Section OF

Clinical question: What is the association between time to clinical stability (TCS) and post-discharge death or readmission in patients hospitalized with community-acquired pneumonia (CAP)?

Background: In patients with CAP, inflammatory response during hospitalization might be associated with adverse outcomes after discharge. Studies have not evaluated if time to clinical stability, a reflection of inflammatory response, can be used to identify patients at high risk of adverse outcomes after discharge.

Study design: Retrospective cohort study.

Setting: Veterans Hospital, Louisville, Ky.

Synopsis: Of 464 hospitalized patients with CAP, those with TCS >3 days had a higher rate of readmission or death within 30 days after discharge compared with those who had a TCS =3 days (26% versus 15%; OR 1.98; 95% CI, 1.19-3.3; P=0.008). Longer TCS during hospitalization was associated with a significantly increased risk of adverse outcomes (adjusted OR 1.06, 1.54, 2.40, 10.53 if TCS was reached at days 2, 3, 4, 5 versus Day 1, respectively). The authors proposed that patients with delays in reaching clinical stability should receive a special discharge management approach to decrease the risk of morbidity and mortality after discharge; this may include close observation, home visits, and a follow-up clinic appointment within 10 days.

As a retrospective cohort study, unaccounted-for confounders might exist between TCS and adverse outcomes. The small sample size precluded development of a fully predictive model. Additionally, the population studied was elderly men in a single hospital, which might limit generalizability.

Bottom line: Hospitalized patients with community-acquired pneumonia whose time to clinical stability was greater than three days had a higher risk of readmission or death within 30 days after discharge.

Citation: Aliberti S, Peyrani P, Filardo G, et al. Association between time to clinical stability and outcomes after discharge in hospitalized patients with community-acquired pneumonia. Chest. 2011;140:482-488.

For more physician reviews of HM-relevant research, visit our website.

Clinical question: What is the association between time to clinical stability (TCS) and post-discharge death or readmission in patients hospitalized with community-acquired pneumonia (CAP)?

Background: In patients with CAP, inflammatory response during hospitalization might be associated with adverse outcomes after discharge. Studies have not evaluated if time to clinical stability, a reflection of inflammatory response, can be used to identify patients at high risk of adverse outcomes after discharge.

Study design: Retrospective cohort study.

Setting: Veterans Hospital, Louisville, Ky.

Synopsis: Of 464 hospitalized patients with CAP, those with TCS >3 days had a higher rate of readmission or death within 30 days after discharge compared with those who had a TCS =3 days (26% versus 15%; OR 1.98; 95% CI, 1.19-3.3; P=0.008). Longer TCS during hospitalization was associated with a significantly increased risk of adverse outcomes (adjusted OR 1.06, 1.54, 2.40, 10.53 if TCS was reached at days 2, 3, 4, 5 versus Day 1, respectively). The authors proposed that patients with delays in reaching clinical stability should receive a special discharge management approach to decrease the risk of morbidity and mortality after discharge; this may include close observation, home visits, and a follow-up clinic appointment within 10 days.

As a retrospective cohort study, unaccounted-for confounders might exist between TCS and adverse outcomes. The small sample size precluded development of a fully predictive model. Additionally, the population studied was elderly men in a single hospital, which might limit generalizability.

Bottom line: Hospitalized patients with community-acquired pneumonia whose time to clinical stability was greater than three days had a higher risk of readmission or death within 30 days after discharge.

Citation: Aliberti S, Peyrani P, Filardo G, et al. Association between time to clinical stability and outcomes after discharge in hospitalized patients with community-acquired pneumonia. Chest. 2011;140:482-488.

For more physician reviews of HM-relevant research, visit our website.

Clinical question: What is the association between time to clinical stability (TCS) and post-discharge death or readmission in patients hospitalized with community-acquired pneumonia (CAP)?

Background: In patients with CAP, inflammatory response during hospitalization might be associated with adverse outcomes after discharge. Studies have not evaluated if time to clinical stability, a reflection of inflammatory response, can be used to identify patients at high risk of adverse outcomes after discharge.

Study design: Retrospective cohort study.

Setting: Veterans Hospital, Louisville, Ky.

Synopsis: Of 464 hospitalized patients with CAP, those with TCS >3 days had a higher rate of readmission or death within 30 days after discharge compared with those who had a TCS =3 days (26% versus 15%; OR 1.98; 95% CI, 1.19-3.3; P=0.008). Longer TCS during hospitalization was associated with a significantly increased risk of adverse outcomes (adjusted OR 1.06, 1.54, 2.40, 10.53 if TCS was reached at days 2, 3, 4, 5 versus Day 1, respectively). The authors proposed that patients with delays in reaching clinical stability should receive a special discharge management approach to decrease the risk of morbidity and mortality after discharge; this may include close observation, home visits, and a follow-up clinic appointment within 10 days.

As a retrospective cohort study, unaccounted-for confounders might exist between TCS and adverse outcomes. The small sample size precluded development of a fully predictive model. Additionally, the population studied was elderly men in a single hospital, which might limit generalizability.

Bottom line: Hospitalized patients with community-acquired pneumonia whose time to clinical stability was greater than three days had a higher risk of readmission or death within 30 days after discharge.

Citation: Aliberti S, Peyrani P, Filardo G, et al. Association between time to clinical stability and outcomes after discharge in hospitalized patients with community-acquired pneumonia. Chest. 2011;140:482-488.

For more physician reviews of HM-relevant research, visit our website.

click for large version

Case

A 54-year-old man with a history of hypertension treated with hydrocholorothiazide and Type 2 diabetes mellitus is admitted with abdominal pain and found to have an incidental 2.1-cm left adrenal mass on CT scan of the abdomen. He denies symptoms of headache, palpitations, weight gain, or muscle weakness. His exam is significant for mildly elevated blood pressure. What is the best approach for evaluation and management of this incidental finding?

Overview

Incidentalomas are mass lesions that are inadvertently discovered during radiolographic diagnostic testing or treatment for other clinical conditions that are unrelated to the incidental mass. In recent decades, improvements in radiographic diagnostic techniques and sensitivity have led to increasing discovery of incidental lesions that are often in the absence of clinical signs or symptoms.¹ Three commonly discovered lesions by hospitalists are pituitary, thyroid, and adrenal incidentalomas.² The concerns associated with these findings relate to the potential for dysfunctional hormone secretion or malignancy.

Patients found with pituitary incidentalomas can be susceptible to several types of adverse outcomes: hormonal hypersecretion, hypopituitarism, neurologic morbidity due to tumor size, and malignancy in rare cases. Thyroid incidentalomas are impalpable nodules discovered in the setting of ultrasound or cross-sectional neck scans, such as positron emission tomography (PET) scans. Discovery of a thyroid incidentaloma raises concern for thyroid malignancy.³ The increased use of abdominal ultrasound, CT scans, and MRI has fueled the growing incidence of adrenal incidentalomas (AIs).

The discovery of an endocrine incidentaloma in the inpatient setting warrants a systematic approach that includes both diagnostic and potentially therapeutic management. A hospitalist should consider an approach that includes (see Table 1):

click for large version

1. Characterization of the incidentaloma, including clinical signs and symptoms, size, hormonal function, and malignant potential;
2. Immediate management, including medical versus surgical treatment; and
3. Post-discharge management, including monitoring.

Review of the Data

Pituitary incidentalomas. The prevalence of pituitary incidentalomas found by CT ranges from 3.7% to 20%, while the prevalence found by MRI approximates 10%. Autopsy studies have revealed a prevalence ranging from 1.5% to 26.7% for adenomas less than 10 mm, considered to be microadenomas. Broad categories of etiologies should be considered: pituitary adenoma, nonpituitary tumors, vascular lesions, infiltrative disorders, and others (see Table 2). The majority of pituitary adenomas secrete prolactin (30% to 40%) or are nonsecreting (30% to 40%). Adenomas secreting adrenocorticotropin hormone (ACTH, 2% to 10%), growth hormone (GH, 2% to 10%), thyroid-stimulating hormone (TSH, <1%), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are much less common.2 Significant morbidity and premature mortality are associated with hyperprolactinemia, acromegaly (growth hormone excess), Cushing’s syndrome, and hyperthyroidism. Additionally, up to 41% of patients with macroadenomas were found to have varying degrees of hypopituitarism due to compression of the hypothalamus, the hypothalamic-pituitary stalk, or the pituitary itself.⁴

Recently, the Endocrine Society released consensus recommendations to guide the evaluation and treatment of pituitary incidentalomas, which are included in the approach outlined below.⁵ A detailed history and physical examination should be obtained with specific inquiry as to signs and symptoms of hormonal excess and mass effect from the tumor. Examples of symptoms of hormone excess can include:

• Prolactin: menstrual irregularity, anovulation, infertility, decreased libido, impotence, osteoporosis;
• Growth hormone: high frequency of colonic polyps and colon cancer (chronic excess);
• TSH: thyrotoxicosis, atrial fibrillation; and
• ACTH: hypertension, osteoporosis, accelerated vascular disease.

Symptoms related to the mass effect of the tumor include visual field defects and hypopituitarism related to the deficient hormone, including:

• FSH/LH: oligomenorrhea, decreased libido, infertility;
• TSH: hypothyroidism (weight gain, constipation, cold intolerance);
• ACTH: adrenal insufficiency (hypotension, hypoglycemia, weight loss); and
• ADH: polyuria, polydypsia.

The size and location of the pituitary lesion must be assessed. Lesions greater than 10 mm are considered macroademonas, and their size will affect their management. If the lesion was initially identified by CT scan, an MRI is recommended to better evaluate it.⁵ If the MRI locates the incidentaloma abutting the optic nerve or chiasm, then the patient should undergo a formal visual field examination.

Indications for an inpatient surgical referral for treatment include: a lesion larger than 2 cm, evidence of mass effect such as visual field defects, neurologic compromise, opthalmoplegia, hypopituitarism, a tumor abutting the optic nerve or chiasm, pituitary apoplexy, and hypersecretion of hormones other than prolactin. Patients with prolactinomas warrant an inpatient endo-crinology consult and may need medical management with a dopamine agonist. Hormone replacement therapy can also be provided for patients with hypopituitarism.^2,5

For patients who do not meet the criteria for inpatient surgical therapy, follow-up management must be arranged at the time of discharge. Clinical, laboratory assessment, and an MRI should be scheduled six months after the initial finding of the incidentaloma with the patient’s PCP or with an endocrinologist.⁵

Thyroid incidentalomas. The prevalence of thyroid nodules based on ultrasound studies ranges from 19% to 46%, with autopsy studies estimating an incidence of approximately 50%.^2,6 Incidence of thyroid nodules also increases with age, as almost 60% of people over the age of 60 harbor a thyroid incidentaloma. The rate of malignancy in the general population has ranged between 8% and 24%; however, in the last decade, the rates have increased by 2.4 times as more sophisticated ultrasound techniques and liberal use of fine-needle aspiration (FNA) biopsies have detected subclinical disease.^7,8

Etiologies for incidental thyroid nodules can be divided into benign and malignant causes. Benign etiologies include thyroid cyst (simple or complex), multinodular goiter, and Hashimoto’s thryoiditis, while malignant causes include papillary, medullary, follicular, Hurthle cell, and anaplastic carcinomas, thyroid lymphomas, and rare instances of metastatic cancers.^2,3

Targeted history and physical examination helps to characterize the thyroid incidentaloma. Historical features, such as palpitations, weight loss, anxiety, new onset atrial fibrillation, or menstrual irregularities, coupled with tachycardia, tremors, proximal muscle weakness, and a palpable nodule aid in the diagnosis of hyperthyroidism. Findings such as a family history of thyroid cancer, symptoms of hoarseness or dysphagia, rapid growth of the nodule, environmental or history of head or neck irradiation along with physical findings of a hard, fixed nodule, or cervical lymphadenopathy increase the suspicion for malignancy.^2,7

The functionality of the nodule can be assessed by checking TSH, free T3, and free T4 levels. Suppression of TSH (< 0.1 mU/L) with elevated levels of free T3 and T4 indicates nodule production of excess thyroid hormone and warrants thyroid scintography. Thyroid scintography will identify the nodule as “hot” (hyperfunctioning) or “cold” (nonfunctioning).²

Regardless of the radiographic modality that initially identified the thyroid incidentaloma, a dedicated thyroid high-resolution ultrasound should be ordered to assess the size, multiplicity (single or multinodular), location, and character (solid, cystic, or mixed).⁷

Recommendations for proceeding to FNA to evaluate for malignancy differ among subspecialty societies. Generally, nodules larger than 1 cm or nodules smaller than 1 cm with risk factors for malignancy should be referred for FNA.^2,7

If diagnostic workup identifies a patient with hyperthyroidism due to an autonomously functional nodule or a nodule that may be at high risk for malignancy, it is appropriate to involve an endocrinologist and possibly a surgical subspecialist prior to discharge. Management of hyperthyroidism can include starting antithyroid agents (methimazole or propylthiouracil), radioactive iodine ablation, or referral for surgery.

Preparation for discharge of the patient whose incidentaloma is nonfunctional or does not appear to be malignant should include appointments to recheck thyroid hormone levels, including TSH as well as a thyroid ultrasound within one year of the initial discovery.

Adrenal incidentaloma. The prevalence of AIs found by CT of the abdomen ranges from 0.4% to 4%, while autopsy studies have found a prevalence of 1.4% to 9% with increasing prevalence with age.^2,9,10 The majority of AIs are benign and nonfunctioning adenomas, in the absence of known malignancy. Other differential diagnoses include Cushing’s syndrome, pheochromocytoma, adrenocortical adenoma, aldosteronoma, and metastatic lesions.

Because functioning adrenal incidentalomas may be clinically silent, any patient found with an AI must undergo biochemical workup as part of their evaluation to assess for pheochromocytoma, Cushing’s syndrome, and if he or she has a history of hypertension or hyperaldosteronism (Conn’s syndrome). Table 3 outlines the approach for characterizing adrenal incidentalomas.^2,11,12 An important point is that imaging studies are not useful in distinguishing a functioning versus nonfunctioning tumor but rather can help to discriminate malignant lesions.¹¹

click for large version

Inpatient surgical consult for resection is indicated if the patient is found to have pheochromocytoma, clinically apparent functioning adrenocortical adenoma, or a tumor size greater than 4 cm. Consultation with an endocrinologist is also recommended if biochemical tests are positive. If the diagnostic workup leads to suspicion for infection or metastatic disease, the patient should be referred for FNA.^2,12

For patients whose lesions do not require surgical resection, repeat CT scan of the abdomen is recommended six months from the initial finding. Hospitalists should also arrange for the patient to repeat biochemical testing, including an overnight dexamethasone test.^12,13

Back to the Case

The patient underwent biochemical testing and was found to have normal levels of plasma-free metanephrines, a plasma aldosterone, plasma renin activity ratio less than 20, and a serum cortisol level of 7 mg/dL after his overnight dexamethasone suppression test. The 24-hour urine collection for free cortisol revealed elevated levels of cortisol in the urine, and the ACTH level was low.

Endocrinology and endocrine surgery teams were consulted, and recommended surgical resection. After surgical resection of his tumor, the patient was started on glucocorticoid replacement and was discharged with a follow-up appointment with endocrinology.

