had Ramsay Hunt syndrome, also known as herpes zoster oticus. It is a rare complication of herpes zoster in which the reactivation of latent varicella-zoster virus infection in the geniculate ganglion causes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Taste perception, hearing (eg, tinnitus, hyperacusis), and lacrimation can be affected.¹

Ramsay Hunt syndrome is generally considered a polycranial neuropathy of cranial nerves VII (facial) and VIII (acoustic). In some cases other cranial neuropathies may be present and may involve cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus). Vestibular disturbances such as vertigo are also often reported. It is more severe in patients with immune deficiency. Because the classic symptoms are not always present at the onset, the syndrome can be misdiagnosed.

DIAGNOSIS

Once the vesicular rash caused by herpes zoster has appeared, the diagnosis is usually readily apparent. The other main disease to consider in the differential diagnosis is herpes simplex. Herpes zoster infection is characterized by a painful sensory prodrome, dermatomal distribution, and lack of a history of a similar rash. However, if the patient has had a similar vesicular rash in the same location, then recurrent zosteriform herpes simplex should be considered. A noninfectious cause to consider is contact dermatitis. However, contact dermatitis usually produces intense itch rather than pain.

If the clinical presentation is uncertain, then viral culture, direct immunofluorescence testing, and a polymerase chain reaction assay is indicated to confirm the diagnosis. Polymerase chain reaction testing is the most sensitive test.³

TREATMENT

The rapid start of antiviral therapy is particularly critical in immunocompromised patients,⁴ even if the vesicles have been present for 72 hours. Immunocompromised patients with Ramsay Hunt syndrome and other forms of complicated herpes zoster infection should be hospitalized for intravenous acyclovir therapy.

Corticosteroids and oral acyclovir (10 mg/kg three times daily for 7 days) are commonly used in Ramsay Hunt syndrome. In a recent review,⁵ combination therapy with a corticosteroid and intravenous acyclovir did not show a benefit over corticosteroids alone in promoting resolution of facial neuropathy after 6 months.⁵ However, randomized clinical trials are needed to evaluate both therapies.

Although antiviral therapy reduces pain associated with acute neuritis, pain syndromes associated with herpes zoster can still be severe. Nonsteroidal antiinflammatory drugs and acetaminophen are useful for mild pain, either alone or in combination with a weak opioid analgesic (eg, tramadol, codeine). For moderate to severe pain that disturbs sleep, a stronger opioid analgesic (eg, oxycodone, morphine) may be necessary.⁶

Vestibular suppressants may be helpful if vestibular symptoms are severe. Temporary relief of otalgia may be achieved by applying a local anesthetic to the trigger point, if in the external auditory canal. Carbamazepine may be helpful, especially in cases of idiopathic geniculate neuralgia.⁷

OTHER CONSIDERATIONS

Once drug therapy is started, the patient should be seen at 2 weeks, 6 weeks, and 3 months to monitor the evolution of nerve paralysis.⁸

A 54-year-old woman presented with a 7-day history of odynophagia, pharyngeal swelling, and painful skin lesions on her left ear. She had been on antiretroviral therapy for human immunodeficiency virus infection but had not been fully compliant with the treatment.

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On examination, she had painful erythematous vesicles and pustules on the left auricle and in the external auditory canal (Figure 1), as well as small vesicles and circumscribed erosions on the left anterior twothirds of her tongue (Figure 2) and left palate. Facial sensory function was normal; however, she had lagophthalmos, a flattened nasolabial fold, ptosis of the oral commissure, and a loss of the forehead wrinkles on the left side of her face—all signs of peripheral facial nerve paralysis.

Q: Which is the most likely diagnosis?

• Ramsay Hunt syndrome
• Herpes simplex
• Contact dermatitis
• Malignant external otitis
• Erysipelas

A: This patient had Ramsay Hunt syndrome, also known as herpes zoster oticus. It is a rare complication of herpes zoster in which the reactivation of latent varicella-zoster virus infection in the geniculate ganglion causes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle. Taste perception, hearing (eg, tinnitus, hyperacusis), and lacrimation can be affected.¹

Ramsay Hunt syndrome is generally considered a polycranial neuropathy of cranial nerves VII (facial) and VIII (acoustic). In some cases other cranial neuropathies may be present and may involve cranial nerves V (trigeminal), IX (glossopharyngeal), and X (vagus). Vestibular disturbances such as vertigo are also often reported. It is more severe in patients with immune deficiency. Because the classic symptoms are not always present at the onset, the syndrome can be misdiagnosed.

