The clinical quality of outpatient care for adults in the United States did not improve consistently from 2002 to 2013, despite numerous local, regional, and national efforts to make it better, according to a report published online Oct. 17 in JAMA Internal Medicine.

“Current deficits in care continue to pose serious hazards to the health of the American public in the form of missed care opportunities as well as waste and potential harm from overuse,” said David M. Levine, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Since a 2003 report showing that American adults received about half of the recommended health care services, many programs have sought to make improvements by expanding quality measurements and public reporting, increasing pay for performance, increasing value-based purchasing by payers, increasing the use of electronic medical records, improving coverage for recommended services, and expanding patient-centered medical homes.

Yet few data are available by which to gauge whether these efforts have been effective, the investigators noted (JAMA Intern Med. 2016 Oct 17; doi:10.1001/jamainternmed.2016.6217).

They analyzed data from a nationally representative annual outpatient survey to determine whether 46 indicators of care quality changed from 2002 to 2013. Sample sizes ranged from 20,679 to 26,509 adults per year, and that information was supplemented by responses from the patients’ clinicians, pharmacies, and employers.

Overall, rates of recommended treatment delivery showed an “anemic” improvement from 36% to 42%, with a few areas showing marked improvement while others showed little improvement or actual declines.

For example, rates of recommended medications for heart failure increased from 41% to 65%; rates for recommended statin therapy for stroke patients increased from 34% to 57%; and rates of recommended smoking-cessation counseling increased from 49% to 61%. However, rates of inappropriate antibiotic prescribing and inappropriate medications in the elderly both worsened.

Recommended colorectal cancer screening improved from 48% to 63%; but recommended breast cancer screening declined from 81% to 77%, and recommended cervical cancer screening declined from 90% to 86%.

Inappropriate cervical cancer screening in the elderly improved, but inappropriate colorectal cancer screening in the elderly worsened.

Of greatest concern, approximately half of elderly adults underwent inappropriate cancer screening when it was unlikely to prolong life. And approximately half of adults who saw a clinician for a viral illness received inappropriate antibiotics. In addition, approximately 15% who consulted a clinician for back pain received an inappropriate lumbar radiograph.

“These areas represent prime targets for efforts to improve the value of care delivered by eliminating services that have a neutral or negative impact on health,” Dr. Levine and his associates said.

The investigators emphasized that these data do not reflect changes resulting from the Affordable Care Act, which was implemented in late 2013. The ACA has encouraged many organizational changes, renewed the focus on primary care, and expanded health insurance coverage to 30 million more people. All of these changes are expected to improve overall health care quality, the study authors noted. But it is not yet known whether these changes will have their intended effect.

This study was supported in part by the National Institutes of Health and the Ryoichi Sasakawa Fellowship Fund. Dr. Levine and his associates reported having no relevant financial disclosures.

The clinical quality of outpatient care for adults in the United States did not improve consistently from 2002 to 2013, despite numerous local, regional, and national efforts to make it better, according to a report published online Oct. 17 in JAMA Internal Medicine.

“Current deficits in care continue to pose serious hazards to the health of the American public in the form of missed care opportunities as well as waste and potential harm from overuse,” said David M. Levine, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Since a 2003 report showing that American adults received about half of the recommended health care services, many programs have sought to make improvements by expanding quality measurements and public reporting, increasing pay for performance, increasing value-based purchasing by payers, increasing the use of electronic medical records, improving coverage for recommended services, and expanding patient-centered medical homes.

Yet few data are available by which to gauge whether these efforts have been effective, the investigators noted (JAMA Intern Med. 2016 Oct 17; doi:10.1001/jamainternmed.2016.6217).

They analyzed data from a nationally representative annual outpatient survey to determine whether 46 indicators of care quality changed from 2002 to 2013. Sample sizes ranged from 20,679 to 26,509 adults per year, and that information was supplemented by responses from the patients’ clinicians, pharmacies, and employers.

Overall, rates of recommended treatment delivery showed an “anemic” improvement from 36% to 42%, with a few areas showing marked improvement while others showed little improvement or actual declines.

For example, rates of recommended medications for heart failure increased from 41% to 65%; rates for recommended statin therapy for stroke patients increased from 34% to 57%; and rates of recommended smoking-cessation counseling increased from 49% to 61%. However, rates of inappropriate antibiotic prescribing and inappropriate medications in the elderly both worsened.

Recommended colorectal cancer screening improved from 48% to 63%; but recommended breast cancer screening declined from 81% to 77%, and recommended cervical cancer screening declined from 90% to 86%.

Inappropriate cervical cancer screening in the elderly improved, but inappropriate colorectal cancer screening in the elderly worsened.

Of greatest concern, approximately half of elderly adults underwent inappropriate cancer screening when it was unlikely to prolong life. And approximately half of adults who saw a clinician for a viral illness received inappropriate antibiotics. In addition, approximately 15% who consulted a clinician for back pain received an inappropriate lumbar radiograph.

“These areas represent prime targets for efforts to improve the value of care delivered by eliminating services that have a neutral or negative impact on health,” Dr. Levine and his associates said.

The investigators emphasized that these data do not reflect changes resulting from the Affordable Care Act, which was implemented in late 2013. The ACA has encouraged many organizational changes, renewed the focus on primary care, and expanded health insurance coverage to 30 million more people. All of these changes are expected to improve overall health care quality, the study authors noted. But it is not yet known whether these changes will have their intended effect.

This study was supported in part by the National Institutes of Health and the Ryoichi Sasakawa Fellowship Fund. Dr. Levine and his associates reported having no relevant financial disclosures.

