Cleveland Clinic Journal of Medicine

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2012. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2012. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

We thank those who reviewed manuscripts submitted to the Cleveland Clinic Journal of Medicine in the year ending December 31, 2012. Reviewing papers for scientific journals is an arduous task and involves considerable time and effort. We are grateful to these reviewers for contributing their expertise this past year.

—Brian F. Mandell, MD, PhD, Editor in Chief

A 55-year-old man presents to the emergency department with a sore throat, odynophagia, hoarseness, and a high-pitched muffled voice for 1 day. He is otherwise healthy, with no fever, chills, or exposure to sick contacts.

Q: Which is the most likely diagnosis?

• Retropharyngeal abscess
• Croup
• Streptococcal pharyngitis (“strep throat”)
• Acute epiglottitis
• Viral upper-respiratory infection

A: The correct answer is acute epiglottitis.

Acute epiglottitis is a cellulitis of the epiglottis and adjacent tissues that, without treatment, can progress to life-threatening airway obstruction.

In children, this entity most often occurs between ages 2 and 4. Previously, it was mainly associated with Haemophilus influenzae type B infection, but since the start of vaccination for this organism, epiglottitis has become less common.

In recent years, Streptococcus pneumoniae and beta-hemolytic streptococci have become the main culprits in epiglottitis in children. In adults, common organisms include H influenzae, S pneumoniae, Staphylococcus aureus, and betahemolytic streptococci. Epiglottitis may also be caused by herpes simplex, varicella-zoster, and influenza viruses. Noninfectious causes include ingestion of a foreign body and thermal injury.

Common signs and symptoms of epiglottitis include sore throat, a high-pitched and muffled voice, labored breathing, and respiratory distress.¹ Since airway obstruction can be remarkably precipitous, it is important to obtain early consultation with an otolaryngologist for laryngoscopy and visualization of the erythematous, swollen epiglottis. Signs of severe upper-airway obstruction may be absent until late in the disease process, making early diagnosis crucial.

On physical examination, the oropharynx will often appear benign. Currently, the preferred diagnostic test for epiglottitis is visualization by laryngoscopy, which has close to 100% sensitivity and specificity.² By comparison, lateral neck radiography has poor sensitivity (38% to 88%) and specificity (78%).^3,4 Bedside ultrasonography has been reported as capable of revealing the “alphabet P sign” in the longitudinal view through the thyrohyoid membrane.⁵

At triage, if clinical suspicion of total airway obstruction is high, the patient may be taken directly to the operating room for visualization of the epiglottis and, if necessary, for endotracheal intubation. When the risk is considered low or moderate, lateral neck radiography may be helpful,⁶ as it will sometimes reveal a swollen epiglottis (ie, “thumb sign”), thickened arytenoepiglottic folds, and obliteration of the epiglottic vallecula. If the radiograph is normal and clinical suspicion is still present, laryngoscopy can be done.

For low-risk, acute epiglottitis, closely monitoring the patient in an intensive care unit is recommended. For severe, high-risk cases, securing the airway is of the utmost importance. In addition to securing the airway, empiric antimicrobial therapy—such as with cefotaxime or ceftriaxone plus clindamycin or vancomycin—is often warranted in both low-risk and high-risk cases. The use of corticosteroids in epiglottitis has not been studied in a randomized, controlled trial, and, though common, it remains controversial.⁷ While undergoing treatment, patients should be closely monitored for respiratory compromise.

HOW OUR PATIENT WAS MANAGED

Our patient had a high-pitched, muffled voice and prominent, tender anterior cervical lymph nodes. No drooling or stridor was noted. The oropharynx appeared normal. Lateral soft-tissue radiography of the neck (Figure 1) revealed several key findings:

• A swollen epiglottis (ie, the “thumb sign”) consistent with acute epiglottitis and a narrowed airway
• Swollen arytenoids
• A shallow V-shaped epiglottic vallecula.

For comparison, Figure 2 shows a normal lateral soft-tissue radiograph of the neck from a different patient.

Our patient was referred to an otolaryngologist, who noted a severely inflamed epiglottis on laryngoscopy.

The patient was given intravenous vancomycin, ceftriaxone, and high-dose corticosteroids and was admitted to the intensive care unit. After his symptoms improved, repeat laryngoscopy revealed markedly diminished inflammation. He was discharged home with an additional course of oral antibiotics.