DIAGNOSIS

Once the vesicular rash caused by herpes zoster has appeared, the diagnosis is usually readily apparent. The other main disease to consider in the differential diagnosis is herpes simplex. Herpes zoster infection is characterized by a painful sensory prodrome, dermatomal distribution, and lack of a history of a similar rash. However, if the patient has had a similar vesicular rash in the same location, then recurrent zosteriform herpes simplex should be considered. A noninfectious cause to consider is contact dermatitis. However, contact dermatitis usually produces intense itch rather than pain.

If the clinical presentation is uncertain, then viral culture, direct immunofluorescence testing, and a polymerase chain reaction assay is indicated to confirm the diagnosis. Polymerase chain reaction testing is the most sensitive test.³

TREATMENT

The rapid start of antiviral therapy is particularly critical in immunocompromised patients,⁴ even if the vesicles have been present for 72 hours. Immunocompromised patients with Ramsay Hunt syndrome and other forms of complicated herpes zoster infection should be hospitalized for intravenous acyclovir therapy.

Corticosteroids and oral acyclovir (10 mg/kg three times daily for 7 days) are commonly used in Ramsay Hunt syndrome. In a recent review,⁵ combination therapy with a corticosteroid and intravenous acyclovir did not show a benefit over corticosteroids alone in promoting resolution of facial neuropathy after 6 months.⁵ However, randomized clinical trials are needed to evaluate both therapies.

Although antiviral therapy reduces pain associated with acute neuritis, pain syndromes associated with herpes zoster can still be severe. Nonsteroidal antiinflammatory drugs and acetaminophen are useful for mild pain, either alone or in combination with a weak opioid analgesic (eg, tramadol, codeine). For moderate to severe pain that disturbs sleep, a stronger opioid analgesic (eg, oxycodone, morphine) may be necessary.⁶

Vestibular suppressants may be helpful if vestibular symptoms are severe. Temporary relief of otalgia may be achieved by applying a local anesthetic to the trigger point, if in the external auditory canal. Carbamazepine may be helpful, especially in cases of idiopathic geniculate neuralgia.⁷

OTHER CONSIDERATIONS

Once drug therapy is started, the patient should be seen at 2 weeks, 6 weeks, and 3 months to monitor the evolution of nerve paralysis.⁸

Varicella-zoster virus (VZV) is a highly neurotropic and ubiquitous alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Reactivation decades later usually results in zoster (shingles), pain with a dermatomal distribution, and rash. Unlike herpes simplex virus type 1 (HSV-1), which becomes latent exclusively in cranial nerve ganglia and reactivates to produce recurrent vesicular lesions around the mouth, and unlike HSV type 2, which becomes latent exclusively in sacral ganglia and reactivates to produce genital herpes, VZV may reactivate from any ganglia to cause zoster anywhere on the body.

See related article

Reactivation of VZV from the geniculate (facial nerve) ganglion leads to the Ramsay Hunt syndrome, ie, facial paralysis accompanied by a rash around the ear (zoster oticus). The syndrome is the second most common cause of atraumatic facial paralysis after Bell palsy (idiopathic facial paralysis). Importantly, virus reactivation from the geniculate ganglion may also be accompanied by zoster rash on the hard palate or on the anterior two-thirds of the tongue (Figure 1).¹ A rash in any of these three skin or mucosal sites in a patient with facial paralysis indicates geniculate ganglionitis. To his credit, Dr. J. Ramsay Hunt recognized that although there is no somatic sensory facial branch to the oropharynx or tongue, virus can still spread from a seventh cranial nerve element to the pharynx or, via special sensory fibers, to the tongue, thus providing an anatomic explanation for zoster rash in patients with facial paralysis (geniculate zoster) not only around the ear, but also on the hard palate or on the anterior two-thirds of the tongue.²

Reprinted from Sweeney CJ, et al. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149–154. With permission from BMJ Publishing Group Ltd.