Bottom Line

An inpatient approach to endocrine incidentalomas should include characterization of the clinical signs and symptoms, size, function, and malignant potential of the lesion. Based on this, inpatient surgical or medical management can be determined. Post-discharge management should include arrangements for surveillance testing and follow-up with appropriate subspecialists.

Dr. Tad-y is assistant professor of medicine and a hospitalist at the University of Colorado Denver.

References

1. Aron DC, Howlett TA. Pituitary incidentalomas. Endocrinol Metab Clin North Am. 2000;29:205-221.
2. Shirodkar M, Jabbour SA. Endocrine incidentalomas. Int J Clin Pract. 2008;62:1423-1431.
3. Burguera B, Gharib H. Thyroid incidentalomas. Prevalence, diagnosis, significance, and management. Endocrinol Metab Clin North Am. 2000;29:187-203.
4. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37:151-171, xi.
5. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:894-904.
6. Gough J, Scott-Coombes D, Fausto Palazzo F. Thyroid incidentaloma: an evidence-based assessment of management strategy. World J Surg. 2008;32:1264-1268.
7. Iyer NG, Shaha AR, Silver CE, et al. Thyroid incidentalomas: to treat or not to treat. Eur Arch Otorhinolaryngol. 2010;267:1019-1026.
8. Jin J, Wilhelm SM, McHenry CR. Incidental thyroid nodule: patterns of diagnosis and rate of malignancy. Am J Surg. 2009;197:320-324.
9. Davenport C, Liew L, Doherty B, et al. The prevalence of adrenal incidentaloma in routine clinical practice. Endocrine. 2011;40:80-83.
10. Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 2011;96: 2004-2015.
11. Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract. 2009;15:450-453.
12. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements. 2002;19:1-25.
13. Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601-610.
14. Chidiac RM, Aron DC. Incidentalomas. A disease of modern technology. Endocrinol Metab Clin North Am. 1997;26:233-253.

click for large version

Case

A 54-year-old man with a history of hypertension treated with hydrocholorothiazide and Type 2 diabetes mellitus is admitted with abdominal pain and found to have an incidental 2.1-cm left adrenal mass on CT scan of the abdomen. He denies symptoms of headache, palpitations, weight gain, or muscle weakness. His exam is significant for mildly elevated blood pressure. What is the best approach for evaluation and management of this incidental finding?

Overview

Incidentalomas are mass lesions that are inadvertently discovered during radiolographic diagnostic testing or treatment for other clinical conditions that are unrelated to the incidental mass. In recent decades, improvements in radiographic diagnostic techniques and sensitivity have led to increasing discovery of incidental lesions that are often in the absence of clinical signs or symptoms.¹ Three commonly discovered lesions by hospitalists are pituitary, thyroid, and adrenal incidentalomas.² The concerns associated with these findings relate to the potential for dysfunctional hormone secretion or malignancy.

Patients found with pituitary incidentalomas can be susceptible to several types of adverse outcomes: hormonal hypersecretion, hypopituitarism, neurologic morbidity due to tumor size, and malignancy in rare cases. Thyroid incidentalomas are impalpable nodules discovered in the setting of ultrasound or cross-sectional neck scans, such as positron emission tomography (PET) scans. Discovery of a thyroid incidentaloma raises concern for thyroid malignancy.³ The increased use of abdominal ultrasound, CT scans, and MRI has fueled the growing incidence of adrenal incidentalomas (AIs).

The discovery of an endocrine incidentaloma in the inpatient setting warrants a systematic approach that includes both diagnostic and potentially therapeutic management. A hospitalist should consider an approach that includes (see Table 1):

click for large version

1. Characterization of the incidentaloma, including clinical signs and symptoms, size, hormonal function, and malignant potential;
2. Immediate management, including medical versus surgical treatment; and
3. Post-discharge management, including monitoring.

Review of the Data

Pituitary incidentalomas. The prevalence of pituitary incidentalomas found by CT ranges from 3.7% to 20%, while the prevalence found by MRI approximates 10%. Autopsy studies have revealed a prevalence ranging from 1.5% to 26.7% for adenomas less than 10 mm, considered to be microadenomas. Broad categories of etiologies should be considered: pituitary adenoma, nonpituitary tumors, vascular lesions, infiltrative disorders, and others (see Table 2). The majority of pituitary adenomas secrete prolactin (30% to 40%) or are nonsecreting (30% to 40%). Adenomas secreting adrenocorticotropin hormone (ACTH, 2% to 10%), growth hormone (GH, 2% to 10%), thyroid-stimulating hormone (TSH, <1%), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are much less common.2 Significant morbidity and premature mortality are associated with hyperprolactinemia, acromegaly (growth hormone excess), Cushing’s syndrome, and hyperthyroidism. Additionally, up to 41% of patients with macroadenomas were found to have varying degrees of hypopituitarism due to compression of the hypothalamus, the hypothalamic-pituitary stalk, or the pituitary itself.⁴

Recently, the Endocrine Society released consensus recommendations to guide the evaluation and treatment of pituitary incidentalomas, which are included in the approach outlined below.⁵ A detailed history and physical examination should be obtained with specific inquiry as to signs and symptoms of hormonal excess and mass effect from the tumor. Examples of symptoms of hormone excess can include:

• Prolactin: menstrual irregularity, anovulation, infertility, decreased libido, impotence, osteoporosis;
• Growth hormone: high frequency of colonic polyps and colon cancer (chronic excess);
• TSH: thyrotoxicosis, atrial fibrillation; and
• ACTH: hypertension, osteoporosis, accelerated vascular disease.

Symptoms related to the mass effect of the tumor include visual field defects and hypopituitarism related to the deficient hormone, including:

• FSH/LH: oligomenorrhea, decreased libido, infertility;
• TSH: hypothyroidism (weight gain, constipation, cold intolerance);
• ACTH: adrenal insufficiency (hypotension, hypoglycemia, weight loss); and
• ADH: polyuria, polydypsia.

The size and location of the pituitary lesion must be assessed. Lesions greater than 10 mm are considered macroademonas, and their size will affect their management. If the lesion was initially identified by CT scan, an MRI is recommended to better evaluate it.⁵ If the MRI locates the incidentaloma abutting the optic nerve or chiasm, then the patient should undergo a formal visual field examination.

Indications for an inpatient surgical referral for treatment include: a lesion larger than 2 cm, evidence of mass effect such as visual field defects, neurologic compromise, opthalmoplegia, hypopituitarism, a tumor abutting the optic nerve or chiasm, pituitary apoplexy, and hypersecretion of hormones other than prolactin. Patients with prolactinomas warrant an inpatient endo-crinology consult and may need medical management with a dopamine agonist. Hormone replacement therapy can also be provided for patients with hypopituitarism.^2,5

For patients who do not meet the criteria for inpatient surgical therapy, follow-up management must be arranged at the time of discharge. Clinical, laboratory assessment, and an MRI should be scheduled six months after the initial finding of the incidentaloma with the patient’s PCP or with an endocrinologist.⁵

Thyroid incidentalomas. The prevalence of thyroid nodules based on ultrasound studies ranges from 19% to 46%, with autopsy studies estimating an incidence of approximately 50%.^2,6 Incidence of thyroid nodules also increases with age, as almost 60% of people over the age of 60 harbor a thyroid incidentaloma. The rate of malignancy in the general population has ranged between 8% and 24%; however, in the last decade, the rates have increased by 2.4 times as more sophisticated ultrasound techniques and liberal use of fine-needle aspiration (FNA) biopsies have detected subclinical disease.^7,8

Etiologies for incidental thyroid nodules can be divided into benign and malignant causes. Benign etiologies include thyroid cyst (simple or complex), multinodular goiter, and Hashimoto’s thryoiditis, while malignant causes include papillary, medullary, follicular, Hurthle cell, and anaplastic carcinomas, thyroid lymphomas, and rare instances of metastatic cancers.^2,3

Targeted history and physical examination helps to characterize the thyroid incidentaloma. Historical features, such as palpitations, weight loss, anxiety, new onset atrial fibrillation, or menstrual irregularities, coupled with tachycardia, tremors, proximal muscle weakness, and a palpable nodule aid in the diagnosis of hyperthyroidism. Findings such as a family history of thyroid cancer, symptoms of hoarseness or dysphagia, rapid growth of the nodule, environmental or history of head or neck irradiation along with physical findings of a hard, fixed nodule, or cervical lymphadenopathy increase the suspicion for malignancy.^2,7

The functionality of the nodule can be assessed by checking TSH, free T3, and free T4 levels. Suppression of TSH (< 0.1 mU/L) with elevated levels of free T3 and T4 indicates nodule production of excess thyroid hormone and warrants thyroid scintography. Thyroid scintography will identify the nodule as “hot” (hyperfunctioning) or “cold” (nonfunctioning).²

Regardless of the radiographic modality that initially identified the thyroid incidentaloma, a dedicated thyroid high-resolution ultrasound should be ordered to assess the size, multiplicity (single or multinodular), location, and character (solid, cystic, or mixed).⁷

Recommendations for proceeding to FNA to evaluate for malignancy differ among subspecialty societies. Generally, nodules larger than 1 cm or nodules smaller than 1 cm with risk factors for malignancy should be referred for FNA.^2,7

If diagnostic workup identifies a patient with hyperthyroidism due to an autonomously functional nodule or a nodule that may be at high risk for malignancy, it is appropriate to involve an endocrinologist and possibly a surgical subspecialist prior to discharge. Management of hyperthyroidism can include starting antithyroid agents (methimazole or propylthiouracil), radioactive iodine ablation, or referral for surgery.

Preparation for discharge of the patient whose incidentaloma is nonfunctional or does not appear to be malignant should include appointments to recheck thyroid hormone levels, including TSH as well as a thyroid ultrasound within one year of the initial discovery.

Adrenal incidentaloma. The prevalence of AIs found by CT of the abdomen ranges from 0.4% to 4%, while autopsy studies have found a prevalence of 1.4% to 9% with increasing prevalence with age.^2,9,10 The majority of AIs are benign and nonfunctioning adenomas, in the absence of known malignancy. Other differential diagnoses include Cushing’s syndrome, pheochromocytoma, adrenocortical adenoma, aldosteronoma, and metastatic lesions.

Because functioning adrenal incidentalomas may be clinically silent, any patient found with an AI must undergo biochemical workup as part of their evaluation to assess for pheochromocytoma, Cushing’s syndrome, and if he or she has a history of hypertension or hyperaldosteronism (Conn’s syndrome). Table 3 outlines the approach for characterizing adrenal incidentalomas.^2,11,12 An important point is that imaging studies are not useful in distinguishing a functioning versus nonfunctioning tumor but rather can help to discriminate malignant lesions.¹¹

click for large version

Inpatient surgical consult for resection is indicated if the patient is found to have pheochromocytoma, clinically apparent functioning adrenocortical adenoma, or a tumor size greater than 4 cm. Consultation with an endocrinologist is also recommended if biochemical tests are positive. If the diagnostic workup leads to suspicion for infection or metastatic disease, the patient should be referred for FNA.^2,12

For patients whose lesions do not require surgical resection, repeat CT scan of the abdomen is recommended six months from the initial finding. Hospitalists should also arrange for the patient to repeat biochemical testing, including an overnight dexamethasone test.^12,13

Back to the Case

The patient underwent biochemical testing and was found to have normal levels of plasma-free metanephrines, a plasma aldosterone, plasma renin activity ratio less than 20, and a serum cortisol level of 7 mg/dL after his overnight dexamethasone suppression test. The 24-hour urine collection for free cortisol revealed elevated levels of cortisol in the urine, and the ACTH level was low.

Endocrinology and endocrine surgery teams were consulted, and recommended surgical resection. After surgical resection of his tumor, the patient was started on glucocorticoid replacement and was discharged with a follow-up appointment with endocrinology.

Bottom Line

An inpatient approach to endocrine incidentalomas should include characterization of the clinical signs and symptoms, size, function, and malignant potential of the lesion. Based on this, inpatient surgical or medical management can be determined. Post-discharge management should include arrangements for surveillance testing and follow-up with appropriate subspecialists.

Dr. Tad-y is assistant professor of medicine and a hospitalist at the University of Colorado Denver.

References

1. Aron DC, Howlett TA. Pituitary incidentalomas. Endocrinol Metab Clin North Am. 2000;29:205-221.
2. Shirodkar M, Jabbour SA. Endocrine incidentalomas. Int J Clin Pract. 2008;62:1423-1431.
3. Burguera B, Gharib H. Thyroid incidentalomas. Prevalence, diagnosis, significance, and management. Endocrinol Metab Clin North Am. 2000;29:187-203.
4. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37:151-171, xi.
5. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:894-904.
6. Gough J, Scott-Coombes D, Fausto Palazzo F. Thyroid incidentaloma: an evidence-based assessment of management strategy. World J Surg. 2008;32:1264-1268.
7. Iyer NG, Shaha AR, Silver CE, et al. Thyroid incidentalomas: to treat or not to treat. Eur Arch Otorhinolaryngol. 2010;267:1019-1026.
8. Jin J, Wilhelm SM, McHenry CR. Incidental thyroid nodule: patterns of diagnosis and rate of malignancy. Am J Surg. 2009;197:320-324.
9. Davenport C, Liew L, Doherty B, et al. The prevalence of adrenal incidentaloma in routine clinical practice. Endocrine. 2011;40:80-83.
10. Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 2011;96: 2004-2015.
11. Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract. 2009;15:450-453.
12. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements. 2002;19:1-25.
13. Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601-610.
14. Chidiac RM, Aron DC. Incidentalomas. A disease of modern technology. Endocrinol Metab Clin North Am. 1997;26:233-253.

click for large version

Case

A 54-year-old man with a history of hypertension treated with hydrocholorothiazide and Type 2 diabetes mellitus is admitted with abdominal pain and found to have an incidental 2.1-cm left adrenal mass on CT scan of the abdomen. He denies symptoms of headache, palpitations, weight gain, or muscle weakness. His exam is significant for mildly elevated blood pressure. What is the best approach for evaluation and management of this incidental finding?

Overview

Incidentalomas are mass lesions that are inadvertently discovered during radiolographic diagnostic testing or treatment for other clinical conditions that are unrelated to the incidental mass. In recent decades, improvements in radiographic diagnostic techniques and sensitivity have led to increasing discovery of incidental lesions that are often in the absence of clinical signs or symptoms.¹ Three commonly discovered lesions by hospitalists are pituitary, thyroid, and adrenal incidentalomas.² The concerns associated with these findings relate to the potential for dysfunctional hormone secretion or malignancy.

Patients found with pituitary incidentalomas can be susceptible to several types of adverse outcomes: hormonal hypersecretion, hypopituitarism, neurologic morbidity due to tumor size, and malignancy in rare cases. Thyroid incidentalomas are impalpable nodules discovered in the setting of ultrasound or cross-sectional neck scans, such as positron emission tomography (PET) scans. Discovery of a thyroid incidentaloma raises concern for thyroid malignancy.³ The increased use of abdominal ultrasound, CT scans, and MRI has fueled the growing incidence of adrenal incidentalomas (AIs).