The clinical quality of outpatient care for adults in the United States did not improve consistently from 2002 to 2013, despite numerous local, regional, and national efforts to make it better, according to a report published online Oct. 17 in JAMA Internal Medicine.

“Current deficits in care continue to pose serious hazards to the health of the American public in the form of missed care opportunities as well as waste and potential harm from overuse,” said David M. Levine, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his associates.

Since a 2003 report showing that American adults received about half of the recommended health care services, many programs have sought to make improvements by expanding quality measurements and public reporting, increasing pay for performance, increasing value-based purchasing by payers, increasing the use of electronic medical records, improving coverage for recommended services, and expanding patient-centered medical homes.

Yet few data are available by which to gauge whether these efforts have been effective, the investigators noted (JAMA Intern Med. 2016 Oct 17; doi:10.1001/jamainternmed.2016.6217).

They analyzed data from a nationally representative annual outpatient survey to determine whether 46 indicators of care quality changed from 2002 to 2013. Sample sizes ranged from 20,679 to 26,509 adults per year, and that information was supplemented by responses from the patients’ clinicians, pharmacies, and employers.

Overall, rates of recommended treatment delivery showed an “anemic” improvement from 36% to 42%, with a few areas showing marked improvement while others showed little improvement or actual declines.

For example, rates of recommended medications for heart failure increased from 41% to 65%; rates for recommended statin therapy for stroke patients increased from 34% to 57%; and rates of recommended smoking-cessation counseling increased from 49% to 61%. However, rates of inappropriate antibiotic prescribing and inappropriate medications in the elderly both worsened.

Recommended colorectal cancer screening improved from 48% to 63%; but recommended breast cancer screening declined from 81% to 77%, and recommended cervical cancer screening declined from 90% to 86%.

Inappropriate cervical cancer screening in the elderly improved, but inappropriate colorectal cancer screening in the elderly worsened.

Of greatest concern, approximately half of elderly adults underwent inappropriate cancer screening when it was unlikely to prolong life. And approximately half of adults who saw a clinician for a viral illness received inappropriate antibiotics. In addition, approximately 15% who consulted a clinician for back pain received an inappropriate lumbar radiograph.

“These areas represent prime targets for efforts to improve the value of care delivered by eliminating services that have a neutral or negative impact on health,” Dr. Levine and his associates said.

The investigators emphasized that these data do not reflect changes resulting from the Affordable Care Act, which was implemented in late 2013. The ACA has encouraged many organizational changes, renewed the focus on primary care, and expanded health insurance coverage to 30 million more people. All of these changes are expected to improve overall health care quality, the study authors noted. But it is not yet known whether these changes will have their intended effect.

This study was supported in part by the National Institutes of Health and the Ryoichi Sasakawa Fellowship Fund. Dr. Levine and his associates reported having no relevant financial disclosures.

The Diagnosis: Sister Mary Joseph Nodule

The umbilical skin biopsy revealed a moderately differentiated adenocarcinoma (Figure) that was positive for cytokeratin 20 and CDX2 and negative for cytokeratin 7 and transcription termination factor 1. The patient subsequently underwent computed tomography of the abdomen and pelvis, which showed multiple soft-tissue nodules on the greater omentum, a soft-tissue density at the umbilicus, and thickening of the gastric mucosa. An upper endoscopy was then performed, which revealed a large fungating ulcerated mass in the stomach. Biopsy of this mass showed an invasive moderately differentiated adenocarcinoma, which was ERBB2 (formerly HER2) negative. Histopathologically, these pleomorphic glands looked similar to the glands seen in the original skin biopsy. With this diagnosis of metastatic gastric adenocarcinoma, our patient chose palliative chemotherapy but declined precipitously and died 2 months after the initial skin biopsy of the umbilical lesion.

When encountering a patient with an umbilical lesion, it is important to consider benign and malignant lesions in the differential diagnosis. A benign lesion may include scar, cyst, pyogenic granuloma, hemangioma, umbilical hernia, endometriosis, polyp, abscess, or the presence of an omphalith.¹ Inflammatory dermatoses such as psoriasis or eczema also should be considered. Malignant lesions could be either primary or secondary, with metastatic disease being the most common.² Sister Mary Joseph nodule (SMJN) is the eponymgiven to an umbilical lesion representing metastatic disease. Sister Mary Joseph was a nurse and surgical assistant to Dr. William Mayo in Rochester, Minnesota, in what is now known as the Mayo Clinic. She is credited to be the first to observe and note the association between an umbilical nodule and intra-abdominal malignancy. Metastasis to the umbilicus is thought to occur by way of contiguous, hematogenous, lymphatic, or direct spread through embryologic remnants from primary cancers of nearby gastrointestinal or pelvic viscera. It is a rare cutaneous sign of internal malignancy, with an estimated prevalence of 1% to 3%.³ The most common primary cancer is gastric adenocarcinoma, though cases of metastasis from pancreatic, endometrial, and less commonly hematopoietic or supradiaphragmatic cancers have been reported.⁴ It is more common in women, likely due to the addition of gynecologic malignancies.¹

The use of dermoscopy has been advocated as an adjuvant tool in delineating benign and malignant umbilical lesions when an atypical polymorphous vascular pattern indicating neovascularization has been observed with neoplastic growth.⁵ Once a suspicious umbilical lesion is identified, the first step should be to obtain a skin biopsy or to use fine needle aspiration for cytology.⁶ Biopsy is especially relevant in the background of cancer history because SMJN may present with cancer recurrence.3 Once one of these is obtained, histological and immunohistochemical analysis will guide further workup and diagnosis of the umbilical lesion.