In geniculate ganglionitis, a rash is usually seen in one but not all three of these skin and mucosal sites. Yet in this issue of the Cleveland Clinic Journal of Medicine, Grillo et al3 describe a patient with facial palsy and rash in all three sites. This remarkable finding underscores the importance of distinguishing Ramsay Hunt syndrome from Bell palsy by checking for rash on the ear, tongue, and hard palate in any patient with acute unilateral peripheral facial weakness. Ramsay Hunt syndrome results from active VZV replication in the geniculate ganglion and requires treatment with antiviral drugs, whereas Bell palsy is usually treated with steroids. Steroid treatment of Ramsay Hunt syndrome misdiagnosed as Bell palsy can potentiate the viral infection. This may partially explain why the outcome of facial paralysis in Ramsay Hunt syndrome is not as good as in idiopathic Bell palsy, in which more than 70% of patients recover full facial function.

Although only cranial nerve VII (facial) was involved in their patient, Grillo et al correctly noted the frequent involvement of other cranial nerves in Ramsay Hunt syndrome. For example, dizziness, vertigo, or hearing loss indicative of involvement of cranial nerve VIII (acoustic) is most likely due to the close proximity of the geniculate ganglion and facial nerve to the vestibulocochlear nerve in the bony facial canal. Patients with this syndrome may also develop dysarthria or dysphagia indicative of lower cranial nerve involvement, reflecting the shared derivation of the facial, glossopharyngeal, and vagus nerves from the same branchial arch. Magnetic resonance imaging, not usually performed in patients with Ramsay Hunt syndrome, may show enhancement in the geniculate ganglion as well as in the intracanalicular and tympanic segments of the facial nerve during its course through the facial canal.

The report by Grillo et al comes at an auspicious time, 100 years after an enlightening series of papers by Dr. Hunt from 1907 to 1915 in which he described herpetic inflammation of the geniculate ganglion,⁴ the sensory system of the facial nerve,⁵ and ultimately the syndrome that bears his name.^2,6 Dr. Hunt received his doctorate from the University of Pennsylvania in 1893 and later became instructor at Cornell University School of Medicine. In 1924, he became full professor at Columbia University School of Medicine. A clinician of Olympian stature, he is also credited with describing two additional syndromes (clinical features produced by carotid artery occlusion and dyssynergia cerebellaris progressiva), although the best known is zoster oticus with peripheral facial palsy.

Importantly, some patients develop peripheral facial paralysis without any rash but with a fourfold rise in antibody to VZV or in association with the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva, indicating that a proportion of patients with Bell palsy have “Ramsay Hunt syndrome zoster sine herpete” or, more accurately, “geniculate zoster sine herpete.” Treatment of such patients with acyclovir-prednisone within 7 days of onset has been shown to improve the outcome of facial palsy.

Because it is now clear that geniculate ganglionitis may present with facial palsy and zoster rash in any or all of three sites, it may be time to call peripheral facial paralysis associated with zoster rash on the ear, tongue, or palate exactly what it is: geniculate zoster. After all, zoster rash on the face is called trigeminal zoster, and zoster rash on the chest is called thoracic zoster. Most important, however, is the recognition that facial paralysis in association with rash on the ear, tongue, or hard palate reflects geniculate zoster and requires immediate antiviral treatment.

Varicella-zoster virus (VZV) is a highly neurotropic and ubiquitous alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Reactivation decades later usually results in zoster (shingles), pain with a dermatomal distribution, and rash. Unlike herpes simplex virus type 1 (HSV-1), which becomes latent exclusively in cranial nerve ganglia and reactivates to produce recurrent vesicular lesions around the mouth, and unlike HSV type 2, which becomes latent exclusively in sacral ganglia and reactivates to produce genital herpes, VZV may reactivate from any ganglia to cause zoster anywhere on the body.

See related article

Reactivation of VZV from the geniculate (facial nerve) ganglion leads to the Ramsay Hunt syndrome, ie, facial paralysis accompanied by a rash around the ear (zoster oticus). The syndrome is the second most common cause of atraumatic facial paralysis after Bell palsy (idiopathic facial paralysis). Importantly, virus reactivation from the geniculate ganglion may also be accompanied by zoster rash on the hard palate or on the anterior two-thirds of the tongue (Figure 1).¹ A rash in any of these three skin or mucosal sites in a patient with facial paralysis indicates geniculate ganglionitis. To his credit, Dr. J. Ramsay Hunt recognized that although there is no somatic sensory facial branch to the oropharynx or tongue, virus can still spread from a seventh cranial nerve element to the pharynx or, via special sensory fibers, to the tongue, thus providing an anatomic explanation for zoster rash in patients with facial paralysis (geniculate zoster) not only around the ear, but also on the hard palate or on the anterior two-thirds of the tongue.²

Reprinted from Sweeney CJ, et al. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149–154. With permission from BMJ Publishing Group Ltd.