The discovery of an endocrine incidentaloma in the inpatient setting warrants a systematic approach that includes both diagnostic and potentially therapeutic management. A hospitalist should consider an approach that includes (see Table 1):

click for large version

1. Characterization of the incidentaloma, including clinical signs and symptoms, size, hormonal function, and malignant potential;
2. Immediate management, including medical versus surgical treatment; and
3. Post-discharge management, including monitoring.

Review of the Data

Pituitary incidentalomas. The prevalence of pituitary incidentalomas found by CT ranges from 3.7% to 20%, while the prevalence found by MRI approximates 10%. Autopsy studies have revealed a prevalence ranging from 1.5% to 26.7% for adenomas less than 10 mm, considered to be microadenomas. Broad categories of etiologies should be considered: pituitary adenoma, nonpituitary tumors, vascular lesions, infiltrative disorders, and others (see Table 2). The majority of pituitary adenomas secrete prolactin (30% to 40%) or are nonsecreting (30% to 40%). Adenomas secreting adrenocorticotropin hormone (ACTH, 2% to 10%), growth hormone (GH, 2% to 10%), thyroid-stimulating hormone (TSH, <1%), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are much less common.2 Significant morbidity and premature mortality are associated with hyperprolactinemia, acromegaly (growth hormone excess), Cushing’s syndrome, and hyperthyroidism. Additionally, up to 41% of patients with macroadenomas were found to have varying degrees of hypopituitarism due to compression of the hypothalamus, the hypothalamic-pituitary stalk, or the pituitary itself.⁴

Recently, the Endocrine Society released consensus recommendations to guide the evaluation and treatment of pituitary incidentalomas, which are included in the approach outlined below.⁵ A detailed history and physical examination should be obtained with specific inquiry as to signs and symptoms of hormonal excess and mass effect from the tumor. Examples of symptoms of hormone excess can include:

• Prolactin: menstrual irregularity, anovulation, infertility, decreased libido, impotence, osteoporosis;
• Growth hormone: high frequency of colonic polyps and colon cancer (chronic excess);
• TSH: thyrotoxicosis, atrial fibrillation; and
• ACTH: hypertension, osteoporosis, accelerated vascular disease.

Symptoms related to the mass effect of the tumor include visual field defects and hypopituitarism related to the deficient hormone, including:

• FSH/LH: oligomenorrhea, decreased libido, infertility;
• TSH: hypothyroidism (weight gain, constipation, cold intolerance);
• ACTH: adrenal insufficiency (hypotension, hypoglycemia, weight loss); and
• ADH: polyuria, polydypsia.

The size and location of the pituitary lesion must be assessed. Lesions greater than 10 mm are considered macroademonas, and their size will affect their management. If the lesion was initially identified by CT scan, an MRI is recommended to better evaluate it.⁵ If the MRI locates the incidentaloma abutting the optic nerve or chiasm, then the patient should undergo a formal visual field examination.

Indications for an inpatient surgical referral for treatment include: a lesion larger than 2 cm, evidence of mass effect such as visual field defects, neurologic compromise, opthalmoplegia, hypopituitarism, a tumor abutting the optic nerve or chiasm, pituitary apoplexy, and hypersecretion of hormones other than prolactin. Patients with prolactinomas warrant an inpatient endo-crinology consult and may need medical management with a dopamine agonist. Hormone replacement therapy can also be provided for patients with hypopituitarism.^2,5

For patients who do not meet the criteria for inpatient surgical therapy, follow-up management must be arranged at the time of discharge. Clinical, laboratory assessment, and an MRI should be scheduled six months after the initial finding of the incidentaloma with the patient’s PCP or with an endocrinologist.⁵

Thyroid incidentalomas. The prevalence of thyroid nodules based on ultrasound studies ranges from 19% to 46%, with autopsy studies estimating an incidence of approximately 50%.^2,6 Incidence of thyroid nodules also increases with age, as almost 60% of people over the age of 60 harbor a thyroid incidentaloma. The rate of malignancy in the general population has ranged between 8% and 24%; however, in the last decade, the rates have increased by 2.4 times as more sophisticated ultrasound techniques and liberal use of fine-needle aspiration (FNA) biopsies have detected subclinical disease.^7,8

Etiologies for incidental thyroid nodules can be divided into benign and malignant causes. Benign etiologies include thyroid cyst (simple or complex), multinodular goiter, and Hashimoto’s thryoiditis, while malignant causes include papillary, medullary, follicular, Hurthle cell, and anaplastic carcinomas, thyroid lymphomas, and rare instances of metastatic cancers.^2,3

Targeted history and physical examination helps to characterize the thyroid incidentaloma. Historical features, such as palpitations, weight loss, anxiety, new onset atrial fibrillation, or menstrual irregularities, coupled with tachycardia, tremors, proximal muscle weakness, and a palpable nodule aid in the diagnosis of hyperthyroidism. Findings such as a family history of thyroid cancer, symptoms of hoarseness or dysphagia, rapid growth of the nodule, environmental or history of head or neck irradiation along with physical findings of a hard, fixed nodule, or cervical lymphadenopathy increase the suspicion for malignancy.^2,7

The functionality of the nodule can be assessed by checking TSH, free T3, and free T4 levels. Suppression of TSH (< 0.1 mU/L) with elevated levels of free T3 and T4 indicates nodule production of excess thyroid hormone and warrants thyroid scintography. Thyroid scintography will identify the nodule as “hot” (hyperfunctioning) or “cold” (nonfunctioning).²

Regardless of the radiographic modality that initially identified the thyroid incidentaloma, a dedicated thyroid high-resolution ultrasound should be ordered to assess the size, multiplicity (single or multinodular), location, and character (solid, cystic, or mixed).⁷

Recommendations for proceeding to FNA to evaluate for malignancy differ among subspecialty societies. Generally, nodules larger than 1 cm or nodules smaller than 1 cm with risk factors for malignancy should be referred for FNA.^2,7

If diagnostic workup identifies a patient with hyperthyroidism due to an autonomously functional nodule or a nodule that may be at high risk for malignancy, it is appropriate to involve an endocrinologist and possibly a surgical subspecialist prior to discharge. Management of hyperthyroidism can include starting antithyroid agents (methimazole or propylthiouracil), radioactive iodine ablation, or referral for surgery.

Preparation for discharge of the patient whose incidentaloma is nonfunctional or does not appear to be malignant should include appointments to recheck thyroid hormone levels, including TSH as well as a thyroid ultrasound within one year of the initial discovery.

Adrenal incidentaloma. The prevalence of AIs found by CT of the abdomen ranges from 0.4% to 4%, while autopsy studies have found a prevalence of 1.4% to 9% with increasing prevalence with age.^2,9,10 The majority of AIs are benign and nonfunctioning adenomas, in the absence of known malignancy. Other differential diagnoses include Cushing’s syndrome, pheochromocytoma, adrenocortical adenoma, aldosteronoma, and metastatic lesions.

Because functioning adrenal incidentalomas may be clinically silent, any patient found with an AI must undergo biochemical workup as part of their evaluation to assess for pheochromocytoma, Cushing’s syndrome, and if he or she has a history of hypertension or hyperaldosteronism (Conn’s syndrome). Table 3 outlines the approach for characterizing adrenal incidentalomas.^2,11,12 An important point is that imaging studies are not useful in distinguishing a functioning versus nonfunctioning tumor but rather can help to discriminate malignant lesions.¹¹

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Inpatient surgical consult for resection is indicated if the patient is found to have pheochromocytoma, clinically apparent functioning adrenocortical adenoma, or a tumor size greater than 4 cm. Consultation with an endocrinologist is also recommended if biochemical tests are positive. If the diagnostic workup leads to suspicion for infection or metastatic disease, the patient should be referred for FNA.^2,12

For patients whose lesions do not require surgical resection, repeat CT scan of the abdomen is recommended six months from the initial finding. Hospitalists should also arrange for the patient to repeat biochemical testing, including an overnight dexamethasone test.^12,13

Back to the Case

The patient underwent biochemical testing and was found to have normal levels of plasma-free metanephrines, a plasma aldosterone, plasma renin activity ratio less than 20, and a serum cortisol level of 7 mg/dL after his overnight dexamethasone suppression test. The 24-hour urine collection for free cortisol revealed elevated levels of cortisol in the urine, and the ACTH level was low.

Endocrinology and endocrine surgery teams were consulted, and recommended surgical resection. After surgical resection of his tumor, the patient was started on glucocorticoid replacement and was discharged with a follow-up appointment with endocrinology.

Bottom Line

An inpatient approach to endocrine incidentalomas should include characterization of the clinical signs and symptoms, size, function, and malignant potential of the lesion. Based on this, inpatient surgical or medical management can be determined. Post-discharge management should include arrangements for surveillance testing and follow-up with appropriate subspecialists.

Dr. Tad-y is assistant professor of medicine and a hospitalist at the University of Colorado Denver.

References

1. Aron DC, Howlett TA. Pituitary incidentalomas. Endocrinol Metab Clin North Am. 2000;29:205-221.
2. Shirodkar M, Jabbour SA. Endocrine incidentalomas. Int J Clin Pract. 2008;62:1423-1431.
3. Burguera B, Gharib H. Thyroid incidentalomas. Prevalence, diagnosis, significance, and management. Endocrinol Metab Clin North Am. 2000;29:187-203.
4. Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008;37:151-171, xi.
5. Freda PU, Beckers AM, Katznelson L, et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:894-904.
6. Gough J, Scott-Coombes D, Fausto Palazzo F. Thyroid incidentaloma: an evidence-based assessment of management strategy. World J Surg. 2008;32:1264-1268.
7. Iyer NG, Shaha AR, Silver CE, et al. Thyroid incidentalomas: to treat or not to treat. Eur Arch Otorhinolaryngol. 2010;267:1019-1026.
8. Jin J, Wilhelm SM, McHenry CR. Incidental thyroid nodule: patterns of diagnosis and rate of malignancy. Am J Surg. 2009;197:320-324.
9. Davenport C, Liew L, Doherty B, et al. The prevalence of adrenal incidentaloma in routine clinical practice. Endocrine. 2011;40:80-83.
10. Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 2011;96: 2004-2015.
11. Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: executive summary of recommendations. Endocr Pract. 2009;15:450-453.
12. NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements. 2002;19:1-25.
13. Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356:601-610.
14. Chidiac RM, Aron DC. Incidentalomas. A disease of modern technology. Endocrinol Metab Clin North Am. 1997;26:233-253.

Clinical question: What is the prognostic influence of atrial fibrillation in patients with acute myocardial infarction?

Background: There have been conflicting reports regarding the prognostic impact of atrial fibrillation (AF) in patients with acute myocardial infarction (MI). This study represents the first meta-analysis performed to quantify the mortality risk associated with AF in MI patients.

Study design: Meta-analysis of observational studies.

Setting: Forty-three studies involving 278,854 patients diagnosed with MI from 1972 to 2000.

Synopsis: The odds ratio (OR) of mortality associated with AF in MI patients was 1.46 (95% confidence interval, 1.35 to 1.58, I2=76%, 23 studies). Although there was significant heterogeneity in included studies, in subgroup analysis, the significant association between AF and mortality was present whether the AF was new (defined as occurring for the first time within one week of MI) with OR of 1.37 (95% confidence interval, 1.26 to 1.49; I2=28%, nine studies) or old (defined as pre-existing before the MI admission) with OR of 1.28 (95% confidence interval, 1.16 to 1.40, I2=24%, four studies). Sensitivity analyses performed by pooling studies according to follow-up duration and adjustment for confounding clinical factors had little effect on the estimates.

Bottom line: AF was associated with increased mortality in patients with MI regardless of the timing of AF development.

Citation: Jabre P, Roger VL, Murad MH, et al. Mortality associated with atrial fibrillation in patients with myocardial infarction. Circulation. 2011;123:1587-1593.

For more physician reviews of HM-related literature, visit our website.

Clinical question: What is the prognostic influence of atrial fibrillation in patients with acute myocardial infarction?

Background: There have been conflicting reports regarding the prognostic impact of atrial fibrillation (AF) in patients with acute myocardial infarction (MI). This study represents the first meta-analysis performed to quantify the mortality risk associated with AF in MI patients.

Study design: Meta-analysis of observational studies.

Setting: Forty-three studies involving 278,854 patients diagnosed with MI from 1972 to 2000.

Synopsis: The odds ratio (OR) of mortality associated with AF in MI patients was 1.46 (95% confidence interval, 1.35 to 1.58, I2=76%, 23 studies). Although there was significant heterogeneity in included studies, in subgroup analysis, the significant association between AF and mortality was present whether the AF was new (defined as occurring for the first time within one week of MI) with OR of 1.37 (95% confidence interval, 1.26 to 1.49; I2=28%, nine studies) or old (defined as pre-existing before the MI admission) with OR of 1.28 (95% confidence interval, 1.16 to 1.40, I2=24%, four studies). Sensitivity analyses performed by pooling studies according to follow-up duration and adjustment for confounding clinical factors had little effect on the estimates.

Bottom line: AF was associated with increased mortality in patients with MI regardless of the timing of AF development.

Citation: Jabre P, Roger VL, Murad MH, et al. Mortality associated with atrial fibrillation in patients with myocardial infarction. Circulation. 2011;123:1587-1593.

For more physician reviews of HM-related literature, visit our website.

Clinical question: What is the prognostic influence of atrial fibrillation in patients with acute myocardial infarction?

Background: There have been conflicting reports regarding the prognostic impact of atrial fibrillation (AF) in patients with acute myocardial infarction (MI). This study represents the first meta-analysis performed to quantify the mortality risk associated with AF in MI patients.

Study design: Meta-analysis of observational studies.

Setting: Forty-three studies involving 278,854 patients diagnosed with MI from 1972 to 2000.

Synopsis: The odds ratio (OR) of mortality associated with AF in MI patients was 1.46 (95% confidence interval, 1.35 to 1.58, I2=76%, 23 studies). Although there was significant heterogeneity in included studies, in subgroup analysis, the significant association between AF and mortality was present whether the AF was new (defined as occurring for the first time within one week of MI) with OR of 1.37 (95% confidence interval, 1.26 to 1.49; I2=28%, nine studies) or old (defined as pre-existing before the MI admission) with OR of 1.28 (95% confidence interval, 1.16 to 1.40, I2=24%, four studies). Sensitivity analyses performed by pooling studies according to follow-up duration and adjustment for confounding clinical factors had little effect on the estimates.

Bottom line: AF was associated with increased mortality in patients with MI regardless of the timing of AF development.

Citation: Jabre P, Roger VL, Murad MH, et al. Mortality associated with atrial fibrillation in patients with myocardial infarction. Circulation. 2011;123:1587-1593.

For more physician reviews of HM-related literature, visit our website.

Clinical question: Is transcatheter aortic-valve replacement comparable to surgical valve replacement in high-operative-risk patients?

Background: In the randomized Placement of Aortic Transcatheter Valves (PARTNER) trial, patients who were not surgical candidates underwent transcatheter aortic-valve replacement, resulting in reduced symptoms and 20% improvement in one-year survival rates. Transcatheter valve replacement has not been compared to surgical replacement in high-operative-risk patients who remain candidates for surgical replacement.

Study design: Randomized controlled trial powered for noninferiority.

Setting: Twenty-five centers in the U.S., Canada, and Germany.