The importance of reviewing such cases lies in the variable presentation of cutaneous metastases such as SMJN and the grim prognosis that accompanies this finding. It presents as a firm indurated plaque or nodule that may present with systemic symptoms suggestive of malignancy, though in 30% of cases it is the sole initial sign.⁷ The nodule may be painful if ulcerated or fissured. Bloody, serous, or purulent discharge may be present. After diagnosis of an SMJN, most patients succumb to the disease within 12 months. Thus, it is vital for dermatologists to investigate umbilical lesions with great caution and a high index of suspicion.

The Diagnosis: Sister Mary Joseph Nodule

The umbilical skin biopsy revealed a moderately differentiated adenocarcinoma (Figure) that was positive for cytokeratin 20 and CDX2 and negative for cytokeratin 7 and transcription termination factor 1. The patient subsequently underwent computed tomography of the abdomen and pelvis, which showed multiple soft-tissue nodules on the greater omentum, a soft-tissue density at the umbilicus, and thickening of the gastric mucosa. An upper endoscopy was then performed, which revealed a large fungating ulcerated mass in the stomach. Biopsy of this mass showed an invasive moderately differentiated adenocarcinoma, which was ERBB2 (formerly HER2) negative. Histopathologically, these pleomorphic glands looked similar to the glands seen in the original skin biopsy. With this diagnosis of metastatic gastric adenocarcinoma, our patient chose palliative chemotherapy but declined precipitously and died 2 months after the initial skin biopsy of the umbilical lesion.

When encountering a patient with an umbilical lesion, it is important to consider benign and malignant lesions in the differential diagnosis. A benign lesion may include scar, cyst, pyogenic granuloma, hemangioma, umbilical hernia, endometriosis, polyp, abscess, or the presence of an omphalith.¹ Inflammatory dermatoses such as psoriasis or eczema also should be considered. Malignant lesions could be either primary or secondary, with metastatic disease being the most common.² Sister Mary Joseph nodule (SMJN) is the eponymgiven to an umbilical lesion representing metastatic disease. Sister Mary Joseph was a nurse and surgical assistant to Dr. William Mayo in Rochester, Minnesota, in what is now known as the Mayo Clinic. She is credited to be the first to observe and note the association between an umbilical nodule and intra-abdominal malignancy. Metastasis to the umbilicus is thought to occur by way of contiguous, hematogenous, lymphatic, or direct spread through embryologic remnants from primary cancers of nearby gastrointestinal or pelvic viscera. It is a rare cutaneous sign of internal malignancy, with an estimated prevalence of 1% to 3%.³ The most common primary cancer is gastric adenocarcinoma, though cases of metastasis from pancreatic, endometrial, and less commonly hematopoietic or supradiaphragmatic cancers have been reported.⁴ It is more common in women, likely due to the addition of gynecologic malignancies.¹

The use of dermoscopy has been advocated as an adjuvant tool in delineating benign and malignant umbilical lesions when an atypical polymorphous vascular pattern indicating neovascularization has been observed with neoplastic growth.⁵ Once a suspicious umbilical lesion is identified, the first step should be to obtain a skin biopsy or to use fine needle aspiration for cytology.⁶ Biopsy is especially relevant in the background of cancer history because SMJN may present with cancer recurrence.3 Once one of these is obtained, histological and immunohistochemical analysis will guide further workup and diagnosis of the umbilical lesion.

The importance of reviewing such cases lies in the variable presentation of cutaneous metastases such as SMJN and the grim prognosis that accompanies this finding. It presents as a firm indurated plaque or nodule that may present with systemic symptoms suggestive of malignancy, though in 30% of cases it is the sole initial sign.⁷ The nodule may be painful if ulcerated or fissured. Bloody, serous, or purulent discharge may be present. After diagnosis of an SMJN, most patients succumb to the disease within 12 months. Thus, it is vital for dermatologists to investigate umbilical lesions with great caution and a high index of suspicion.

The Diagnosis: Sister Mary Joseph Nodule

The umbilical skin biopsy revealed a moderately differentiated adenocarcinoma (Figure) that was positive for cytokeratin 20 and CDX2 and negative for cytokeratin 7 and transcription termination factor 1. The patient subsequently underwent computed tomography of the abdomen and pelvis, which showed multiple soft-tissue nodules on the greater omentum, a soft-tissue density at the umbilicus, and thickening of the gastric mucosa. An upper endoscopy was then performed, which revealed a large fungating ulcerated mass in the stomach. Biopsy of this mass showed an invasive moderately differentiated adenocarcinoma, which was ERBB2 (formerly HER2) negative. Histopathologically, these pleomorphic glands looked similar to the glands seen in the original skin biopsy. With this diagnosis of metastatic gastric adenocarcinoma, our patient chose palliative chemotherapy but declined precipitously and died 2 months after the initial skin biopsy of the umbilical lesion.