A 55-year-old man presents to the emergency department with a sore throat, odynophagia, hoarseness, and a high-pitched muffled voice for 1 day. He is otherwise healthy, with no fever, chills, or exposure to sick contacts.

Q: Which is the most likely diagnosis?

• Retropharyngeal abscess
• Croup
• Streptococcal pharyngitis (“strep throat”)
• Acute epiglottitis
• Viral upper-respiratory infection

A: The correct answer is acute epiglottitis.

Acute epiglottitis is a cellulitis of the epiglottis and adjacent tissues that, without treatment, can progress to life-threatening airway obstruction.

In children, this entity most often occurs between ages 2 and 4. Previously, it was mainly associated with Haemophilus influenzae type B infection, but since the start of vaccination for this organism, epiglottitis has become less common.

In recent years, Streptococcus pneumoniae and beta-hemolytic streptococci have become the main culprits in epiglottitis in children. In adults, common organisms include H influenzae, S pneumoniae, Staphylococcus aureus, and betahemolytic streptococci. Epiglottitis may also be caused by herpes simplex, varicella-zoster, and influenza viruses. Noninfectious causes include ingestion of a foreign body and thermal injury.

Common signs and symptoms of epiglottitis include sore throat, a high-pitched and muffled voice, labored breathing, and respiratory distress.¹ Since airway obstruction can be remarkably precipitous, it is important to obtain early consultation with an otolaryngologist for laryngoscopy and visualization of the erythematous, swollen epiglottis. Signs of severe upper-airway obstruction may be absent until late in the disease process, making early diagnosis crucial.

On physical examination, the oropharynx will often appear benign. Currently, the preferred diagnostic test for epiglottitis is visualization by laryngoscopy, which has close to 100% sensitivity and specificity.² By comparison, lateral neck radiography has poor sensitivity (38% to 88%) and specificity (78%).^3,4 Bedside ultrasonography has been reported as capable of revealing the “alphabet P sign” in the longitudinal view through the thyrohyoid membrane.⁵

At triage, if clinical suspicion of total airway obstruction is high, the patient may be taken directly to the operating room for visualization of the epiglottis and, if necessary, for endotracheal intubation. When the risk is considered low or moderate, lateral neck radiography may be helpful,⁶ as it will sometimes reveal a swollen epiglottis (ie, “thumb sign”), thickened arytenoepiglottic folds, and obliteration of the epiglottic vallecula. If the radiograph is normal and clinical suspicion is still present, laryngoscopy can be done.

For low-risk, acute epiglottitis, closely monitoring the patient in an intensive care unit is recommended. For severe, high-risk cases, securing the airway is of the utmost importance. In addition to securing the airway, empiric antimicrobial therapy—such as with cefotaxime or ceftriaxone plus clindamycin or vancomycin—is often warranted in both low-risk and high-risk cases. The use of corticosteroids in epiglottitis has not been studied in a randomized, controlled trial, and, though common, it remains controversial.⁷ While undergoing treatment, patients should be closely monitored for respiratory compromise.

HOW OUR PATIENT WAS MANAGED

Our patient had a high-pitched, muffled voice and prominent, tender anterior cervical lymph nodes. No drooling or stridor was noted. The oropharynx appeared normal. Lateral soft-tissue radiography of the neck (Figure 1) revealed several key findings:

• A swollen epiglottis (ie, the “thumb sign”) consistent with acute epiglottitis and a narrowed airway
• Swollen arytenoids
• A shallow V-shaped epiglottic vallecula.

For comparison, Figure 2 shows a normal lateral soft-tissue radiograph of the neck from a different patient.

Our patient was referred to an otolaryngologist, who noted a severely inflamed epiglottis on laryngoscopy.

The patient was given intravenous vancomycin, ceftriaxone, and high-dose corticosteroids and was admitted to the intensive care unit. After his symptoms improved, repeat laryngoscopy revealed markedly diminished inflammation. He was discharged home with an additional course of oral antibiotics.

A 55-year-old man presents to the emergency department with a sore throat, odynophagia, hoarseness, and a high-pitched muffled voice for 1 day. He is otherwise healthy, with no fever, chills, or exposure to sick contacts.

Q: Which is the most likely diagnosis?

• Retropharyngeal abscess
• Croup
• Streptococcal pharyngitis (“strep throat”)
• Acute epiglottitis
• Viral upper-respiratory infection

A: The correct answer is acute epiglottitis.