Synopsis: Six-hundred ninety-nine high-operative-risk patients with severe aortic stenosis were randomized to undergo transcatheter aortic-valve replacement or surgical replacement. In the intention-to-treat analysis, all-cause mortality rates were 3.4% in the transcatheter group and 6.5% in the surgical group at 30 days (P=0.07) and 24.2% vs. 26.8% at one year (P=0.44). Rates of major stroke were 3.8% in the transcatheter group compared with 2.1% in the surgical group at 30 days (P=0.20) and 5.1% vs. 2.4% at one year (P=0.07).

The transcatheter group had a significantly higher rate of major vascular complications, but had lower rates of major bleeding and new onset-atrial fibrillation. At one year, improvement in cardiac symptoms and the six-minute-walk distance were not significantly different in the two groups.

Bottom line: In high-operative-risk patients with severe aortic stenosis, transcatheter and surgical aortic-valve replacement had similar mortality at 30 days and one year, but there were a few significant differences in periprocedural risks.

Citation: Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198.

For more physician reviews of HM-related literature, visit our website.

Clinical question: Is transcatheter aortic-valve replacement comparable to surgical valve replacement in high-operative-risk patients?

Background: In the randomized Placement of Aortic Transcatheter Valves (PARTNER) trial, patients who were not surgical candidates underwent transcatheter aortic-valve replacement, resulting in reduced symptoms and 20% improvement in one-year survival rates. Transcatheter valve replacement has not been compared to surgical replacement in high-operative-risk patients who remain candidates for surgical replacement.

Study design: Randomized controlled trial powered for noninferiority.

Setting: Twenty-five centers in the U.S., Canada, and Germany.

Synopsis: Six-hundred ninety-nine high-operative-risk patients with severe aortic stenosis were randomized to undergo transcatheter aortic-valve replacement or surgical replacement. In the intention-to-treat analysis, all-cause mortality rates were 3.4% in the transcatheter group and 6.5% in the surgical group at 30 days (P=0.07) and 24.2% vs. 26.8% at one year (P=0.44). Rates of major stroke were 3.8% in the transcatheter group compared with 2.1% in the surgical group at 30 days (P=0.20) and 5.1% vs. 2.4% at one year (P=0.07).

The transcatheter group had a significantly higher rate of major vascular complications, but had lower rates of major bleeding and new onset-atrial fibrillation. At one year, improvement in cardiac symptoms and the six-minute-walk distance were not significantly different in the two groups.

Bottom line: In high-operative-risk patients with severe aortic stenosis, transcatheter and surgical aortic-valve replacement had similar mortality at 30 days and one year, but there were a few significant differences in periprocedural risks.

Citation: Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198.

For more physician reviews of HM-related literature, visit our website.

Clinical question: Is transcatheter aortic-valve replacement comparable to surgical valve replacement in high-operative-risk patients?

Background: In the randomized Placement of Aortic Transcatheter Valves (PARTNER) trial, patients who were not surgical candidates underwent transcatheter aortic-valve replacement, resulting in reduced symptoms and 20% improvement in one-year survival rates. Transcatheter valve replacement has not been compared to surgical replacement in high-operative-risk patients who remain candidates for surgical replacement.

Study design: Randomized controlled trial powered for noninferiority.

Setting: Twenty-five centers in the U.S., Canada, and Germany.

Synopsis: Six-hundred ninety-nine high-operative-risk patients with severe aortic stenosis were randomized to undergo transcatheter aortic-valve replacement or surgical replacement. In the intention-to-treat analysis, all-cause mortality rates were 3.4% in the transcatheter group and 6.5% in the surgical group at 30 days (P=0.07) and 24.2% vs. 26.8% at one year (P=0.44). Rates of major stroke were 3.8% in the transcatheter group compared with 2.1% in the surgical group at 30 days (P=0.20) and 5.1% vs. 2.4% at one year (P=0.07).

The transcatheter group had a significantly higher rate of major vascular complications, but had lower rates of major bleeding and new onset-atrial fibrillation. At one year, improvement in cardiac symptoms and the six-minute-walk distance were not significantly different in the two groups.

Bottom line: In high-operative-risk patients with severe aortic stenosis, transcatheter and surgical aortic-valve replacement had similar mortality at 30 days and one year, but there were a few significant differences in periprocedural risks.

Citation: Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198.

For more physician reviews of HM-related literature, visit our website.

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Case

A 52-year-old white woman presents to the ED after a motor vehicle accident with a fractured left femur. After surgical repair of the fracture, she is treated with enoxaparin 40 mg daily for VTE prophylaxis. Upon admission to the hospital, her platelet count is 180x109/L. On postoperative day three, it is 140x109/L; on postoperative day six, it is 78x109/L. Because of persistent swelling of the left leg, a venous ultrasound is obtained; results are negative for DVT. Is the decrease in the platelet count concerning for heparin-induced thrombocytopenia?

Overview

Approximately one-third of hospitalized patients are exposed to heparin each year.¹ A well-described, life-threatening adverse effect of heparin use is thrombocytopenia, also called heparin-induced thrombocytopenia (HIT). Studies suggest that the frequency of HIT in the U.S. is as high as 1% to 5% in patients exposed to unfractionated heparin.^1,2

There are two types of HIT. Type 2 HIT is more serious, with risk for life- or limb-threatening complications. Type 1 HIT is a nonimmune disorder caused by the direct effect of heparin on platelet activation, which is characterized by a drop in thrombocyte count within the first 48 hours of heparin exposure. The platelet count is expected to normalize with continued heparin exposure in Type 1 HIT. Type 2 HIT is an immune-mediated disorder in which heparin-dependent IgG recognizes complexes of heparin and platelet factor 4 (PF4), which subsequently induce platelet activation via the platelet Fc gammaRIIa receptor. A positive feedback loop occurs, causing further release of PF4 and platelet activation, which can lead to devastating prothrombotic complications.

Individuals affected by Type 2 HIT have a 20% to 50% risk of developing new thrombotic events, and also have a 10% rate of major morbidity, including limb ischemia requiring amputation, cerebrovascular events, myocardial infarction, DVT, or pulmonary embolus.^1,2

Until recently, the mortality rate in HIT has been reported as high as 20%; however, earlier diagnosis and treatment have resulted in a better prognosis, with mortality and major morbidity of 6% to 10%.² Low-molecular-weight heparin (LMWH) carries a lower risk for development of HIT; as such, one measure to reduce the risk of HIT is to use LMWH in place of unfractionated heparin.³

Review of the Data

When to suspect HIT. HIT should be considered as a potential diagnosis anytime there is a drop in platelet count, either during or shortly following heparin exposure. The differential diagnosis for thrombocytopenia during heparin exposure is broad and includes:

• Disseminated intravascular coagulation;
• Drug-induced thrombocytopenia;
• Hemolytic-uremic syndrome;
• Immune thrombocytopenic purpura;
• Post-transfusion thrombocytopenia;
• Systemic lupus erythematosus; and
• Thrombotic thrombocytopenic purpura.

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The 2009 Clinical Practice Guideline on Evaluation and Management of HIT provided by the American Society of Hematology recommends the use of Warkentin’s 4Ts clinical probability scoring system as a guide in determining the probability of HIT in patients with thrombocytopenia who are exposed to heparin.⁴ The 4Ts scoring system is detailed in Table 1.

In patients with intermediate to high clinical probability of HIT (4-5 points and 6-8 points, respectively, on the 4Ts scoring system), immunologic and functional assays could further guide management. In patients with a low probability of HIT (4Ts score <3), the diagnosis is unlikely and an alternative diagnoses should be considered. Immunologic and functional assays are not recommended for these patients, and heparin can be continued.

Laboratory and diagnostic workups. Immunologic assays (polyspecific ELISA, IgG-specific ELISA, and particle gel immunoassay) detect antibodies against the PF4 heparin complexes regardless of their capacity to activate platelets. These tests are highly sensitive but less specific for HIT because they also detect PF4-heparin antibodies in patients who do not have HIT; therefore, immunoassays have a lower positive predictive value but a high negative predictive value (>95%).⁵

Functional assays (serotonin release assay, heparin-induced platelet activation assay, and platelet aggregation test) detect antibodies that induce heparin-dependent platelet activation. These assays are highly sensitive and specific but are not available at many medical centers. The positive predictive value of these assays is higher (89% to 100%).⁵

Figure 1 provides a diagnostic and initial treatment algorithm for suspected HIT. Immunoassays to detect PF4-heparin antibodies are recommended when clinical probability of HIT is intermediate to high. In these patients, a negative result on serologic testing has a high negative predictive value and suggests that an alternative diagnosis is more likely. In patients with a positive serologic test and intermediate probability of HIT, a functional assay might be beneficial, as a positive result increases the probability of HIT. For patients with high probability of HIT and a positive immunologic assay, functional assays might not be indicated as the diagnosis is likely.

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Treatment. If the probability of HIT is intermediate to high based on the 4Ts scoring system, all heparin products, including heparin flushes, should be immediately discontinued and a laboratory investigation for HIT antibodies should be undertaken. An investigation for lower-limb DVT also should be pursued in patients with high probability of HIT, as the risk of thrombosis is more than 30-fold higher than controls, and studies show that approximately 25% of patients with HIT present with both thrombocytopenia and thrombosis.⁵ In addition, the presence of thrombosis might influence duration of anticoagulation.

Avoid platelet transfusions, as this might propagate thrombosis.

Anticoagulation. With a significant risk of thrombosis associated with this disorder, treatment with an alternative anticoagulant should be started. Vitamin K antagonists, such as warfarin, cannot be given in acute HIT because of the high risk of inducing skin necrosis and venous limb gangrene. Such anticoagulation should not be used until the platelet count increases to greater than 150x109/L. If warfarin already has been given, reversal with vitamin K is indicated.

Consequently, an alternative anticoagulant bridge to warfarin therapy must be used. Usually, the bridging agent will be one of two intravenous direct thrombin inhibitors (argatroban and lepirudin) approved for this purpose.⁶ Both are associated with a higher risk of bleeding. Argatroban is hepatically cleared; lepirudin is renally cleared. Table 2 summarizes dosing information for these agents. A third direct thrombin inhibitor, bivalirudin, is approved for treatment of HIT, but only during percutaneous coronary intervention.⁶

Finally, the recently FDA-approved oral direct thrombin inhibitor dabigatrin has not been studied in or approved for HIT.

Other rational therapies include the factor Xa inhibitors danaparoid and fondaparinux. However, only danaparoid is FDA-approved for use in the treatment of HIT. It can, in cases of low or moderate suspicion of HIT, be given in prophylactic doses, lowering the risk of major bleeding.

Duration of treatment. Whichever bridging anticoagulant is chosen, it should be continued until the platelet count has fully recovered. Further, prior to discontinuation, warfarin therapy should be administered for at least five days and the international normalized ratio (INR) should be therapeutic for approximately 48 hours.

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The subsequent length of warfarin therapy is dependent upon the presence or absence of an associated thrombosis. With the presence of a thrombus, the duration should be as defined for other provoked thromboses (three to six months). With no thrombus, the duration should be at least 30 days.

Future anticoagulation in patients with a prior diagnosis of HIT. A history of HIT does not appear to be a risk factor for a higher frequency of forming heparin antibodies upon re-exposure to heparin.⁷ Therefore, in patients with an important indication for heparin (i.e. cardiac or vascular surgery) and a remote history of HIT (>100 days), heparin can be used. In patients with a subacute history of HIT in whom surgery cannot be delayed, heparin products should be avoided and laboratory investigation should be pursued.

If the immunoassay is positive but the functional assay is negative, it is reasonable to use heparin. If both the immunologic and the functional assays are positive, the patient should be considered as having acute HIT, and bivalirudin is recommended.⁴

Back to the Case

Our patient has acute thrombocytopenia with a fall in platelets greater than 50% from baseline. The decrease is within the appropriate time frame for HIT. No thrombosis is found, but no alternate explanation for the thrombocytopenia is apparent. The 4Ts score of 6 indicates high risk for HIT. Heparin was discontinued, and argatroban at a rate of 2 mcg/kg/min was initiated. The immunoassay was positive.

Argatroban was continued until the platelet count reached 150x109/L, at which point warfarin therapy, 5 mg daily, was started. After four days, the INR was 2.2. After another 24 hours, argatroban was discontinued. She was instructed to continue warfarin for another 30 days.

Bottom Line

Evaluation for HIT combines clinical judgment, summarized in the 4Ts, with laboratory evaluation including an immunoassay and possibly a functional assay. Treatment requires immediate discontinuation of heparin, early initiation of a direct thrombin inhibitor, and bridging to warfarin to continue treatment for at least 30 days. TH

Drs. Smith and Rice are members of the Section of Hospital Medicine at Vanderbilt University in Nashville, Tenn.

References

1. Heparin-Induced Thrombocytopenia. MedScape Reference website. Available at: http://emedicine.medscape.com/article/1357846. Accessed Aug. 31, 2010.
2. Heparin-Induced Thrombocytopenia. Orpha.net website. Available at: http://www.orpha.net/data/patho/GB/uk-HIT.pdf. Accessed Aug. 31, 2010.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335.
4. American Society of Hematology Guidelines: Immune Thrombocytopenia (HIT). American Society of Hematology website. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 28, 2011.
5. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61:77-90.
6. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S.
7. Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin N Am. 2010;24:755-775.

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Case

A 52-year-old white woman presents to the ED after a motor vehicle accident with a fractured left femur. After surgical repair of the fracture, she is treated with enoxaparin 40 mg daily for VTE prophylaxis. Upon admission to the hospital, her platelet count is 180x109/L. On postoperative day three, it is 140x109/L; on postoperative day six, it is 78x109/L. Because of persistent swelling of the left leg, a venous ultrasound is obtained; results are negative for DVT. Is the decrease in the platelet count concerning for heparin-induced thrombocytopenia?

Overview

Approximately one-third of hospitalized patients are exposed to heparin each year.¹ A well-described, life-threatening adverse effect of heparin use is thrombocytopenia, also called heparin-induced thrombocytopenia (HIT). Studies suggest that the frequency of HIT in the U.S. is as high as 1% to 5% in patients exposed to unfractionated heparin.^1,2

There are two types of HIT. Type 2 HIT is more serious, with risk for life- or limb-threatening complications. Type 1 HIT is a nonimmune disorder caused by the direct effect of heparin on platelet activation, which is characterized by a drop in thrombocyte count within the first 48 hours of heparin exposure. The platelet count is expected to normalize with continued heparin exposure in Type 1 HIT. Type 2 HIT is an immune-mediated disorder in which heparin-dependent IgG recognizes complexes of heparin and platelet factor 4 (PF4), which subsequently induce platelet activation via the platelet Fc gammaRIIa receptor. A positive feedback loop occurs, causing further release of PF4 and platelet activation, which can lead to devastating prothrombotic complications.