When encountering a patient with an umbilical lesion, it is important to consider benign and malignant lesions in the differential diagnosis. A benign lesion may include scar, cyst, pyogenic granuloma, hemangioma, umbilical hernia, endometriosis, polyp, abscess, or the presence of an omphalith.¹ Inflammatory dermatoses such as psoriasis or eczema also should be considered. Malignant lesions could be either primary or secondary, with metastatic disease being the most common.² Sister Mary Joseph nodule (SMJN) is the eponymgiven to an umbilical lesion representing metastatic disease. Sister Mary Joseph was a nurse and surgical assistant to Dr. William Mayo in Rochester, Minnesota, in what is now known as the Mayo Clinic. She is credited to be the first to observe and note the association between an umbilical nodule and intra-abdominal malignancy. Metastasis to the umbilicus is thought to occur by way of contiguous, hematogenous, lymphatic, or direct spread through embryologic remnants from primary cancers of nearby gastrointestinal or pelvic viscera. It is a rare cutaneous sign of internal malignancy, with an estimated prevalence of 1% to 3%.³ The most common primary cancer is gastric adenocarcinoma, though cases of metastasis from pancreatic, endometrial, and less commonly hematopoietic or supradiaphragmatic cancers have been reported.⁴ It is more common in women, likely due to the addition of gynecologic malignancies.¹

The use of dermoscopy has been advocated as an adjuvant tool in delineating benign and malignant umbilical lesions when an atypical polymorphous vascular pattern indicating neovascularization has been observed with neoplastic growth.⁵ Once a suspicious umbilical lesion is identified, the first step should be to obtain a skin biopsy or to use fine needle aspiration for cytology.⁶ Biopsy is especially relevant in the background of cancer history because SMJN may present with cancer recurrence.3 Once one of these is obtained, histological and immunohistochemical analysis will guide further workup and diagnosis of the umbilical lesion.

The importance of reviewing such cases lies in the variable presentation of cutaneous metastases such as SMJN and the grim prognosis that accompanies this finding. It presents as a firm indurated plaque or nodule that may present with systemic symptoms suggestive of malignancy, though in 30% of cases it is the sole initial sign.⁷ The nodule may be painful if ulcerated or fissured. Bloody, serous, or purulent discharge may be present. After diagnosis of an SMJN, most patients succumb to the disease within 12 months. Thus, it is vital for dermatologists to investigate umbilical lesions with great caution and a high index of suspicion.

The troubling, frustrating part of acne: the persistent acne scars that are often a prolonged battle for most of our patients. We have many techniques to deal with postinflammatory hyperpigmentation (PIH). However, postinflammatory erythema (PIE), the erythematous scars often seen in acne and other inflammatory skin conditions, is not well understood. And despite its pervasive nature, very little data exist that identify its etiology and effective treatment options.

Inflammatory acne scars are not all the same. PIH, often seen with Fitzpatrick skin types III-VI, is related to brown spots, not red spots. Hyperpigmentation is caused by an excess production of melanin. There are treatments for PIH in our armamentarium – such as microdermabrasion, chemical peels, hydroquinone, and vitamin C – that inhibit melanogenesis and blend the skin discoloration.

References

1. J Clin Aesthet Dermatol. 2013 Sep;6(9):46-7.

2. J Am Acad Dermatol. 2009 May;60(5):801-7.
 

Dr. Talakoub and Dr. Wesley are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected].

The troubling, frustrating part of acne: the persistent acne scars that are often a prolonged battle for most of our patients. We have many techniques to deal with postinflammatory hyperpigmentation (PIH). However, postinflammatory erythema (PIE), the erythematous scars often seen in acne and other inflammatory skin conditions, is not well understood. And despite its pervasive nature, very little data exist that identify its etiology and effective treatment options.

Inflammatory acne scars are not all the same. PIH, often seen with Fitzpatrick skin types III-VI, is related to brown spots, not red spots. Hyperpigmentation is caused by an excess production of melanin. There are treatments for PIH in our armamentarium – such as microdermabrasion, chemical peels, hydroquinone, and vitamin C – that inhibit melanogenesis and blend the skin discoloration.

References

1. J Clin Aesthet Dermatol. 2013 Sep;6(9):46-7.

2. J Am Acad Dermatol. 2009 May;60(5):801-7.
 

Dr. Talakoub and Dr. Wesley are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected].

The troubling, frustrating part of acne: the persistent acne scars that are often a prolonged battle for most of our patients. We have many techniques to deal with postinflammatory hyperpigmentation (PIH). However, postinflammatory erythema (PIE), the erythematous scars often seen in acne and other inflammatory skin conditions, is not well understood. And despite its pervasive nature, very little data exist that identify its etiology and effective treatment options.

Inflammatory acne scars are not all the same. PIH, often seen with Fitzpatrick skin types III-VI, is related to brown spots, not red spots. Hyperpigmentation is caused by an excess production of melanin. There are treatments for PIH in our armamentarium – such as microdermabrasion, chemical peels, hydroquinone, and vitamin C – that inhibit melanogenesis and blend the skin discoloration.

References

1. J Clin Aesthet Dermatol. 2013 Sep;6(9):46-7.

2. J Am Acad Dermatol. 2009 May;60(5):801-7.
 

Dr. Talakoub and Dr. Wesley are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Talakoub. Write to them at [email protected].

Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?

Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.

Study Design: Retrospective observational cohort study.

Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.

Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.

Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.

Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.

Short Take

Intranasal Live Attenuated Influenza Vaccine Not Recommended

The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.

Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.

Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?

Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.

Study Design: Retrospective observational cohort study.

Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.

Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.

Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.

Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.

Short Take

Intranasal Live Attenuated Influenza Vaccine Not Recommended

The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.

Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.

Clinical Question: Can an objective measurement of critical illness inform intensive care unit (ICU) transfer timeliness?

Background: Early intervention has shown mortality benefit in many critical illness syndromes, yet heterogeneity in timing of ICU transfer exists. Previous studies examining ICU transfer timeliness have mostly focused on subjective criteria.

Study Design: Retrospective observational cohort study.

Setting: Medical-surgical units at five hospitals including the University of Chicago and NorthShore University HealthSystem in Illinois.