Acute epiglottitis is a cellulitis of the epiglottis and adjacent tissues that, without treatment, can progress to life-threatening airway obstruction.

In children, this entity most often occurs between ages 2 and 4. Previously, it was mainly associated with Haemophilus influenzae type B infection, but since the start of vaccination for this organism, epiglottitis has become less common.

In recent years, Streptococcus pneumoniae and beta-hemolytic streptococci have become the main culprits in epiglottitis in children. In adults, common organisms include H influenzae, S pneumoniae, Staphylococcus aureus, and betahemolytic streptococci. Epiglottitis may also be caused by herpes simplex, varicella-zoster, and influenza viruses. Noninfectious causes include ingestion of a foreign body and thermal injury.

Common signs and symptoms of epiglottitis include sore throat, a high-pitched and muffled voice, labored breathing, and respiratory distress.¹ Since airway obstruction can be remarkably precipitous, it is important to obtain early consultation with an otolaryngologist for laryngoscopy and visualization of the erythematous, swollen epiglottis. Signs of severe upper-airway obstruction may be absent until late in the disease process, making early diagnosis crucial.

On physical examination, the oropharynx will often appear benign. Currently, the preferred diagnostic test for epiglottitis is visualization by laryngoscopy, which has close to 100% sensitivity and specificity.² By comparison, lateral neck radiography has poor sensitivity (38% to 88%) and specificity (78%).^3,4 Bedside ultrasonography has been reported as capable of revealing the “alphabet P sign” in the longitudinal view through the thyrohyoid membrane.⁵

At triage, if clinical suspicion of total airway obstruction is high, the patient may be taken directly to the operating room for visualization of the epiglottis and, if necessary, for endotracheal intubation. When the risk is considered low or moderate, lateral neck radiography may be helpful,⁶ as it will sometimes reveal a swollen epiglottis (ie, “thumb sign”), thickened arytenoepiglottic folds, and obliteration of the epiglottic vallecula. If the radiograph is normal and clinical suspicion is still present, laryngoscopy can be done.

For low-risk, acute epiglottitis, closely monitoring the patient in an intensive care unit is recommended. For severe, high-risk cases, securing the airway is of the utmost importance. In addition to securing the airway, empiric antimicrobial therapy—such as with cefotaxime or ceftriaxone plus clindamycin or vancomycin—is often warranted in both low-risk and high-risk cases. The use of corticosteroids in epiglottitis has not been studied in a randomized, controlled trial, and, though common, it remains controversial.⁷ While undergoing treatment, patients should be closely monitored for respiratory compromise.

HOW OUR PATIENT WAS MANAGED

Our patient had a high-pitched, muffled voice and prominent, tender anterior cervical lymph nodes. No drooling or stridor was noted. The oropharynx appeared normal. Lateral soft-tissue radiography of the neck (Figure 1) revealed several key findings:

• A swollen epiglottis (ie, the “thumb sign”) consistent with acute epiglottitis and a narrowed airway
• Swollen arytenoids
• A shallow V-shaped epiglottic vallecula.

For comparison, Figure 2 shows a normal lateral soft-tissue radiograph of the neck from a different patient.

Our patient was referred to an otolaryngologist, who noted a severely inflamed epiglottis on laryngoscopy.

The patient was given intravenous vancomycin, ceftriaxone, and high-dose corticosteroids and was admitted to the intensive care unit. After his symptoms improved, repeat laryngoscopy revealed markedly diminished inflammation. He was discharged home with an additional course of oral antibiotics.

A 48-year-old man with hypertension was being evaluated for a noncardiac issue (progressive multifocal leukoencephalopathy). He had been an active runner and did not have any cardiovascular symptoms at the time. The electrocardiogram (ECG) shown in Figure 1 was a routine study done as a part of that evaluation. His cardiovascular examination was unremarkable, without murmur, S3, or S4. His pulse was regular at 72 beats per minute, and his blood pressure was 112/76 mm Hg.

Q: Which of the following electrocardiographic findings suggest left ventricular hypertrophy?