Individuals affected by Type 2 HIT have a 20% to 50% risk of developing new thrombotic events, and also have a 10% rate of major morbidity, including limb ischemia requiring amputation, cerebrovascular events, myocardial infarction, DVT, or pulmonary embolus.^1,2

Until recently, the mortality rate in HIT has been reported as high as 20%; however, earlier diagnosis and treatment have resulted in a better prognosis, with mortality and major morbidity of 6% to 10%.² Low-molecular-weight heparin (LMWH) carries a lower risk for development of HIT; as such, one measure to reduce the risk of HIT is to use LMWH in place of unfractionated heparin.³

Review of the Data

When to suspect HIT. HIT should be considered as a potential diagnosis anytime there is a drop in platelet count, either during or shortly following heparin exposure. The differential diagnosis for thrombocytopenia during heparin exposure is broad and includes:

• Disseminated intravascular coagulation;
• Drug-induced thrombocytopenia;
• Hemolytic-uremic syndrome;
• Immune thrombocytopenic purpura;
• Post-transfusion thrombocytopenia;
• Systemic lupus erythematosus; and
• Thrombotic thrombocytopenic purpura.

click for large version

The 2009 Clinical Practice Guideline on Evaluation and Management of HIT provided by the American Society of Hematology recommends the use of Warkentin’s 4Ts clinical probability scoring system as a guide in determining the probability of HIT in patients with thrombocytopenia who are exposed to heparin.⁴ The 4Ts scoring system is detailed in Table 1.

In patients with intermediate to high clinical probability of HIT (4-5 points and 6-8 points, respectively, on the 4Ts scoring system), immunologic and functional assays could further guide management. In patients with a low probability of HIT (4Ts score <3), the diagnosis is unlikely and an alternative diagnoses should be considered. Immunologic and functional assays are not recommended for these patients, and heparin can be continued.

Laboratory and diagnostic workups. Immunologic assays (polyspecific ELISA, IgG-specific ELISA, and particle gel immunoassay) detect antibodies against the PF4 heparin complexes regardless of their capacity to activate platelets. These tests are highly sensitive but less specific for HIT because they also detect PF4-heparin antibodies in patients who do not have HIT; therefore, immunoassays have a lower positive predictive value but a high negative predictive value (>95%).⁵

Functional assays (serotonin release assay, heparin-induced platelet activation assay, and platelet aggregation test) detect antibodies that induce heparin-dependent platelet activation. These assays are highly sensitive and specific but are not available at many medical centers. The positive predictive value of these assays is higher (89% to 100%).⁵

Figure 1 provides a diagnostic and initial treatment algorithm for suspected HIT. Immunoassays to detect PF4-heparin antibodies are recommended when clinical probability of HIT is intermediate to high. In these patients, a negative result on serologic testing has a high negative predictive value and suggests that an alternative diagnosis is more likely. In patients with a positive serologic test and intermediate probability of HIT, a functional assay might be beneficial, as a positive result increases the probability of HIT. For patients with high probability of HIT and a positive immunologic assay, functional assays might not be indicated as the diagnosis is likely.

click for large version

Treatment. If the probability of HIT is intermediate to high based on the 4Ts scoring system, all heparin products, including heparin flushes, should be immediately discontinued and a laboratory investigation for HIT antibodies should be undertaken. An investigation for lower-limb DVT also should be pursued in patients with high probability of HIT, as the risk of thrombosis is more than 30-fold higher than controls, and studies show that approximately 25% of patients with HIT present with both thrombocytopenia and thrombosis.⁵ In addition, the presence of thrombosis might influence duration of anticoagulation.

Avoid platelet transfusions, as this might propagate thrombosis.

Anticoagulation. With a significant risk of thrombosis associated with this disorder, treatment with an alternative anticoagulant should be started. Vitamin K antagonists, such as warfarin, cannot be given in acute HIT because of the high risk of inducing skin necrosis and venous limb gangrene. Such anticoagulation should not be used until the platelet count increases to greater than 150x109/L. If warfarin already has been given, reversal with vitamin K is indicated.

Consequently, an alternative anticoagulant bridge to warfarin therapy must be used. Usually, the bridging agent will be one of two intravenous direct thrombin inhibitors (argatroban and lepirudin) approved for this purpose.⁶ Both are associated with a higher risk of bleeding. Argatroban is hepatically cleared; lepirudin is renally cleared. Table 2 summarizes dosing information for these agents. A third direct thrombin inhibitor, bivalirudin, is approved for treatment of HIT, but only during percutaneous coronary intervention.⁶

Finally, the recently FDA-approved oral direct thrombin inhibitor dabigatrin has not been studied in or approved for HIT.

Other rational therapies include the factor Xa inhibitors danaparoid and fondaparinux. However, only danaparoid is FDA-approved for use in the treatment of HIT. It can, in cases of low or moderate suspicion of HIT, be given in prophylactic doses, lowering the risk of major bleeding.

Duration of treatment. Whichever bridging anticoagulant is chosen, it should be continued until the platelet count has fully recovered. Further, prior to discontinuation, warfarin therapy should be administered for at least five days and the international normalized ratio (INR) should be therapeutic for approximately 48 hours.

click for large version

The subsequent length of warfarin therapy is dependent upon the presence or absence of an associated thrombosis. With the presence of a thrombus, the duration should be as defined for other provoked thromboses (three to six months). With no thrombus, the duration should be at least 30 days.

Future anticoagulation in patients with a prior diagnosis of HIT. A history of HIT does not appear to be a risk factor for a higher frequency of forming heparin antibodies upon re-exposure to heparin.⁷ Therefore, in patients with an important indication for heparin (i.e. cardiac or vascular surgery) and a remote history of HIT (>100 days), heparin can be used. In patients with a subacute history of HIT in whom surgery cannot be delayed, heparin products should be avoided and laboratory investigation should be pursued.

If the immunoassay is positive but the functional assay is negative, it is reasonable to use heparin. If both the immunologic and the functional assays are positive, the patient should be considered as having acute HIT, and bivalirudin is recommended.⁴

Back to the Case

Our patient has acute thrombocytopenia with a fall in platelets greater than 50% from baseline. The decrease is within the appropriate time frame for HIT. No thrombosis is found, but no alternate explanation for the thrombocytopenia is apparent. The 4Ts score of 6 indicates high risk for HIT. Heparin was discontinued, and argatroban at a rate of 2 mcg/kg/min was initiated. The immunoassay was positive.

Argatroban was continued until the platelet count reached 150x109/L, at which point warfarin therapy, 5 mg daily, was started. After four days, the INR was 2.2. After another 24 hours, argatroban was discontinued. She was instructed to continue warfarin for another 30 days.

Bottom Line

Evaluation for HIT combines clinical judgment, summarized in the 4Ts, with laboratory evaluation including an immunoassay and possibly a functional assay. Treatment requires immediate discontinuation of heparin, early initiation of a direct thrombin inhibitor, and bridging to warfarin to continue treatment for at least 30 days. TH

Drs. Smith and Rice are members of the Section of Hospital Medicine at Vanderbilt University in Nashville, Tenn.

References

1. Heparin-Induced Thrombocytopenia. MedScape Reference website. Available at: http://emedicine.medscape.com/article/1357846. Accessed Aug. 31, 2010.
2. Heparin-Induced Thrombocytopenia. Orpha.net website. Available at: http://www.orpha.net/data/patho/GB/uk-HIT.pdf. Accessed Aug. 31, 2010.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335.
4. American Society of Hematology Guidelines: Immune Thrombocytopenia (HIT). American Society of Hematology website. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 28, 2011.
5. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61:77-90.
6. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S.
7. Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin N Am. 2010;24:755-775.

click for large version

Case

A 52-year-old white woman presents to the ED after a motor vehicle accident with a fractured left femur. After surgical repair of the fracture, she is treated with enoxaparin 40 mg daily for VTE prophylaxis. Upon admission to the hospital, her platelet count is 180x109/L. On postoperative day three, it is 140x109/L; on postoperative day six, it is 78x109/L. Because of persistent swelling of the left leg, a venous ultrasound is obtained; results are negative for DVT. Is the decrease in the platelet count concerning for heparin-induced thrombocytopenia?

Overview

Approximately one-third of hospitalized patients are exposed to heparin each year.¹ A well-described, life-threatening adverse effect of heparin use is thrombocytopenia, also called heparin-induced thrombocytopenia (HIT). Studies suggest that the frequency of HIT in the U.S. is as high as 1% to 5% in patients exposed to unfractionated heparin.^1,2

There are two types of HIT. Type 2 HIT is more serious, with risk for life- or limb-threatening complications. Type 1 HIT is a nonimmune disorder caused by the direct effect of heparin on platelet activation, which is characterized by a drop in thrombocyte count within the first 48 hours of heparin exposure. The platelet count is expected to normalize with continued heparin exposure in Type 1 HIT. Type 2 HIT is an immune-mediated disorder in which heparin-dependent IgG recognizes complexes of heparin and platelet factor 4 (PF4), which subsequently induce platelet activation via the platelet Fc gammaRIIa receptor. A positive feedback loop occurs, causing further release of PF4 and platelet activation, which can lead to devastating prothrombotic complications.

Individuals affected by Type 2 HIT have a 20% to 50% risk of developing new thrombotic events, and also have a 10% rate of major morbidity, including limb ischemia requiring amputation, cerebrovascular events, myocardial infarction, DVT, or pulmonary embolus.^1,2

Until recently, the mortality rate in HIT has been reported as high as 20%; however, earlier diagnosis and treatment have resulted in a better prognosis, with mortality and major morbidity of 6% to 10%.² Low-molecular-weight heparin (LMWH) carries a lower risk for development of HIT; as such, one measure to reduce the risk of HIT is to use LMWH in place of unfractionated heparin.³

Review of the Data

When to suspect HIT. HIT should be considered as a potential diagnosis anytime there is a drop in platelet count, either during or shortly following heparin exposure. The differential diagnosis for thrombocytopenia during heparin exposure is broad and includes:

• Disseminated intravascular coagulation;
• Drug-induced thrombocytopenia;
• Hemolytic-uremic syndrome;
• Immune thrombocytopenic purpura;
• Post-transfusion thrombocytopenia;
• Systemic lupus erythematosus; and
• Thrombotic thrombocytopenic purpura.

click for large version

The 2009 Clinical Practice Guideline on Evaluation and Management of HIT provided by the American Society of Hematology recommends the use of Warkentin’s 4Ts clinical probability scoring system as a guide in determining the probability of HIT in patients with thrombocytopenia who are exposed to heparin.⁴ The 4Ts scoring system is detailed in Table 1.

In patients with intermediate to high clinical probability of HIT (4-5 points and 6-8 points, respectively, on the 4Ts scoring system), immunologic and functional assays could further guide management. In patients with a low probability of HIT (4Ts score <3), the diagnosis is unlikely and an alternative diagnoses should be considered. Immunologic and functional assays are not recommended for these patients, and heparin can be continued.

Laboratory and diagnostic workups. Immunologic assays (polyspecific ELISA, IgG-specific ELISA, and particle gel immunoassay) detect antibodies against the PF4 heparin complexes regardless of their capacity to activate platelets. These tests are highly sensitive but less specific for HIT because they also detect PF4-heparin antibodies in patients who do not have HIT; therefore, immunoassays have a lower positive predictive value but a high negative predictive value (>95%).⁵

Functional assays (serotonin release assay, heparin-induced platelet activation assay, and platelet aggregation test) detect antibodies that induce heparin-dependent platelet activation. These assays are highly sensitive and specific but are not available at many medical centers. The positive predictive value of these assays is higher (89% to 100%).⁵

Figure 1 provides a diagnostic and initial treatment algorithm for suspected HIT. Immunoassays to detect PF4-heparin antibodies are recommended when clinical probability of HIT is intermediate to high. In these patients, a negative result on serologic testing has a high negative predictive value and suggests that an alternative diagnosis is more likely. In patients with a positive serologic test and intermediate probability of HIT, a functional assay might be beneficial, as a positive result increases the probability of HIT. For patients with high probability of HIT and a positive immunologic assay, functional assays might not be indicated as the diagnosis is likely.

click for large version

Treatment. If the probability of HIT is intermediate to high based on the 4Ts scoring system, all heparin products, including heparin flushes, should be immediately discontinued and a laboratory investigation for HIT antibodies should be undertaken. An investigation for lower-limb DVT also should be pursued in patients with high probability of HIT, as the risk of thrombosis is more than 30-fold higher than controls, and studies show that approximately 25% of patients with HIT present with both thrombocytopenia and thrombosis.⁵ In addition, the presence of thrombosis might influence duration of anticoagulation.

Avoid platelet transfusions, as this might propagate thrombosis.

Anticoagulation. With a significant risk of thrombosis associated with this disorder, treatment with an alternative anticoagulant should be started. Vitamin K antagonists, such as warfarin, cannot be given in acute HIT because of the high risk of inducing skin necrosis and venous limb gangrene. Such anticoagulation should not be used until the platelet count increases to greater than 150x109/L. If warfarin already has been given, reversal with vitamin K is indicated.

Consequently, an alternative anticoagulant bridge to warfarin therapy must be used. Usually, the bridging agent will be one of two intravenous direct thrombin inhibitors (argatroban and lepirudin) approved for this purpose.⁶ Both are associated with a higher risk of bleeding. Argatroban is hepatically cleared; lepirudin is renally cleared. Table 2 summarizes dosing information for these agents. A third direct thrombin inhibitor, bivalirudin, is approved for treatment of HIT, but only during percutaneous coronary intervention.⁶

Finally, the recently FDA-approved oral direct thrombin inhibitor dabigatrin has not been studied in or approved for HIT.

Other rational therapies include the factor Xa inhibitors danaparoid and fondaparinux. However, only danaparoid is FDA-approved for use in the treatment of HIT. It can, in cases of low or moderate suspicion of HIT, be given in prophylactic doses, lowering the risk of major bleeding.

Duration of treatment. Whichever bridging anticoagulant is chosen, it should be continued until the platelet count has fully recovered. Further, prior to discontinuation, warfarin therapy should be administered for at least five days and the international normalized ratio (INR) should be therapeutic for approximately 48 hours.

click for large version

The subsequent length of warfarin therapy is dependent upon the presence or absence of an associated thrombosis. With the presence of a thrombus, the duration should be as defined for other provoked thromboses (three to six months). With no thrombus, the duration should be at least 30 days.

Future anticoagulation in patients with a prior diagnosis of HIT. A history of HIT does not appear to be a risk factor for a higher frequency of forming heparin antibodies upon re-exposure to heparin.⁷ Therefore, in patients with an important indication for heparin (i.e. cardiac or vascular surgery) and a remote history of HIT (>100 days), heparin can be used. In patients with a subacute history of HIT in whom surgery cannot be delayed, heparin products should be avoided and laboratory investigation should be pursued.

If the immunoassay is positive but the functional assay is negative, it is reasonable to use heparin. If both the immunologic and the functional assays are positive, the patient should be considered as having acute HIT, and bivalirudin is recommended.⁴

Back to the Case

Our patient has acute thrombocytopenia with a fall in platelets greater than 50% from baseline. The decrease is within the appropriate time frame for HIT. No thrombosis is found, but no alternate explanation for the thrombocytopenia is apparent. The 4Ts score of 6 indicates high risk for HIT. Heparin was discontinued, and argatroban at a rate of 2 mcg/kg/min was initiated. The immunoassay was positive.

Argatroban was continued until the platelet count reached 150x109/L, at which point warfarin therapy, 5 mg daily, was started. After four days, the INR was 2.2. After another 24 hours, argatroban was discontinued. She was instructed to continue warfarin for another 30 days.