Synopsis: All medical-surgical ward patients between November 2008 and January 2013 were scored using eCART, a previously validated objective scoring system, to decide when transfer was appropriate. Of those, 3,789 patients reached the predetermined threshold for critical illness. Transfers more than six hours after crossing the threshold were considered delayed. Patients with delayed transfer had a statistically significant increase in length of stay (LOS) and in-hospital mortality (33.2% versus 24.5%; P < 0.001), and the mortality increase was linear, with a 3% increase in odds for each one hour of further transfer delay (P < 0.001). The rate of change of eCART score did influence time of transfer, and the authors suggest that rapid changes were more likely to be recognized. They postulate that routine implementation of eCART or similar objective scoring may lead to earlier recognition of necessary ICU transfer and thus improve mortality and LOS, and they suggest this as a topic for future trials.

Bottom Line: Delayed ICU transfer negatively affects LOS and in-hospital mortality. Objective criteria may identify more appropriate timing of transfer. Clinical trials to investigate this are warranted.

Citation: Churpek MM, Wendlandt B, Zadravecz FJ, Adhikari R, Winslow C, Edelson DP. Association between intensive care unit transfer delay and hospital mortality: a multicenter investigation [published online ahead of print June 28, 2016]. J Hosp Med. doi:10.1002/jhm.2630.

Short Take

Intranasal Live Attenuated Influenza Vaccine Not Recommended

The Centers for Disease Control and Prevention recommends against use of the nasal spray live attenuated influenza vaccine. This is based on data showing poor effectiveness in prior years.

Citation: ACIP votes down use of LAIV for 2016-2017 flu season [press release]. CDC website.

Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?

Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.

Study Design: Retrospective study of a quality improvement bundle.

Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.

Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.

Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.

Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.

Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.

Short Take

New Framework for Learners’ Clinical Reasoning

A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).

Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.

Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?

Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.

Study Design: Retrospective study of a quality improvement bundle.

Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.

Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.

Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.

Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.

Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.

Short Take

New Framework for Learners’ Clinical Reasoning

A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).

Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.

Clinical Question: Does increased fluid administration in patients with sepsis with intermediate lactate levels improve outcomes?

Background: The Surviving Sepsis Campaign bundle, which improves ED mortality, targets patients with hypotension or lactate levels >4 mmol/L. No similar optimal treatment strategy exists for less severe sepsis patients even though such patients are more common in hospitalized populations.

Study Design: Retrospective study of a quality improvement bundle.

Setting: 21 community-based hospitals in the Kaiser Permanente Northern California system.

Synopsis: This study evaluated implementation of a treatment bundle for 18,122 hemodynamically stable sepsis patients presenting to the ED with lactate levels between 2 and 4 mmol/L during the 12 months prior to and after bundle implementation. The bundle included antibiotic administration within three hours, repeated lactate levels within four hours, and 30 mL/kg or ≥2 L of intravenous fluids within three hours of initial lactate result. Patients with kidney disease and/or heart failure were separately evaluated because of the perceived risk of fluid administration.

Treatment after bundle implementation was associated with an adjusted hospital mortality odds ratio of 0.81 (95% CI, 0.66–0.99; P = 0.04). Significant reductions in hospital mortality were observed in patients with heart failure and/or kidney disease (P < 0.01) but not without (P > 0.4). This correlated with increased fluid administration in patients with heart failure and/or kidney disease following bundle implementation. This is not a randomized controlled study, which invites biases and confounding.

Bottom Line: Increased fluid administration improved mortality in patients with kidney disease and heart failure presenting with sepsis.

Reference: Liu V, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270.

Short Take

New Framework for Learners’ Clinical Reasoning

A qualitative study involving 37 emergency medicine residents found that clinical reasoning through individual cases progresses from case framing (phase 1) to pattern recognition (phase 2), then self-monitoring (phase 3).

Citation: Adams E, Goyder C, Heneghan C, Brand L, Ajjawi R. Clinical reasoning of junior doctors in emergency medicine: a grounded theory study [published online ahead of print June 23, 2016]. Emerg Med J. doi:10.1136/emermed-2015-205650.

Takotsubo cardiomyopathy (TCM) is a transient left ventricular (LV) wall motion abnormality often associated with acute medical illnesses, catastrophic life events, and intense physical or emotional stress.^1,2 Takotsubo cardiomyopathy also is known as stress-induced transient cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy, and broken heart syndrome. The first reported case occurred in 1990 in Japan and accounts for 2% of all suspected acute coronary syndromes. Postmenopausal women seem to be at a higher risk for developing the disease, as about 90% of takotsubo cardiomyopathy occurs in postmenopausal women.³

Diagnosis of TCM is difficult, and there is an ongoing debate about the diagnostic criteria. The Mayo Clinic proposed the following criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma and myocarditis.⁴

Depending on the part of the LV involved, TCM can be classified into apical ballooning variant (most common), an inverted or reverse takotsubo variant (basal akinesis with hyper dynamic apex), or a midventricular takotsubo variant.⁵

Several investigators have proposed the role of catecholamine in the pathogeneses of TCM.^6,7 Previous case reports have shown that the clinical circumstances with elevated catecholamine can result in TCM.^8,9 The authors recently encountered a case of a patient who developed apical ballooning TCM after an inadvertent injection of a high dose of epinephrine.

Case Report

A 60-year-old man with a history of hypertension, alcohol abuse, tobacco use, non-Hodgkin lymphoma, and recently diagnosed squamous cell carcinoma of the right glossopalatine fossa was admitted to the chemotherapy infusion clinic at the Kansas City VAMC to receive his first dose of cetuximab. Forty-five minutes after starting the test-dose infusion, the patient developed shortness of breath along with hives on his trunk and extremities. His blood pressure was 80/50 mm Hg; heart rate, 100 bpm; 16 breaths per minute respiration rate; and oxygen saturation by pulse oximetry was 90% on ambient air. The patient reported no chest pain, and a cardiac examination was unremarkable without wheezing on lung auscultation.