• Sum of the S wave in V₁ and the R wave in V₆ ≥ 35 mm
• Sum of the S wave in V₃ and the R wave in aVL > 28 mm (men)
• Sum of the S wave in V₃ and the R wave in aVL > 20 mm (women)
• All of the above

A: The correct answer is all of the above.^1,2

Our patient’s ECG shows sinus bradycardia and left ventricular hypertrophy, suggested by prominent voltage (sum of S in V1 and R in V6 ≥ 35 mm) and supported by ST-segment and T-wave changes in the lateral and midprecordial leads. Classic changes of left ventricular hypertrophy often include increased voltage and downsloping ST-segment depression with negative T waves in V5 and V6 (secondary repolarization changes or “strain” pattern).

Notable on this tracing are the large, asymmetric negative T waves in leads V₃ through V₆. Giant T waves are defined as negative T waves with voltage greater than 10 mm.³ Although there is no specific pattern of ventricular hypertrophy on an ECG that establishes the diagnosis of hypertrophic cardiomyopathy, left ventricular hypertrophy with T waves of this quality suggest the possibility of hypertrophic cardiomyopathy with apical hypertrophy.

Q: What are the other causes of giant negative T waves?

• Subarachnoid hemorrhage
• Complete heart block
• Non-Q-wave myocardial infarction
• All of the above

A: The correct answer is all of the above. Additional causes of dramatic T-wave inversion are listed in Table 1. Clinically, non-Q-wave myocardial infarction with T-wave changes and acute central nervous system injury are probably the most commonly seen.⁴

Echocardiography in this patient revealed severe apical hypertrophy of the ventricle with distal cavity obliteration. The left ventricular outflow-tract gradient was normal. The mitral valve appeared normal, and there was no resting systolic anterior motion.

Cardiac magnetic resonance imaging showed the apical variant of hypertrophic cardiomyopathy but no evidence of left ventricular noncompaction, which is a differential diagnosis of apical hypertrophic obstructive cardiomyopathy. This disease was first described in Japan by Yamaguchi et al⁵ and Sakamoto et al⁶ and is regarded as a subgroup of nonobstructive hypertrophic cardiomyopathy. The prognosis of apical hypertrophic cardiomyopathy with regard to sudden cardiac death is believed to be better than that of other forms of hypertrophic cardiomyopathy.³

A 48-year-old man with hypertension was being evaluated for a noncardiac issue (progressive multifocal leukoencephalopathy). He had been an active runner and did not have any cardiovascular symptoms at the time. The electrocardiogram (ECG) shown in Figure 1 was a routine study done as a part of that evaluation. His cardiovascular examination was unremarkable, without murmur, S3, or S4. His pulse was regular at 72 beats per minute, and his blood pressure was 112/76 mm Hg.

Q: Which of the following electrocardiographic findings suggest left ventricular hypertrophy?

• Sum of the S wave in V₁ and the R wave in V₆ ≥ 35 mm
• Sum of the S wave in V₃ and the R wave in aVL > 28 mm (men)
• Sum of the S wave in V₃ and the R wave in aVL > 20 mm (women)
• All of the above

A: The correct answer is all of the above.^1,2

Our patient’s ECG shows sinus bradycardia and left ventricular hypertrophy, suggested by prominent voltage (sum of S in V1 and R in V6 ≥ 35 mm) and supported by ST-segment and T-wave changes in the lateral and midprecordial leads. Classic changes of left ventricular hypertrophy often include increased voltage and downsloping ST-segment depression with negative T waves in V5 and V6 (secondary repolarization changes or “strain” pattern).

Notable on this tracing are the large, asymmetric negative T waves in leads V₃ through V₆. Giant T waves are defined as negative T waves with voltage greater than 10 mm.³ Although there is no specific pattern of ventricular hypertrophy on an ECG that establishes the diagnosis of hypertrophic cardiomyopathy, left ventricular hypertrophy with T waves of this quality suggest the possibility of hypertrophic cardiomyopathy with apical hypertrophy.

Q: What are the other causes of giant negative T waves?

• Subarachnoid hemorrhage
• Complete heart block
• Non-Q-wave myocardial infarction
• All of the above

A: The correct answer is all of the above. Additional causes of dramatic T-wave inversion are listed in Table 1. Clinically, non-Q-wave myocardial infarction with T-wave changes and acute central nervous system injury are probably the most commonly seen.⁴

Echocardiography in this patient revealed severe apical hypertrophy of the ventricle with distal cavity obliteration. The left ventricular outflow-tract gradient was normal. The mitral valve appeared normal, and there was no resting systolic anterior motion.