Bottom Line

Evaluation for HIT combines clinical judgment, summarized in the 4Ts, with laboratory evaluation including an immunoassay and possibly a functional assay. Treatment requires immediate discontinuation of heparin, early initiation of a direct thrombin inhibitor, and bridging to warfarin to continue treatment for at least 30 days. TH

Drs. Smith and Rice are members of the Section of Hospital Medicine at Vanderbilt University in Nashville, Tenn.

References

1. Heparin-Induced Thrombocytopenia. MedScape Reference website. Available at: http://emedicine.medscape.com/article/1357846. Accessed Aug. 31, 2010.
2. Heparin-Induced Thrombocytopenia. Orpha.net website. Available at: http://www.orpha.net/data/patho/GB/uk-HIT.pdf. Accessed Aug. 31, 2010.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335.
4. American Society of Hematology Guidelines: Immune Thrombocytopenia (HIT). American Society of Hematology website. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 28, 2011.
5. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61:77-90.
6. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S.
7. Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin N Am. 2010;24:755-775.

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Screening for AAA
2. Adverse events in atrial fibrillation
3. Biological treatment of inflammatory bowel diseases
4. Steroid treatment of inflammatory bowel diseases
5. Levofloxacin for H. pylori
6. Natural history of tako-tsubo cardiomyopathy
7. Predicting postoperative pulmonary complications
8. Code status and goals of care in the ICU

New Screening Strategy To Identify Large Abdominal Aortic Aneurysms

Clinical question: Can an effective scoring system be developed to better identify patients at risk for large abdominal aortic aneurysms (AAA)?

Background: Screening reduces AAA-related mortality by about half in men aged >65. The United States Preventive Services Task Force (USPSTF) has recommended screening for AAA in men aged 65 to 75 with a history of smoking. However, more than 50% of AAA ruptures occur in individuals outside this patient cohort, and only some AAAs detected are large enough to warrant surgery.

Study design: Retrospective, observational cohort study.

Setting: More than 20,000 screening sites across the U.S.

Synopsis: Researchers collected demographics and risk factors from 3.1 million people undergoing ultrasound screening for AAA by Life Line Screening Inc. At the screening visit, subjects completed a questionnaire about their health status and medical history. Screening data also included diameter of the infrarenal abdominal aorta. To construct and test a risk model, the screened individuals were randomly allocated into two equal groups: a data set used for model development and one for validation.

Most of the AAAs greater than 5 cm in diameter discovered were in males (84.4%) and among subjects with a smoking history (83%). Other risk factors for large AAAs included advanced age, peripheral arterial disease, and obesity. The authors estimate that there are about 121,000 people with >5.0 cm aneurysms in the general population. Current guidelines would detect only 33.7% of the existing large AAAs. Study limitations include possible selection bias, as a majority of patients were self-referred. Also, the database did not include all comorbidities that could affect the risk of AAA. The self-reported nature of health data might cause misclassification of a patient’s true health status.

Bottom line: A screening strategy based on a newly developed scoring system is an effective way to identify patients at risk of large abdominal aortic aneurysms.

Citation: Greco G, Egorova NN, Gelijns AC, et al. Development of a novel scoring tool for the identification of large >5 cm abdominal aortic aneurysms. Ann Surg. 2010;252(4):675-682.

Risk Factors for Adverse Events in Patients with Symptomatic Atrial Fibrillation

Clinical question: What are the predictors of 30-day adverse events in ED patients evaluated for symptomatic atrial fibrillation?

Background: Atrial fibrillation (AF) affects more than 2 million people in the U.S. and accounts for nearly 1% of ED visits. Physicians have little information to guide risk stratification, and they admit more than 65% of patients. A strategy to better define the ED management of patients presenting with atrial fibrillation is required.

Study design: Retrospective, observational cohort study.

Setting: Urban academic tertiary-care referral center with an adult ED.

Synopsis: A systematic review of the electronic medical records of all ED patients presenting with symptomatic atrial fibrillation over a three-year period was performed. Predefined adverse outcomes included 30-day ED return visits, unscheduled hospitalizations, cardiovascular complications, or death.

Of 832 eligible patients, 216 (25.9%) experienced at least one of the 30-day adverse events. Adverse events occurred in 181 of the 638 (28.4%) admitted patients and 35 of the 192 (18.2%) patients discharged from the ED. Increasing age, complaint of dyspnea, smoking history, inadequate ventricular rate control, and patients receiving beta-blockers were factors independently associated with higher risk for adverse events.

Study results were limited by a number of factors. This was a single-center, retrospective, observational study, with all of its inherent limitations. The predictor model did not include laboratory data, such as BNP or troponin. Patients might have experienced additional events within the 30 days that were treated at other hospitals and not recorded in the database. Patient disposition might have affected the results, as patients initially admitted from the ED had a higher rate of 30-day adverse events than patients who were discharged from the ED.

Bottom line: Patients with increased age, smoking history, complaints of dyspnea, inadequate ventricular rate control in the ED, and home beta-blocker therapy are more likely to experience an atrial-fibrillation-related adverse event within 30 days.

Citation: Barrett TW, Martin AR, Storrow AB, et al. A clinical prediction model to estimate risk for 30-day adverse events in emergency department patients with symptomatic atrial fibrillation. Ann Emerg Med. 2011;57 (1):1-12.

Biological Therapies Are Effective in Inducing Remission in Inflammatory Bowel Disease

Clinical question: Are biological therapies useful in the treatment of ulcerative colitis (UC) and Crohn’s disease (CD)?

Background: Patients with CD and UC often experience flares of disease activity, despite maintenance therapy with 5-aminosalicylic acid compounds. These flares are usually treated with corticosteroids, which carry numerous adverse side effects. The role of biological therapies in inducing remission is uncertain.

Study design: Systematic review and meta-analysis.

Setting: Twenty-seven randomized controlled trials involving 7,416 patients.

Synopsis: Anti-TNF α antibodies and natalizumab were both superior to placebo in inducing remission of luminal CD (RR of no remission 0.87 and 0.88, respectively). Anti-TNF antibodies also were superior to placebo in preventing relapse of luminal CD (RR of relapse=0.71). Infliximab was superior to placebo in inducing remission of moderate to severely active UC (RR=0.72; 95% CI, 0.57-0.91). There were no significantly increased adverse drug effects with anti-TNF α antibodies or with infliximab compared with placebo. Natalizumab caused significantly higher rates of headache.

Limitations include risk of publication bias inherent in meta-analyses. There also was evidence of moderate heterogeneity in the studies analyzed. Finally, not every study was consistent in reporting adverse drug effects.

Bottom line: Biological therapies are superior to placebo in inducing remission of active UC and CD, as well as preventing relapse of quiescent CD.

Citation: Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011; 106(4):644-659.

Glucocortico­steroids Probably Effective in Treatment of Inflammatory Bowel Disease, Primarily in Active Ulcerative Colitis

Clinical question: Is glucocorticosteroid therapy effective in the treatment of active IBD and in preventing relapses?

Background: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases of unclear etiology. Use of standard glucocorticosteroids and budesonide is widespread in inflammatory bowel disease (IBD) treatment. To date, there has been no large-scale meta-analysis to examine the effectiveness of both treatments in CD and UC.

Study design: Systematic review and meta-analysis.

Setting: Twenty randomized controlled trials totaling 2,398 patients.

Synopsis: Standard glucocorticosteroids were superior to placebo for UC remission (RR of no remission=0.65; 95% CI, 0.45-0.93). Both trials of standard glucocorticosteroids in CD remission reported a statistically significant effect, but the overall effect was not significant due to heterogeneity of the studies. Budesonide was superior to placebo for CD remission (RR=0.73; 95% CI, 0.63-0.84) but not in preventing CD relapse (RR=0.93; 95% CI, 0.83-1.04). Standard glucocorticosteroids were superior to budesonide for CD remission (RR=0.82; 95% CI, 0.68-0.98) but with more adverse effects (RR=1.64; 95% CI, 1.34-2.00).

The limitations of the study include the poor overall quality of the studies included in the meta-analysis, with only one study judged as low risk of bias. There was intermediate to high heterogeneity between study results.

Bottom line: Standard glucocorticosteroids are likely effective in inducing remission in UC and, possibly, in CD. Budesonide probably is effective at inducing remission in active CD. Neither therapy was recommended in preventing relapse of UC and CD.

Citation: Ford AC, Bernstein CN, Khan KJ, et al. Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):590-599.

Levofloxacin Effective in Treatment of H. Pylori in Settings of High Clarithromycin Resistance

Clinical question: In areas with high H. pylori clarithromycin resistance rates, is levofloxacin more effective in eradicating H. pylori than standard clarithromycin, based treatment regimens?

Background: The rise in antimicrobial drug resistance is a major cause for the decreasing rate of H. pylori eradication. In areas with higher than 15% H. pyloriclarithromycin-resistant strains, quadruple therapy has been suggested as first-line therapy. The efficacy of a levofloxacin-based sequential therapy in eradicating H. pylori is undetermined.

Study design: Prospective, randomized, controlled multicenter study with a parallel-group design.

Setting: Five gastroenterology clinics in Italy.

Synopsis: Researchers randomly assigned 375 patients who were infected with H. pylori and naive to treatment to one of three groups. All three treatment groups received an initial five days of omeprazole 20 mg BID and amoxicillin 1 gm BID, then five days of omeprazole 20 mg BID and tinidazole 500 mg BID. The groups also received either clarithromycin 500 mg BID, levofloxacin 250 mg BID, or levofloxacin 500 mg BID, respectively, during the second five days of treatment.

Eradication rates were 80.8% (95% CI, 72.8% to 87.3%) with clarithromycin sequential therapy, 96.0% (95% CI, 90.9% to 98.7%) with levofloxacin-250 sequential therapy, and 96.8% (95% CI, 92.0% to 99.1%) with levofloxacin-500 sequential therapy.

The clarithromycin-group eradication rate was significantly lower than both levofloxacin groups. No significant difference was observed between the levofloxacin-250 and levofloxacin-500 groups. No differences in prevalence of antimicrobial resistance or incidence of adverse events were observed between the groups. Levofloxacin-250 therapy does offer cost savings when compared with clarithromycin sequential therapy.

A potential limitation to the study is referral bias, as each of the patients first were sent by their primary physicians to a specialized GI clinic.

Bottom line: In areas with a high prevalence of clarithromycin-resistant strains of H. pylori levofloxacin-containing sequential therapy should be considered for a first-line eradication regimen.

Citation: Romano M, Cuomo A, Gravina AG, et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial. Gut. 2010;59(11):1465-1470.

Tako-Tsubo Cardiomyopathy Is Associated with Higher Hospital Readmission Rates and Long-Term Mortality

Clinical question: What is the natural history of patients who develop tako-tsubo cardiomyopathy?

Background: Stress-induced or tako-tsubo cardiomyopathy (TTC) is a rare acute cardiac syndrome, characterized by chest pain or dyspnea, ischemic electrocardiographic changes, transient left ventricular (LV) dysfunction, and limited release of cardiac injury markers, in the absence of epicardial coronary artery disease (CAD). The long-term outcome of this condition is unknown.

Study design: Prospective, case-control study.

Setting: Five urban-based hospitals in Italy.

Synopsis: One hundred-sixteen patients with TTC were included in the five-year study period. Patients were followed up at one and six months, then annually thereafter. Primary endpoints were death, TTC recurrence, and rehospitalization for any cause.

Mean initial LV ejection fraction (LVEF) was 36%. Two patients died of refractory heart failure during hospitalization. Of the patients who were discharged alive, all except one showed complete LV functional recovery.

At follow-up (mean two years), only 64 (55%) patients were asymptomatic. Rehospitalization rate was high (25%), with chest pain and dyspnea the most common causes. Only two patients had a recurrence of TTC. Eleven patients died (seven from cardiovascular causes). There was no significant difference in mortality or in other clinical events between patients with and without severe LV dysfunction at presentation. The standardized mortality ratio was 3.40 (95% CI, 1.83-6.34) in the TTC population, compared with the age- and sex-specific mortality of the general population.

The study is limited by a lack of patients with subclinical TTC disease and those who might have suffered from sudden cardiac death prior to enrollment, leading to a possible sampling bias, as well as the nonrandomized use of beta-blockers.

Bottom line: Tako-tsubo disease is associated with rare recurrence of the disease, common recurrence of chest pain and dyspnea, and three times the mortality rate of the general population.

Citation: Parodi G, Bellandi B, Del Pace S, et al. Natural history of tako-tsubo cardiomyopathy. Chest. 2011;139(4):887-892.

Seven Independent Risk Factors Predict Postoperative Pulmonary Complications

Clinical question: What are the clinical risk factors that predict higher rates of postoperative pulmonary complications?

Background: Postoperative pulmonary complications (PPCs) are a major cause of postoperative morbidity, mortality, and prolonged hospital stays. Previous studies looking at risk factors for PPCs were limited by sampling bias and small sample sizes.

Study design: Prospective, randomized-sample cohort study.

Setting: Fifty-nine participating Spanish hospitals (community, intermediate referral, or major tertiary-care facilities).

Synopsis: Patients undergoing surgical procedures with general, neuraxial, or regional anesthesia were selected randomly. The main outcome was the development of at least one of the following: respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis. Of 2,464 patients enrolled, 252 events were observed in 123 patients (5%). The 30-day mortality rate was significantly higher in patients suffering a PPC than those who did not (19.5% vs. 0.5%). Additionally, regression modeling identified seven independent risk factors: low preoperative arterial oxygen saturation, acute respiratory infection within one month of surgery, advanced age, preoperative anemia, upper abdominal or intrathoracic surgery, surgical duration more than two hours, and emergency surgery.

The study was underpowered to assess the significance of all potential risk factors for PPCs. Also, given the number of centers involved in the study, variation in assessing development of PPCs is likely.

Bottom line: Postoperative pulmonary complications are a major cause of morbidity and mortality. Seven independent risk factors were identified for the development of PPCs, which could be useful in preoperative risk stratification.

Citation: Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113(6):1338-1350.

Code Status Orders and Goals of Medical ICU Care

Clinical question: How familiar are patients in the medical ICU (MICU) or their surrogates regarding code-status orders and goals of care, what are their preferences, and to what extent do they and their physicians differ?

Background: Discussions about code-status orders and goals of care carry great import in the MICU. However, little data exist on patients’ code-status preferences and goals of care. More knowledge of these issues can help physicians deliver more patient-centered care.

Study design: Prospective interviews.

Setting: Twenty-six-bed MICU at a large Midwestern academic medical center.

Synopsis: Data were collected from December 2008 to December 2009 on a random sample of patients—or their surrogates—admitted to the MICU. Of 135 eligible patients/surrogates, 100 completed interviews. Patients primarily were white (95%) and from the ages of 41 to 80 (79%).

Only 28% of participants recalled having a discussion about CPR and one goal of care, while 27% recalled no discussion at all; 83% preferred full code status but had limited knowledge of CPR and its outcomes in the hospital setting. Only 4% were able to identify all components of CPR, and they estimated the mean probability of survival following in-hospital arrest with CPR to be 71.8%, although data suggest survival is closer to 18%. There was a correlation between a higher estimation of survival following CPR and preference for it. After learning about the evidence-based likelihood of a good neurologic outcome following CPR, 8% of the participants became less interested.

Discrepancies between patients’ stated code status and that in the medical record was identified 16% of the time. Additionally, 67.7% of participants differed with their physicians regarding the most important goal of care.