A clinical diagnosis of acute anaphylaxis reaction was considered; the test dose of cetuximab was discontinued, and the patient was given 50 mg of diphenhydramine, followed by an inadvertent administration of 1 mg of epinephrine intravenously (recommended dose 0.1 mg). After 3 minutes of administration of the medication, the patient’s blood pressure increased to190/110 with a pulse rate of 120 bpm.

An electrocardiogram (EKG) showed ST elevation in the precordial and inferior leads consistent with inferior and anterior myocardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), elevated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocardiogram showed a LV ejection fraction of 40% with akinesis involving the apical anterior, mid and distal anteroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3).

Given these echocardiographic findings, persistent EKG changes, and elevated troponin levels, an emergent coronary angiography along with left ventriculography was performed. The left ventriculogram demonstrated apical ballooning consistent with TCM (Figures 4 and 5). The left epicardial coronary arteries did not reveal any obstructive disease (Figure 6).

The subsequent hospital course was unremarkable, and the patient was discharged on guideline-directed medications for systolic dysfunction (ie, beta blockers and angiotensin-converting-enzyme inhibitors). Serum levels of epinephrine were not checked. A follow-up echocardiogram performed after 8 weeks showed complete recovery of the LV function (Figures 7a and 7b). The temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine.

Discussion

The pathogenesis of stress-induced cardiomyopathy is not fully understood. Various hypotheses have been suggested, including catecholamine excess, coronary vasospasm, microvascular dysfunction, and dynamic midcavity or LV outflow tract obstruction.^1,10 The hypothesis implicating catecholamine excess in the pathogenesis of TCM is supported by animal studies.⁷ These studies suggest that catecholamines possibly play a role by “direct toxicity to myocardial cells” as evidenced by histologic findings of myofibrillar degeneration, contraction band necrosis, and leukocyte infiltration in harvested hearts from experimental animals and patients undergoing autopsy.^7,11 Similarly, cultured cardiomyocytes exposed to high doses of epinephrine showed apoptic changes. Pretreatment of these cells with α- and β-adrenoreceptor blockers significantly attenuated these changes.⁷

However, myocardial necrosis alone cannot explain the entire picture, because most patients with TCM regain full recovery of LV function within several days of the event, and the degree of LV dysfunction is inconsistent with the mild elevations in cardiac

The role of estrogen also has been implicated in the pathogenesis of TCM. From a prevalence standpoint, almost 90% of TCM occurs in postmenopausal women.^11,12 Estrogen plays a critical role in protecting the myocardium, possibly by down regulating β-adrenergic receptors. Postmenopausal women who do not receive estrogen replacement therapy lose this protection and may be more vulnerable to the catecholamine surge that is associated with stress.¹¹ Overall, the catecholamines play a central role in the pathogenesis. This case suggests that exogenous administration of epinephrine in suprapharmacologic doses can be sufficient to replicate the stressful situation and induce TCM.

Conclusion

The authors’ case report describes the induction of apical ballooning TCM by administration of supratherapeutic doses of epinephrine and supports the role of catecholamines in the pathophysiology of TCM. It is hoped that this report will help clinicians to suspect, recognize, and manage this disease and be aware of possible iatrogenic causes.

Takotsubo cardiomyopathy (TCM) is a transient left ventricular (LV) wall motion abnormality often associated with acute medical illnesses, catastrophic life events, and intense physical or emotional stress.^1,2 Takotsubo cardiomyopathy also is known as stress-induced transient cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy, and broken heart syndrome. The first reported case occurred in 1990 in Japan and accounts for 2% of all suspected acute coronary syndromes. Postmenopausal women seem to be at a higher risk for developing the disease, as about 90% of takotsubo cardiomyopathy occurs in postmenopausal women.³

Diagnosis of TCM is difficult, and there is an ongoing debate about the diagnostic criteria. The Mayo Clinic proposed the following criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma and myocarditis.⁴

Depending on the part of the LV involved, TCM can be classified into apical ballooning variant (most common), an inverted or reverse takotsubo variant (basal akinesis with hyper dynamic apex), or a midventricular takotsubo variant.⁵

Several investigators have proposed the role of catecholamine in the pathogeneses of TCM.^6,7 Previous case reports have shown that the clinical circumstances with elevated catecholamine can result in TCM.^8,9 The authors recently encountered a case of a patient who developed apical ballooning TCM after an inadvertent injection of a high dose of epinephrine.

Case Report

A 60-year-old man with a history of hypertension, alcohol abuse, tobacco use, non-Hodgkin lymphoma, and recently diagnosed squamous cell carcinoma of the right glossopalatine fossa was admitted to the chemotherapy infusion clinic at the Kansas City VAMC to receive his first dose of cetuximab. Forty-five minutes after starting the test-dose infusion, the patient developed shortness of breath along with hives on his trunk and extremities. His blood pressure was 80/50 mm Hg; heart rate, 100 bpm; 16 breaths per minute respiration rate; and oxygen saturation by pulse oximetry was 90% on ambient air. The patient reported no chest pain, and a cardiac examination was unremarkable without wheezing on lung auscultation.

A clinical diagnosis of acute anaphylaxis reaction was considered; the test dose of cetuximab was discontinued, and the patient was given 50 mg of diphenhydramine, followed by an inadvertent administration of 1 mg of epinephrine intravenously (recommended dose 0.1 mg). After 3 minutes of administration of the medication, the patient’s blood pressure increased to190/110 with a pulse rate of 120 bpm.