In geniculate ganglionitis, a rash is usually seen in one but not all three of these skin and mucosal sites. Yet in this issue of the Cleveland Clinic Journal of Medicine, Grillo et al3 describe a patient with facial palsy and rash in all three sites. This remarkable finding underscores the importance of distinguishing Ramsay Hunt syndrome from Bell palsy by checking for rash on the ear, tongue, and hard palate in any patient with acute unilateral peripheral facial weakness. Ramsay Hunt syndrome results from active VZV replication in the geniculate ganglion and requires treatment with antiviral drugs, whereas Bell palsy is usually treated with steroids. Steroid treatment of Ramsay Hunt syndrome misdiagnosed as Bell palsy can potentiate the viral infection. This may partially explain why the outcome of facial paralysis in Ramsay Hunt syndrome is not as good as in idiopathic Bell palsy, in which more than 70% of patients recover full facial function.

Although only cranial nerve VII (facial) was involved in their patient, Grillo et al correctly noted the frequent involvement of other cranial nerves in Ramsay Hunt syndrome. For example, dizziness, vertigo, or hearing loss indicative of involvement of cranial nerve VIII (acoustic) is most likely due to the close proximity of the geniculate ganglion and facial nerve to the vestibulocochlear nerve in the bony facial canal. Patients with this syndrome may also develop dysarthria or dysphagia indicative of lower cranial nerve involvement, reflecting the shared derivation of the facial, glossopharyngeal, and vagus nerves from the same branchial arch. Magnetic resonance imaging, not usually performed in patients with Ramsay Hunt syndrome, may show enhancement in the geniculate ganglion as well as in the intracanalicular and tympanic segments of the facial nerve during its course through the facial canal.

The report by Grillo et al comes at an auspicious time, 100 years after an enlightening series of papers by Dr. Hunt from 1907 to 1915 in which he described herpetic inflammation of the geniculate ganglion,⁴ the sensory system of the facial nerve,⁵ and ultimately the syndrome that bears his name.^2,6 Dr. Hunt received his doctorate from the University of Pennsylvania in 1893 and later became instructor at Cornell University School of Medicine. In 1924, he became full professor at Columbia University School of Medicine. A clinician of Olympian stature, he is also credited with describing two additional syndromes (clinical features produced by carotid artery occlusion and dyssynergia cerebellaris progressiva), although the best known is zoster oticus with peripheral facial palsy.

Importantly, some patients develop peripheral facial paralysis without any rash but with a fourfold rise in antibody to VZV or in association with the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva, indicating that a proportion of patients with Bell palsy have “Ramsay Hunt syndrome zoster sine herpete” or, more accurately, “geniculate zoster sine herpete.” Treatment of such patients with acyclovir-prednisone within 7 days of onset has been shown to improve the outcome of facial palsy.

Because it is now clear that geniculate ganglionitis may present with facial palsy and zoster rash in any or all of three sites, it may be time to call peripheral facial paralysis associated with zoster rash on the ear, tongue, or palate exactly what it is: geniculate zoster. After all, zoster rash on the face is called trigeminal zoster, and zoster rash on the chest is called thoracic zoster. Most important, however, is the recognition that facial paralysis in association with rash on the ear, tongue, or hard palate reflects geniculate zoster and requires immediate antiviral treatment.

Varicella-zoster virus (VZV) is a highly neurotropic and ubiquitous alpha-herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Reactivation decades later usually results in zoster (shingles), pain with a dermatomal distribution, and rash. Unlike herpes simplex virus type 1 (HSV-1), which becomes latent exclusively in cranial nerve ganglia and reactivates to produce recurrent vesicular lesions around the mouth, and unlike HSV type 2, which becomes latent exclusively in sacral ganglia and reactivates to produce genital herpes, VZV may reactivate from any ganglia to cause zoster anywhere on the body.