Bottom line: Discussions about code status and goals of care in the MICU occur less frequently than recommended, leading to widespread discrepancies between patients/surrogates and their physicians regarding the most important goal of care. This is compounded by the fact that patients and their surrogates have limited knowledge about in-hospital CPR and its likelihood of success.

Citation: Gehlbach TG, Shinkunas LA, Forman-Hoffman VL, Thomas KW, Schmidt GA, Kaldjian LC. Code status orders and goals of care in the medical ICU. Chest. 2011;139:802-809. TH

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Screening for AAA
2. Adverse events in atrial fibrillation
3. Biological treatment of inflammatory bowel diseases
4. Steroid treatment of inflammatory bowel diseases
5. Levofloxacin for H. pylori
6. Natural history of tako-tsubo cardiomyopathy
7. Predicting postoperative pulmonary complications
8. Code status and goals of care in the ICU

New Screening Strategy To Identify Large Abdominal Aortic Aneurysms

Clinical question: Can an effective scoring system be developed to better identify patients at risk for large abdominal aortic aneurysms (AAA)?

Background: Screening reduces AAA-related mortality by about half in men aged >65. The United States Preventive Services Task Force (USPSTF) has recommended screening for AAA in men aged 65 to 75 with a history of smoking. However, more than 50% of AAA ruptures occur in individuals outside this patient cohort, and only some AAAs detected are large enough to warrant surgery.

Study design: Retrospective, observational cohort study.

Setting: More than 20,000 screening sites across the U.S.

Synopsis: Researchers collected demographics and risk factors from 3.1 million people undergoing ultrasound screening for AAA by Life Line Screening Inc. At the screening visit, subjects completed a questionnaire about their health status and medical history. Screening data also included diameter of the infrarenal abdominal aorta. To construct and test a risk model, the screened individuals were randomly allocated into two equal groups: a data set used for model development and one for validation.

Most of the AAAs greater than 5 cm in diameter discovered were in males (84.4%) and among subjects with a smoking history (83%). Other risk factors for large AAAs included advanced age, peripheral arterial disease, and obesity. The authors estimate that there are about 121,000 people with >5.0 cm aneurysms in the general population. Current guidelines would detect only 33.7% of the existing large AAAs. Study limitations include possible selection bias, as a majority of patients were self-referred. Also, the database did not include all comorbidities that could affect the risk of AAA. The self-reported nature of health data might cause misclassification of a patient’s true health status.

Bottom line: A screening strategy based on a newly developed scoring system is an effective way to identify patients at risk of large abdominal aortic aneurysms.

Citation: Greco G, Egorova NN, Gelijns AC, et al. Development of a novel scoring tool for the identification of large >5 cm abdominal aortic aneurysms. Ann Surg. 2010;252(4):675-682.

Risk Factors for Adverse Events in Patients with Symptomatic Atrial Fibrillation

Clinical question: What are the predictors of 30-day adverse events in ED patients evaluated for symptomatic atrial fibrillation?

Background: Atrial fibrillation (AF) affects more than 2 million people in the U.S. and accounts for nearly 1% of ED visits. Physicians have little information to guide risk stratification, and they admit more than 65% of patients. A strategy to better define the ED management of patients presenting with atrial fibrillation is required.

Study design: Retrospective, observational cohort study.

Setting: Urban academic tertiary-care referral center with an adult ED.

Synopsis: A systematic review of the electronic medical records of all ED patients presenting with symptomatic atrial fibrillation over a three-year period was performed. Predefined adverse outcomes included 30-day ED return visits, unscheduled hospitalizations, cardiovascular complications, or death.

Of 832 eligible patients, 216 (25.9%) experienced at least one of the 30-day adverse events. Adverse events occurred in 181 of the 638 (28.4%) admitted patients and 35 of the 192 (18.2%) patients discharged from the ED. Increasing age, complaint of dyspnea, smoking history, inadequate ventricular rate control, and patients receiving beta-blockers were factors independently associated with higher risk for adverse events.

Study results were limited by a number of factors. This was a single-center, retrospective, observational study, with all of its inherent limitations. The predictor model did not include laboratory data, such as BNP or troponin. Patients might have experienced additional events within the 30 days that were treated at other hospitals and not recorded in the database. Patient disposition might have affected the results, as patients initially admitted from the ED had a higher rate of 30-day adverse events than patients who were discharged from the ED.

Bottom line: Patients with increased age, smoking history, complaints of dyspnea, inadequate ventricular rate control in the ED, and home beta-blocker therapy are more likely to experience an atrial-fibrillation-related adverse event within 30 days.

Citation: Barrett TW, Martin AR, Storrow AB, et al. A clinical prediction model to estimate risk for 30-day adverse events in emergency department patients with symptomatic atrial fibrillation. Ann Emerg Med. 2011;57 (1):1-12.

Biological Therapies Are Effective in Inducing Remission in Inflammatory Bowel Disease

Clinical question: Are biological therapies useful in the treatment of ulcerative colitis (UC) and Crohn’s disease (CD)?

Background: Patients with CD and UC often experience flares of disease activity, despite maintenance therapy with 5-aminosalicylic acid compounds. These flares are usually treated with corticosteroids, which carry numerous adverse side effects. The role of biological therapies in inducing remission is uncertain.

Study design: Systematic review and meta-analysis.

Setting: Twenty-seven randomized controlled trials involving 7,416 patients.

Synopsis: Anti-TNF α antibodies and natalizumab were both superior to placebo in inducing remission of luminal CD (RR of no remission 0.87 and 0.88, respectively). Anti-TNF antibodies also were superior to placebo in preventing relapse of luminal CD (RR of relapse=0.71). Infliximab was superior to placebo in inducing remission of moderate to severely active UC (RR=0.72; 95% CI, 0.57-0.91). There were no significantly increased adverse drug effects with anti-TNF α antibodies or with infliximab compared with placebo. Natalizumab caused significantly higher rates of headache.

Limitations include risk of publication bias inherent in meta-analyses. There also was evidence of moderate heterogeneity in the studies analyzed. Finally, not every study was consistent in reporting adverse drug effects.

Bottom line: Biological therapies are superior to placebo in inducing remission of active UC and CD, as well as preventing relapse of quiescent CD.

Citation: Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011; 106(4):644-659.

Glucocortico­steroids Probably Effective in Treatment of Inflammatory Bowel Disease, Primarily in Active Ulcerative Colitis

Clinical question: Is glucocorticosteroid therapy effective in the treatment of active IBD and in preventing relapses?

Background: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases of unclear etiology. Use of standard glucocorticosteroids and budesonide is widespread in inflammatory bowel disease (IBD) treatment. To date, there has been no large-scale meta-analysis to examine the effectiveness of both treatments in CD and UC.

Study design: Systematic review and meta-analysis.

Setting: Twenty randomized controlled trials totaling 2,398 patients.

Synopsis: Standard glucocorticosteroids were superior to placebo for UC remission (RR of no remission=0.65; 95% CI, 0.45-0.93). Both trials of standard glucocorticosteroids in CD remission reported a statistically significant effect, but the overall effect was not significant due to heterogeneity of the studies. Budesonide was superior to placebo for CD remission (RR=0.73; 95% CI, 0.63-0.84) but not in preventing CD relapse (RR=0.93; 95% CI, 0.83-1.04). Standard glucocorticosteroids were superior to budesonide for CD remission (RR=0.82; 95% CI, 0.68-0.98) but with more adverse effects (RR=1.64; 95% CI, 1.34-2.00).

The limitations of the study include the poor overall quality of the studies included in the meta-analysis, with only one study judged as low risk of bias. There was intermediate to high heterogeneity between study results.

Bottom line: Standard glucocorticosteroids are likely effective in inducing remission in UC and, possibly, in CD. Budesonide probably is effective at inducing remission in active CD. Neither therapy was recommended in preventing relapse of UC and CD.

Citation: Ford AC, Bernstein CN, Khan KJ, et al. Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):590-599.

Levofloxacin Effective in Treatment of H. Pylori in Settings of High Clarithromycin Resistance

Clinical question: In areas with high H. pylori clarithromycin resistance rates, is levofloxacin more effective in eradicating H. pylori than standard clarithromycin, based treatment regimens?

Background: The rise in antimicrobial drug resistance is a major cause for the decreasing rate of H. pylori eradication. In areas with higher than 15% H. pyloriclarithromycin-resistant strains, quadruple therapy has been suggested as first-line therapy. The efficacy of a levofloxacin-based sequential therapy in eradicating H. pylori is undetermined.

Study design: Prospective, randomized, controlled multicenter study with a parallel-group design.

Setting: Five gastroenterology clinics in Italy.

Synopsis: Researchers randomly assigned 375 patients who were infected with H. pylori and naive to treatment to one of three groups. All three treatment groups received an initial five days of omeprazole 20 mg BID and amoxicillin 1 gm BID, then five days of omeprazole 20 mg BID and tinidazole 500 mg BID. The groups also received either clarithromycin 500 mg BID, levofloxacin 250 mg BID, or levofloxacin 500 mg BID, respectively, during the second five days of treatment.

Eradication rates were 80.8% (95% CI, 72.8% to 87.3%) with clarithromycin sequential therapy, 96.0% (95% CI, 90.9% to 98.7%) with levofloxacin-250 sequential therapy, and 96.8% (95% CI, 92.0% to 99.1%) with levofloxacin-500 sequential therapy.

The clarithromycin-group eradication rate was significantly lower than both levofloxacin groups. No significant difference was observed between the levofloxacin-250 and levofloxacin-500 groups. No differences in prevalence of antimicrobial resistance or incidence of adverse events were observed between the groups. Levofloxacin-250 therapy does offer cost savings when compared with clarithromycin sequential therapy.

A potential limitation to the study is referral bias, as each of the patients first were sent by their primary physicians to a specialized GI clinic.

Bottom line: In areas with a high prevalence of clarithromycin-resistant strains of H. pylori levofloxacin-containing sequential therapy should be considered for a first-line eradication regimen.

Citation: Romano M, Cuomo A, Gravina AG, et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial. Gut. 2010;59(11):1465-1470.

Tako-Tsubo Cardiomyopathy Is Associated with Higher Hospital Readmission Rates and Long-Term Mortality

Clinical question: What is the natural history of patients who develop tako-tsubo cardiomyopathy?

Background: Stress-induced or tako-tsubo cardiomyopathy (TTC) is a rare acute cardiac syndrome, characterized by chest pain or dyspnea, ischemic electrocardiographic changes, transient left ventricular (LV) dysfunction, and limited release of cardiac injury markers, in the absence of epicardial coronary artery disease (CAD). The long-term outcome of this condition is unknown.

Study design: Prospective, case-control study.

Setting: Five urban-based hospitals in Italy.

Synopsis: One hundred-sixteen patients with TTC were included in the five-year study period. Patients were followed up at one and six months, then annually thereafter. Primary endpoints were death, TTC recurrence, and rehospitalization for any cause.

Mean initial LV ejection fraction (LVEF) was 36%. Two patients died of refractory heart failure during hospitalization. Of the patients who were discharged alive, all except one showed complete LV functional recovery.

At follow-up (mean two years), only 64 (55%) patients were asymptomatic. Rehospitalization rate was high (25%), with chest pain and dyspnea the most common causes. Only two patients had a recurrence of TTC. Eleven patients died (seven from cardiovascular causes). There was no significant difference in mortality or in other clinical events between patients with and without severe LV dysfunction at presentation. The standardized mortality ratio was 3.40 (95% CI, 1.83-6.34) in the TTC population, compared with the age- and sex-specific mortality of the general population.

The study is limited by a lack of patients with subclinical TTC disease and those who might have suffered from sudden cardiac death prior to enrollment, leading to a possible sampling bias, as well as the nonrandomized use of beta-blockers.

Bottom line: Tako-tsubo disease is associated with rare recurrence of the disease, common recurrence of chest pain and dyspnea, and three times the mortality rate of the general population.

Citation: Parodi G, Bellandi B, Del Pace S, et al. Natural history of tako-tsubo cardiomyopathy. Chest. 2011;139(4):887-892.

Seven Independent Risk Factors Predict Postoperative Pulmonary Complications

Clinical question: What are the clinical risk factors that predict higher rates of postoperative pulmonary complications?

Background: Postoperative pulmonary complications (PPCs) are a major cause of postoperative morbidity, mortality, and prolonged hospital stays. Previous studies looking at risk factors for PPCs were limited by sampling bias and small sample sizes.

Study design: Prospective, randomized-sample cohort study.

Setting: Fifty-nine participating Spanish hospitals (community, intermediate referral, or major tertiary-care facilities).

Synopsis: Patients undergoing surgical procedures with general, neuraxial, or regional anesthesia were selected randomly. The main outcome was the development of at least one of the following: respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis. Of 2,464 patients enrolled, 252 events were observed in 123 patients (5%). The 30-day mortality rate was significantly higher in patients suffering a PPC than those who did not (19.5% vs. 0.5%). Additionally, regression modeling identified seven independent risk factors: low preoperative arterial oxygen saturation, acute respiratory infection within one month of surgery, advanced age, preoperative anemia, upper abdominal or intrathoracic surgery, surgical duration more than two hours, and emergency surgery.

The study was underpowered to assess the significance of all potential risk factors for PPCs. Also, given the number of centers involved in the study, variation in assessing development of PPCs is likely.

Bottom line: Postoperative pulmonary complications are a major cause of morbidity and mortality. Seven independent risk factors were identified for the development of PPCs, which could be useful in preoperative risk stratification.

Citation: Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113(6):1338-1350.

Code Status Orders and Goals of Medical ICU Care

Clinical question: How familiar are patients in the medical ICU (MICU) or their surrogates regarding code-status orders and goals of care, what are their preferences, and to what extent do they and their physicians differ?

Background: Discussions about code-status orders and goals of care carry great import in the MICU. However, little data exist on patients’ code-status preferences and goals of care. More knowledge of these issues can help physicians deliver more patient-centered care.

Study design: Prospective interviews.

Setting: Twenty-six-bed MICU at a large Midwestern academic medical center.

Synopsis: Data were collected from December 2008 to December 2009 on a random sample of patients—or their surrogates—admitted to the MICU. Of 135 eligible patients/surrogates, 100 completed interviews. Patients primarily were white (95%) and from the ages of 41 to 80 (79%).

Only 28% of participants recalled having a discussion about CPR and one goal of care, while 27% recalled no discussion at all; 83% preferred full code status but had limited knowledge of CPR and its outcomes in the hospital setting. Only 4% were able to identify all components of CPR, and they estimated the mean probability of survival following in-hospital arrest with CPR to be 71.8%, although data suggest survival is closer to 18%. There was a correlation between a higher estimation of survival following CPR and preference for it. After learning about the evidence-based likelihood of a good neurologic outcome following CPR, 8% of the participants became less interested.

Discrepancies between patients’ stated code status and that in the medical record was identified 16% of the time. Additionally, 67.7% of participants differed with their physicians regarding the most important goal of care.

Bottom line: Discussions about code status and goals of care in the MICU occur less frequently than recommended, leading to widespread discrepancies between patients/surrogates and their physicians regarding the most important goal of care. This is compounded by the fact that patients and their surrogates have limited knowledge about in-hospital CPR and its likelihood of success.