An electrocardiogram (EKG) showed ST elevation in the precordial and inferior leads consistent with inferior and anterior myocardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), elevated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocardiogram showed a LV ejection fraction of 40% with akinesis involving the apical anterior, mid and distal anteroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3).

Given these echocardiographic findings, persistent EKG changes, and elevated troponin levels, an emergent coronary angiography along with left ventriculography was performed. The left ventriculogram demonstrated apical ballooning consistent with TCM (Figures 4 and 5). The left epicardial coronary arteries did not reveal any obstructive disease (Figure 6).

The subsequent hospital course was unremarkable, and the patient was discharged on guideline-directed medications for systolic dysfunction (ie, beta blockers and angiotensin-converting-enzyme inhibitors). Serum levels of epinephrine were not checked. A follow-up echocardiogram performed after 8 weeks showed complete recovery of the LV function (Figures 7a and 7b). The temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine.

Discussion

The pathogenesis of stress-induced cardiomyopathy is not fully understood. Various hypotheses have been suggested, including catecholamine excess, coronary vasospasm, microvascular dysfunction, and dynamic midcavity or LV outflow tract obstruction.^1,10 The hypothesis implicating catecholamine excess in the pathogenesis of TCM is supported by animal studies.⁷ These studies suggest that catecholamines possibly play a role by “direct toxicity to myocardial cells” as evidenced by histologic findings of myofibrillar degeneration, contraction band necrosis, and leukocyte infiltration in harvested hearts from experimental animals and patients undergoing autopsy.^7,11 Similarly, cultured cardiomyocytes exposed to high doses of epinephrine showed apoptic changes. Pretreatment of these cells with α- and β-adrenoreceptor blockers significantly attenuated these changes.⁷

However, myocardial necrosis alone cannot explain the entire picture, because most patients with TCM regain full recovery of LV function within several days of the event, and the degree of LV dysfunction is inconsistent with the mild elevations in cardiac

The role of estrogen also has been implicated in the pathogenesis of TCM. From a prevalence standpoint, almost 90% of TCM occurs in postmenopausal women.^11,12 Estrogen plays a critical role in protecting the myocardium, possibly by down regulating β-adrenergic receptors. Postmenopausal women who do not receive estrogen replacement therapy lose this protection and may be more vulnerable to the catecholamine surge that is associated with stress.¹¹ Overall, the catecholamines play a central role in the pathogenesis. This case suggests that exogenous administration of epinephrine in suprapharmacologic doses can be sufficient to replicate the stressful situation and induce TCM.

Conclusion

The authors’ case report describes the induction of apical ballooning TCM by administration of supratherapeutic doses of epinephrine and supports the role of catecholamines in the pathophysiology of TCM. It is hoped that this report will help clinicians to suspect, recognize, and manage this disease and be aware of possible iatrogenic causes.

Takotsubo cardiomyopathy (TCM) is a transient left ventricular (LV) wall motion abnormality often associated with acute medical illnesses, catastrophic life events, and intense physical or emotional stress.^1,2 Takotsubo cardiomyopathy also is known as stress-induced transient cardiomyopathy, apical ballooning syndrome, ampulla cardiomyopathy, and broken heart syndrome. The first reported case occurred in 1990 in Japan and accounts for 2% of all suspected acute coronary syndromes. Postmenopausal women seem to be at a higher risk for developing the disease, as about 90% of takotsubo cardiomyopathy occurs in postmenopausal women.³

Diagnosis of TCM is difficult, and there is an ongoing debate about the diagnostic criteria. The Mayo Clinic proposed the following criteria: (1) transient hypokinesis, akinesis, or dyskinesis of the LV mid-segments with or without apical involvement; the regional wall motion abnormalities extend beyond a single epicardial vascular distribution; a stressful trigger is often but not always present; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new electrocardiographic abnormalities (either ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (4) absence of pheochromocytoma and myocarditis.⁴

Depending on the part of the LV involved, TCM can be classified into apical ballooning variant (most common), an inverted or reverse takotsubo variant (basal akinesis with hyper dynamic apex), or a midventricular takotsubo variant.⁵

Several investigators have proposed the role of catecholamine in the pathogeneses of TCM.^6,7 Previous case reports have shown that the clinical circumstances with elevated catecholamine can result in TCM.^8,9 The authors recently encountered a case of a patient who developed apical ballooning TCM after an inadvertent injection of a high dose of epinephrine.

Case Report

A 60-year-old man with a history of hypertension, alcohol abuse, tobacco use, non-Hodgkin lymphoma, and recently diagnosed squamous cell carcinoma of the right glossopalatine fossa was admitted to the chemotherapy infusion clinic at the Kansas City VAMC to receive his first dose of cetuximab. Forty-five minutes after starting the test-dose infusion, the patient developed shortness of breath along with hives on his trunk and extremities. His blood pressure was 80/50 mm Hg; heart rate, 100 bpm; 16 breaths per minute respiration rate; and oxygen saturation by pulse oximetry was 90% on ambient air. The patient reported no chest pain, and a cardiac examination was unremarkable without wheezing on lung auscultation.

A clinical diagnosis of acute anaphylaxis reaction was considered; the test dose of cetuximab was discontinued, and the patient was given 50 mg of diphenhydramine, followed by an inadvertent administration of 1 mg of epinephrine intravenously (recommended dose 0.1 mg). After 3 minutes of administration of the medication, the patient’s blood pressure increased to190/110 with a pulse rate of 120 bpm.