See related article

Reactivation of VZV from the geniculate (facial nerve) ganglion leads to the Ramsay Hunt syndrome, ie, facial paralysis accompanied by a rash around the ear (zoster oticus). The syndrome is the second most common cause of atraumatic facial paralysis after Bell palsy (idiopathic facial paralysis). Importantly, virus reactivation from the geniculate ganglion may also be accompanied by zoster rash on the hard palate or on the anterior two-thirds of the tongue (Figure 1).¹ A rash in any of these three skin or mucosal sites in a patient with facial paralysis indicates geniculate ganglionitis. To his credit, Dr. J. Ramsay Hunt recognized that although there is no somatic sensory facial branch to the oropharynx or tongue, virus can still spread from a seventh cranial nerve element to the pharynx or, via special sensory fibers, to the tongue, thus providing an anatomic explanation for zoster rash in patients with facial paralysis (geniculate zoster) not only around the ear, but also on the hard palate or on the anterior two-thirds of the tongue.²

Reprinted from Sweeney CJ, et al. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001; 71:149–154. With permission from BMJ Publishing Group Ltd.

In geniculate ganglionitis, a rash is usually seen in one but not all three of these skin and mucosal sites. Yet in this issue of the Cleveland Clinic Journal of Medicine, Grillo et al3 describe a patient with facial palsy and rash in all three sites. This remarkable finding underscores the importance of distinguishing Ramsay Hunt syndrome from Bell palsy by checking for rash on the ear, tongue, and hard palate in any patient with acute unilateral peripheral facial weakness. Ramsay Hunt syndrome results from active VZV replication in the geniculate ganglion and requires treatment with antiviral drugs, whereas Bell palsy is usually treated with steroids. Steroid treatment of Ramsay Hunt syndrome misdiagnosed as Bell palsy can potentiate the viral infection. This may partially explain why the outcome of facial paralysis in Ramsay Hunt syndrome is not as good as in idiopathic Bell palsy, in which more than 70% of patients recover full facial function.

Although only cranial nerve VII (facial) was involved in their patient, Grillo et al correctly noted the frequent involvement of other cranial nerves in Ramsay Hunt syndrome. For example, dizziness, vertigo, or hearing loss indicative of involvement of cranial nerve VIII (acoustic) is most likely due to the close proximity of the geniculate ganglion and facial nerve to the vestibulocochlear nerve in the bony facial canal. Patients with this syndrome may also develop dysarthria or dysphagia indicative of lower cranial nerve involvement, reflecting the shared derivation of the facial, glossopharyngeal, and vagus nerves from the same branchial arch. Magnetic resonance imaging, not usually performed in patients with Ramsay Hunt syndrome, may show enhancement in the geniculate ganglion as well as in the intracanalicular and tympanic segments of the facial nerve during its course through the facial canal.

The report by Grillo et al comes at an auspicious time, 100 years after an enlightening series of papers by Dr. Hunt from 1907 to 1915 in which he described herpetic inflammation of the geniculate ganglion,⁴ the sensory system of the facial nerve,⁵ and ultimately the syndrome that bears his name.^2,6 Dr. Hunt received his doctorate from the University of Pennsylvania in 1893 and later became instructor at Cornell University School of Medicine. In 1924, he became full professor at Columbia University School of Medicine. A clinician of Olympian stature, he is also credited with describing two additional syndromes (clinical features produced by carotid artery occlusion and dyssynergia cerebellaris progressiva), although the best known is zoster oticus with peripheral facial palsy.

Importantly, some patients develop peripheral facial paralysis without any rash but with a fourfold rise in antibody to VZV or in association with the presence of VZV DNA in auricular skin, blood mononuclear cells, middle ear fluid, or saliva, indicating that a proportion of patients with Bell palsy have “Ramsay Hunt syndrome zoster sine herpete” or, more accurately, “geniculate zoster sine herpete.” Treatment of such patients with acyclovir-prednisone within 7 days of onset has been shown to improve the outcome of facial palsy.

Because it is now clear that geniculate ganglionitis may present with facial palsy and zoster rash in any or all of three sites, it may be time to call peripheral facial paralysis associated with zoster rash on the ear, tongue, or palate exactly what it is: geniculate zoster. After all, zoster rash on the face is called trigeminal zoster, and zoster rash on the chest is called thoracic zoster. Most important, however, is the recognition that facial paralysis in association with rash on the ear, tongue, or hard palate reflects geniculate zoster and requires immediate antiviral treatment.