Cardiac magnetic resonance imaging showed the apical variant of hypertrophic cardiomyopathy but no evidence of left ventricular noncompaction, which is a differential diagnosis of apical hypertrophic obstructive cardiomyopathy. This disease was first described in Japan by Yamaguchi et al⁵ and Sakamoto et al⁶ and is regarded as a subgroup of nonobstructive hypertrophic cardiomyopathy. The prognosis of apical hypertrophic cardiomyopathy with regard to sudden cardiac death is believed to be better than that of other forms of hypertrophic cardiomyopathy.³

A 48-year-old man with hypertension was being evaluated for a noncardiac issue (progressive multifocal leukoencephalopathy). He had been an active runner and did not have any cardiovascular symptoms at the time. The electrocardiogram (ECG) shown in Figure 1 was a routine study done as a part of that evaluation. His cardiovascular examination was unremarkable, without murmur, S3, or S4. His pulse was regular at 72 beats per minute, and his blood pressure was 112/76 mm Hg.

Q: Which of the following electrocardiographic findings suggest left ventricular hypertrophy?

• Sum of the S wave in V₁ and the R wave in V₆ ≥ 35 mm
• Sum of the S wave in V₃ and the R wave in aVL > 28 mm (men)
• Sum of the S wave in V₃ and the R wave in aVL > 20 mm (women)
• All of the above

A: The correct answer is all of the above.^1,2

Our patient’s ECG shows sinus bradycardia and left ventricular hypertrophy, suggested by prominent voltage (sum of S in V1 and R in V6 ≥ 35 mm) and supported by ST-segment and T-wave changes in the lateral and midprecordial leads. Classic changes of left ventricular hypertrophy often include increased voltage and downsloping ST-segment depression with negative T waves in V5 and V6 (secondary repolarization changes or “strain” pattern).

Notable on this tracing are the large, asymmetric negative T waves in leads V₃ through V₆. Giant T waves are defined as negative T waves with voltage greater than 10 mm.³ Although there is no specific pattern of ventricular hypertrophy on an ECG that establishes the diagnosis of hypertrophic cardiomyopathy, left ventricular hypertrophy with T waves of this quality suggest the possibility of hypertrophic cardiomyopathy with apical hypertrophy.

Q: What are the other causes of giant negative T waves?

• Subarachnoid hemorrhage
• Complete heart block
• Non-Q-wave myocardial infarction
• All of the above

A: The correct answer is all of the above. Additional causes of dramatic T-wave inversion are listed in Table 1. Clinically, non-Q-wave myocardial infarction with T-wave changes and acute central nervous system injury are probably the most commonly seen.⁴

Echocardiography in this patient revealed severe apical hypertrophy of the ventricle with distal cavity obliteration. The left ventricular outflow-tract gradient was normal. The mitral valve appeared normal, and there was no resting systolic anterior motion.

Cardiac magnetic resonance imaging showed the apical variant of hypertrophic cardiomyopathy but no evidence of left ventricular noncompaction, which is a differential diagnosis of apical hypertrophic obstructive cardiomyopathy. This disease was first described in Japan by Yamaguchi et al⁵ and Sakamoto et al⁶ and is regarded as a subgroup of nonobstructive hypertrophic cardiomyopathy. The prognosis of apical hypertrophic cardiomyopathy with regard to sudden cardiac death is believed to be better than that of other forms of hypertrophic cardiomyopathy.³

With great enthusiasm, I introduce our two new deputy editors, and inform you of the career change of our exiting deputy editor, Dr. Tim Gilligan.

Tim, a practicing oncologist and program director of Cleveland Clinic’s hematology-oncology fellowship program, is transitioning from his work at the Journal to further pursue his interest in promoting physician communication skills. He is now co-director of the Clinic’s new Center for Excellence in Health Care Communication. Tim will refine and implement a coaching program for physicians in communication skills and will continue to conduct educational sessions for physicians on communication at institutions around the country. He will also continue his work with the American Society of Clinical Oncology as chair of their measures-of-quality subcommittee and as co-chair of the panel writing guidelines on the management of testicular cancer.

Joining us as deputy editors are Pelin Batur and Jim Pile—two superb clinician-educators who have divergent interests and experience, but who share a genuine passion for creating and delivering high-quality postgraduate and continuing medical education (CME) material and programs.