An electrocardiogram (EKG) showed ST elevation in the precordial and inferior leads consistent with inferior and anterior myocardial injury (Figure 1). Pertinent laboratory studies revealed normal serum potassium (4.4 mEq/L), elevated serum glucose (219 mg/dL), and elevated troponin-I, (1.180 ng/mL; reference range 0-0.3 ng/mL). An emergent transthoracic echocardiogram showed a LV ejection fraction of 40% with akinesis involving the apical anterior, mid and distal anteroseptal, and anterolateral wall with no significant valvular abnormalities (Figures 2 and 3).

Given these echocardiographic findings, persistent EKG changes, and elevated troponin levels, an emergent coronary angiography along with left ventriculography was performed. The left ventriculogram demonstrated apical ballooning consistent with TCM (Figures 4 and 5). The left epicardial coronary arteries did not reveal any obstructive disease (Figure 6).

The subsequent hospital course was unremarkable, and the patient was discharged on guideline-directed medications for systolic dysfunction (ie, beta blockers and angiotensin-converting-enzyme inhibitors). Serum levels of epinephrine were not checked. A follow-up echocardiogram performed after 8 weeks showed complete recovery of the LV function (Figures 7a and 7b). The temporal sequence of events was highly suggestive of TCM, possibly due to the supratherapeutic dose of epinephrine.

Discussion

The pathogenesis of stress-induced cardiomyopathy is not fully understood. Various hypotheses have been suggested, including catecholamine excess, coronary vasospasm, microvascular dysfunction, and dynamic midcavity or LV outflow tract obstruction.^1,10 The hypothesis implicating catecholamine excess in the pathogenesis of TCM is supported by animal studies.⁷ These studies suggest that catecholamines possibly play a role by “direct toxicity to myocardial cells” as evidenced by histologic findings of myofibrillar degeneration, contraction band necrosis, and leukocyte infiltration in harvested hearts from experimental animals and patients undergoing autopsy.^7,11 Similarly, cultured cardiomyocytes exposed to high doses of epinephrine showed apoptic changes. Pretreatment of these cells with α- and β-adrenoreceptor blockers significantly attenuated these changes.⁷

However, myocardial necrosis alone cannot explain the entire picture, because most patients with TCM regain full recovery of LV function within several days of the event, and the degree of LV dysfunction is inconsistent with the mild elevations in cardiac

The role of estrogen also has been implicated in the pathogenesis of TCM. From a prevalence standpoint, almost 90% of TCM occurs in postmenopausal women.^11,12 Estrogen plays a critical role in protecting the myocardium, possibly by down regulating β-adrenergic receptors. Postmenopausal women who do not receive estrogen replacement therapy lose this protection and may be more vulnerable to the catecholamine surge that is associated with stress.¹¹ Overall, the catecholamines play a central role in the pathogenesis. This case suggests that exogenous administration of epinephrine in suprapharmacologic doses can be sufficient to replicate the stressful situation and induce TCM.

Conclusion

The authors’ case report describes the induction of apical ballooning TCM by administration of supratherapeutic doses of epinephrine and supports the role of catecholamines in the pathophysiology of TCM. It is hoped that this report will help clinicians to suspect, recognize, and manage this disease and be aware of possible iatrogenic causes.

DNA coiled around histones

Image by Eric Smith

Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).

Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.

Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.

Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.

The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.

With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.

The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.

The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.

Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.

When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.

However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.

The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.

They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.

DNA coiled around histones

Image by Eric Smith

Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).

Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.

Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.

Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.

The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.

With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.

The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.

The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.

Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.

When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.

However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.

The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.

They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.

DNA coiled around histones

Image by Eric Smith

Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).

Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.

Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.

Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.

The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.

With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.

The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.

The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.

Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.

When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.

However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.

The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.

They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.

VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.

Niels Olson/Wikimedia Commons/CC BY-SA 3.0

[email protected]


 

VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.

Niels Olson/Wikimedia Commons/CC BY-SA 3.0

[email protected]


 

VIENNA – The novel oral anticoagulants may provide effective adjunctive therapy in patients with calciphylaxis, Brian J. King, MD, said at the annual congress of the European Academy of Dermatology and Venereology.

He presented a retrospective case series of 16 patients with a confirmed diagnosis of calciphylaxis who were treated with NOACs at the Mayo Clinic in Rochester, Minn., where he is a dermatology resident. The results were impressive, particularly given that the estimated 1-year survival following diagnosis of calciphylaxis is only 45%.

Niels Olson/Wikimedia Commons/CC BY-SA 3.0

[email protected]


 

VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.

To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.

Bruce Jancin/Frontline Medical News

[email protected]


 

VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.

To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.

Bruce Jancin/Frontline Medical News

[email protected]


 

VIENNA – Diverse strategies aimed at preventing childhood atopic dermatitis (AD) now under study include installation of home water softeners, daily use of emollients starting at birth, and maternal consumption of probiotics beginning late in pregnancy, Carsten Flohr, PhD, said at a joint program of the International Eczema Council and the International Psoriasis Council held in conjunction with the annual congress of the European Academy of Dermatology and Venereology.

To date there is no effective method for preventing AD. Preventive strategies are needed sorely because the prevalence of pediatric AD worldwide is expected to increase substantially. It appears to have stabilized at roughly 20% in many affluent countries, but the global burden of the disease will climb as low-income countries – where AD is historically uncommon – become more developed and urbanized. This trend has been well documented via the International Study of Asthma and Allergies in Childhood (ISAAC), which in several phases has studied nearly 2 million children in more than 100 countries, noted Dr. Flohr of St. John’s Institute of Dermatology at King’s College London.

Bruce Jancin/Frontline Medical News

[email protected]