Pelin is a practicing general internist with additional fellowship training in women’s health. She is a North American Menopause Society-certified menopause practitioner and the Education Director for Primary Care Women’s Health at the Clinic, and she lectures nationally and internationally on women’s health issues. Jim is a practicing hospitalist and consultant in infectious disease at the Clinic. He is the former editor of The Hospitalist, he is current deputy editor of the Journal of Hospital Medicine, and he fulfills various education-focused roles at the Clinic and with the Society of Hospital Medicine.

In addition to our expectation that they will increase the Journal’s offerings within their clinical areas of interest, particularly hospital medicine and women’s health, they both will follow Tim’s lead in enhancing the depth and breadth of our CME activities, as well as expanding our online and digital presence. I am confident their efforts will enable us to even further improve the quality and utility of our practice- and evidencebased papers for you, our clinician readers.

With great enthusiasm, I introduce our two new deputy editors, and inform you of the career change of our exiting deputy editor, Dr. Tim Gilligan.

Tim, a practicing oncologist and program director of Cleveland Clinic’s hematology-oncology fellowship program, is transitioning from his work at the Journal to further pursue his interest in promoting physician communication skills. He is now co-director of the Clinic’s new Center for Excellence in Health Care Communication. Tim will refine and implement a coaching program for physicians in communication skills and will continue to conduct educational sessions for physicians on communication at institutions around the country. He will also continue his work with the American Society of Clinical Oncology as chair of their measures-of-quality subcommittee and as co-chair of the panel writing guidelines on the management of testicular cancer.

Joining us as deputy editors are Pelin Batur and Jim Pile—two superb clinician-educators who have divergent interests and experience, but who share a genuine passion for creating and delivering high-quality postgraduate and continuing medical education (CME) material and programs.

Pelin is a practicing general internist with additional fellowship training in women’s health. She is a North American Menopause Society-certified menopause practitioner and the Education Director for Primary Care Women’s Health at the Clinic, and she lectures nationally and internationally on women’s health issues. Jim is a practicing hospitalist and consultant in infectious disease at the Clinic. He is the former editor of The Hospitalist, he is current deputy editor of the Journal of Hospital Medicine, and he fulfills various education-focused roles at the Clinic and with the Society of Hospital Medicine.

In addition to our expectation that they will increase the Journal’s offerings within their clinical areas of interest, particularly hospital medicine and women’s health, they both will follow Tim’s lead in enhancing the depth and breadth of our CME activities, as well as expanding our online and digital presence. I am confident their efforts will enable us to even further improve the quality and utility of our practice- and evidencebased papers for you, our clinician readers.

With great enthusiasm, I introduce our two new deputy editors, and inform you of the career change of our exiting deputy editor, Dr. Tim Gilligan.

Tim, a practicing oncologist and program director of Cleveland Clinic’s hematology-oncology fellowship program, is transitioning from his work at the Journal to further pursue his interest in promoting physician communication skills. He is now co-director of the Clinic’s new Center for Excellence in Health Care Communication. Tim will refine and implement a coaching program for physicians in communication skills and will continue to conduct educational sessions for physicians on communication at institutions around the country. He will also continue his work with the American Society of Clinical Oncology as chair of their measures-of-quality subcommittee and as co-chair of the panel writing guidelines on the management of testicular cancer.

Joining us as deputy editors are Pelin Batur and Jim Pile—two superb clinician-educators who have divergent interests and experience, but who share a genuine passion for creating and delivering high-quality postgraduate and continuing medical education (CME) material and programs.

Pelin is a practicing general internist with additional fellowship training in women’s health. She is a North American Menopause Society-certified menopause practitioner and the Education Director for Primary Care Women’s Health at the Clinic, and she lectures nationally and internationally on women’s health issues. Jim is a practicing hospitalist and consultant in infectious disease at the Clinic. He is the former editor of The Hospitalist, he is current deputy editor of the Journal of Hospital Medicine, and he fulfills various education-focused roles at the Clinic and with the Society of Hospital Medicine.

In addition to our expectation that they will increase the Journal’s offerings within their clinical areas of interest, particularly hospital medicine and women’s health, they both will follow Tim’s lead in enhancing the depth and breadth of our CME activities, as well as expanding our online and digital presence. I am confident their efforts will enable us to even further improve the quality and utility of our practice- and evidencebased papers for you, our clinician readers.

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.