Citation: Gehlbach TG, Shinkunas LA, Forman-Hoffman VL, Thomas KW, Schmidt GA, Kaldjian LC. Code status orders and goals of care in the medical ICU. Chest. 2011;139:802-809. TH

In This Edition

Literature At A Glance

A guide to this month’s studies

1. Screening for AAA
2. Adverse events in atrial fibrillation
3. Biological treatment of inflammatory bowel diseases
4. Steroid treatment of inflammatory bowel diseases
5. Levofloxacin for H. pylori
6. Natural history of tako-tsubo cardiomyopathy
7. Predicting postoperative pulmonary complications
8. Code status and goals of care in the ICU

New Screening Strategy To Identify Large Abdominal Aortic Aneurysms

Clinical question: Can an effective scoring system be developed to better identify patients at risk for large abdominal aortic aneurysms (AAA)?

Background: Screening reduces AAA-related mortality by about half in men aged >65. The United States Preventive Services Task Force (USPSTF) has recommended screening for AAA in men aged 65 to 75 with a history of smoking. However, more than 50% of AAA ruptures occur in individuals outside this patient cohort, and only some AAAs detected are large enough to warrant surgery.

Study design: Retrospective, observational cohort study.

Setting: More than 20,000 screening sites across the U.S.

Synopsis: Researchers collected demographics and risk factors from 3.1 million people undergoing ultrasound screening for AAA by Life Line Screening Inc. At the screening visit, subjects completed a questionnaire about their health status and medical history. Screening data also included diameter of the infrarenal abdominal aorta. To construct and test a risk model, the screened individuals were randomly allocated into two equal groups: a data set used for model development and one for validation.

Most of the AAAs greater than 5 cm in diameter discovered were in males (84.4%) and among subjects with a smoking history (83%). Other risk factors for large AAAs included advanced age, peripheral arterial disease, and obesity. The authors estimate that there are about 121,000 people with >5.0 cm aneurysms in the general population. Current guidelines would detect only 33.7% of the existing large AAAs. Study limitations include possible selection bias, as a majority of patients were self-referred. Also, the database did not include all comorbidities that could affect the risk of AAA. The self-reported nature of health data might cause misclassification of a patient’s true health status.

Bottom line: A screening strategy based on a newly developed scoring system is an effective way to identify patients at risk of large abdominal aortic aneurysms.

Citation: Greco G, Egorova NN, Gelijns AC, et al. Development of a novel scoring tool for the identification of large >5 cm abdominal aortic aneurysms. Ann Surg. 2010;252(4):675-682.

Risk Factors for Adverse Events in Patients with Symptomatic Atrial Fibrillation

Clinical question: What are the predictors of 30-day adverse events in ED patients evaluated for symptomatic atrial fibrillation?

Background: Atrial fibrillation (AF) affects more than 2 million people in the U.S. and accounts for nearly 1% of ED visits. Physicians have little information to guide risk stratification, and they admit more than 65% of patients. A strategy to better define the ED management of patients presenting with atrial fibrillation is required.

Study design: Retrospective, observational cohort study.

Setting: Urban academic tertiary-care referral center with an adult ED.

Synopsis: A systematic review of the electronic medical records of all ED patients presenting with symptomatic atrial fibrillation over a three-year period was performed. Predefined adverse outcomes included 30-day ED return visits, unscheduled hospitalizations, cardiovascular complications, or death.

Of 832 eligible patients, 216 (25.9%) experienced at least one of the 30-day adverse events. Adverse events occurred in 181 of the 638 (28.4%) admitted patients and 35 of the 192 (18.2%) patients discharged from the ED. Increasing age, complaint of dyspnea, smoking history, inadequate ventricular rate control, and patients receiving beta-blockers were factors independently associated with higher risk for adverse events.

Study results were limited by a number of factors. This was a single-center, retrospective, observational study, with all of its inherent limitations. The predictor model did not include laboratory data, such as BNP or troponin. Patients might have experienced additional events within the 30 days that were treated at other hospitals and not recorded in the database. Patient disposition might have affected the results, as patients initially admitted from the ED had a higher rate of 30-day adverse events than patients who were discharged from the ED.

Bottom line: Patients with increased age, smoking history, complaints of dyspnea, inadequate ventricular rate control in the ED, and home beta-blocker therapy are more likely to experience an atrial-fibrillation-related adverse event within 30 days.

Citation: Barrett TW, Martin AR, Storrow AB, et al. A clinical prediction model to estimate risk for 30-day adverse events in emergency department patients with symptomatic atrial fibrillation. Ann Emerg Med. 2011;57 (1):1-12.

Biological Therapies Are Effective in Inducing Remission in Inflammatory Bowel Disease

Clinical question: Are biological therapies useful in the treatment of ulcerative colitis (UC) and Crohn’s disease (CD)?

Background: Patients with CD and UC often experience flares of disease activity, despite maintenance therapy with 5-aminosalicylic acid compounds. These flares are usually treated with corticosteroids, which carry numerous adverse side effects. The role of biological therapies in inducing remission is uncertain.

Study design: Systematic review and meta-analysis.

Setting: Twenty-seven randomized controlled trials involving 7,416 patients.

Synopsis: Anti-TNF α antibodies and natalizumab were both superior to placebo in inducing remission of luminal CD (RR of no remission 0.87 and 0.88, respectively). Anti-TNF antibodies also were superior to placebo in preventing relapse of luminal CD (RR of relapse=0.71). Infliximab was superior to placebo in inducing remission of moderate to severely active UC (RR=0.72; 95% CI, 0.57-0.91). There were no significantly increased adverse drug effects with anti-TNF α antibodies or with infliximab compared with placebo. Natalizumab caused significantly higher rates of headache.

Limitations include risk of publication bias inherent in meta-analyses. There also was evidence of moderate heterogeneity in the studies analyzed. Finally, not every study was consistent in reporting adverse drug effects.

Bottom line: Biological therapies are superior to placebo in inducing remission of active UC and CD, as well as preventing relapse of quiescent CD.

Citation: Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011; 106(4):644-659.

Glucocortico­steroids Probably Effective in Treatment of Inflammatory Bowel Disease, Primarily in Active Ulcerative Colitis

Clinical question: Is glucocorticosteroid therapy effective in the treatment of active IBD and in preventing relapses?

Background: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases of unclear etiology. Use of standard glucocorticosteroids and budesonide is widespread in inflammatory bowel disease (IBD) treatment. To date, there has been no large-scale meta-analysis to examine the effectiveness of both treatments in CD and UC.

Study design: Systematic review and meta-analysis.

Setting: Twenty randomized controlled trials totaling 2,398 patients.

Synopsis: Standard glucocorticosteroids were superior to placebo for UC remission (RR of no remission=0.65; 95% CI, 0.45-0.93). Both trials of standard glucocorticosteroids in CD remission reported a statistically significant effect, but the overall effect was not significant due to heterogeneity of the studies. Budesonide was superior to placebo for CD remission (RR=0.73; 95% CI, 0.63-0.84) but not in preventing CD relapse (RR=0.93; 95% CI, 0.83-1.04). Standard glucocorticosteroids were superior to budesonide for CD remission (RR=0.82; 95% CI, 0.68-0.98) but with more adverse effects (RR=1.64; 95% CI, 1.34-2.00).

The limitations of the study include the poor overall quality of the studies included in the meta-analysis, with only one study judged as low risk of bias. There was intermediate to high heterogeneity between study results.

Bottom line: Standard glucocorticosteroids are likely effective in inducing remission in UC and, possibly, in CD. Budesonide probably is effective at inducing remission in active CD. Neither therapy was recommended in preventing relapse of UC and CD.

Citation: Ford AC, Bernstein CN, Khan KJ, et al. Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):590-599.

Levofloxacin Effective in Treatment of H. Pylori in Settings of High Clarithromycin Resistance

Clinical question: In areas with high H. pylori clarithromycin resistance rates, is levofloxacin more effective in eradicating H. pylori than standard clarithromycin, based treatment regimens?

Background: The rise in antimicrobial drug resistance is a major cause for the decreasing rate of H. pylori eradication. In areas with higher than 15% H. pyloriclarithromycin-resistant strains, quadruple therapy has been suggested as first-line therapy. The efficacy of a levofloxacin-based sequential therapy in eradicating H. pylori is undetermined.

Study design: Prospective, randomized, controlled multicenter study with a parallel-group design.

Setting: Five gastroenterology clinics in Italy.

Synopsis: Researchers randomly assigned 375 patients who were infected with H. pylori and naive to treatment to one of three groups. All three treatment groups received an initial five days of omeprazole 20 mg BID and amoxicillin 1 gm BID, then five days of omeprazole 20 mg BID and tinidazole 500 mg BID. The groups also received either clarithromycin 500 mg BID, levofloxacin 250 mg BID, or levofloxacin 500 mg BID, respectively, during the second five days of treatment.

Eradication rates were 80.8% (95% CI, 72.8% to 87.3%) with clarithromycin sequential therapy, 96.0% (95% CI, 90.9% to 98.7%) with levofloxacin-250 sequential therapy, and 96.8% (95% CI, 92.0% to 99.1%) with levofloxacin-500 sequential therapy.

The clarithromycin-group eradication rate was significantly lower than both levofloxacin groups. No significant difference was observed between the levofloxacin-250 and levofloxacin-500 groups. No differences in prevalence of antimicrobial resistance or incidence of adverse events were observed between the groups. Levofloxacin-250 therapy does offer cost savings when compared with clarithromycin sequential therapy.

A potential limitation to the study is referral bias, as each of the patients first were sent by their primary physicians to a specialized GI clinic.

Bottom line: In areas with a high prevalence of clarithromycin-resistant strains of H. pylori levofloxacin-containing sequential therapy should be considered for a first-line eradication regimen.

Citation: Romano M, Cuomo A, Gravina AG, et al. Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial. Gut. 2010;59(11):1465-1470.

Tako-Tsubo Cardiomyopathy Is Associated with Higher Hospital Readmission Rates and Long-Term Mortality

Clinical question: What is the natural history of patients who develop tako-tsubo cardiomyopathy?

Background: Stress-induced or tako-tsubo cardiomyopathy (TTC) is a rare acute cardiac syndrome, characterized by chest pain or dyspnea, ischemic electrocardiographic changes, transient left ventricular (LV) dysfunction, and limited release of cardiac injury markers, in the absence of epicardial coronary artery disease (CAD). The long-term outcome of this condition is unknown.

Study design: Prospective, case-control study.

Setting: Five urban-based hospitals in Italy.

Synopsis: One hundred-sixteen patients with TTC were included in the five-year study period. Patients were followed up at one and six months, then annually thereafter. Primary endpoints were death, TTC recurrence, and rehospitalization for any cause.

Mean initial LV ejection fraction (LVEF) was 36%. Two patients died of refractory heart failure during hospitalization. Of the patients who were discharged alive, all except one showed complete LV functional recovery.

At follow-up (mean two years), only 64 (55%) patients were asymptomatic. Rehospitalization rate was high (25%), with chest pain and dyspnea the most common causes. Only two patients had a recurrence of TTC. Eleven patients died (seven from cardiovascular causes). There was no significant difference in mortality or in other clinical events between patients with and without severe LV dysfunction at presentation. The standardized mortality ratio was 3.40 (95% CI, 1.83-6.34) in the TTC population, compared with the age- and sex-specific mortality of the general population.

The study is limited by a lack of patients with subclinical TTC disease and those who might have suffered from sudden cardiac death prior to enrollment, leading to a possible sampling bias, as well as the nonrandomized use of beta-blockers.

Bottom line: Tako-tsubo disease is associated with rare recurrence of the disease, common recurrence of chest pain and dyspnea, and three times the mortality rate of the general population.

Citation: Parodi G, Bellandi B, Del Pace S, et al. Natural history of tako-tsubo cardiomyopathy. Chest. 2011;139(4):887-892.

Seven Independent Risk Factors Predict Postoperative Pulmonary Complications

Clinical question: What are the clinical risk factors that predict higher rates of postoperative pulmonary complications?

Background: Postoperative pulmonary complications (PPCs) are a major cause of postoperative morbidity, mortality, and prolonged hospital stays. Previous studies looking at risk factors for PPCs were limited by sampling bias and small sample sizes.

Study design: Prospective, randomized-sample cohort study.

Setting: Fifty-nine participating Spanish hospitals (community, intermediate referral, or major tertiary-care facilities).

Synopsis: Patients undergoing surgical procedures with general, neuraxial, or regional anesthesia were selected randomly. The main outcome was the development of at least one of the following: respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis. Of 2,464 patients enrolled, 252 events were observed in 123 patients (5%). The 30-day mortality rate was significantly higher in patients suffering a PPC than those who did not (19.5% vs. 0.5%). Additionally, regression modeling identified seven independent risk factors: low preoperative arterial oxygen saturation, acute respiratory infection within one month of surgery, advanced age, preoperative anemia, upper abdominal or intrathoracic surgery, surgical duration more than two hours, and emergency surgery.

The study was underpowered to assess the significance of all potential risk factors for PPCs. Also, given the number of centers involved in the study, variation in assessing development of PPCs is likely.

Bottom line: Postoperative pulmonary complications are a major cause of morbidity and mortality. Seven independent risk factors were identified for the development of PPCs, which could be useful in preoperative risk stratification.

Citation: Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113(6):1338-1350.

Code Status Orders and Goals of Medical ICU Care

Clinical question: How familiar are patients in the medical ICU (MICU) or their surrogates regarding code-status orders and goals of care, what are their preferences, and to what extent do they and their physicians differ?

Background: Discussions about code-status orders and goals of care carry great import in the MICU. However, little data exist on patients’ code-status preferences and goals of care. More knowledge of these issues can help physicians deliver more patient-centered care.

Study design: Prospective interviews.

Setting: Twenty-six-bed MICU at a large Midwestern academic medical center.

Synopsis: Data were collected from December 2008 to December 2009 on a random sample of patients—or their surrogates—admitted to the MICU. Of 135 eligible patients/surrogates, 100 completed interviews. Patients primarily were white (95%) and from the ages of 41 to 80 (79%).

Only 28% of participants recalled having a discussion about CPR and one goal of care, while 27% recalled no discussion at all; 83% preferred full code status but had limited knowledge of CPR and its outcomes in the hospital setting. Only 4% were able to identify all components of CPR, and they estimated the mean probability of survival following in-hospital arrest with CPR to be 71.8%, although data suggest survival is closer to 18%. There was a correlation between a higher estimation of survival following CPR and preference for it. After learning about the evidence-based likelihood of a good neurologic outcome following CPR, 8% of the participants became less interested.

Discrepancies between patients’ stated code status and that in the medical record was identified 16% of the time. Additionally, 67.7% of participants differed with their physicians regarding the most important goal of care.

Bottom line: Discussions about code status and goals of care in the MICU occur less frequently than recommended, leading to widespread discrepancies between patients/surrogates and their physicians regarding the most important goal of care. This is compounded by the fact that patients and their surrogates have limited knowledge about in-hospital CPR and its likelihood of success.

Citation: Gehlbach TG, Shinkunas LA, Forman-Hoffman VL, Thomas KW, Schmidt GA, Kaldjian LC. Code status orders and goals of care in the medical ICU. Chest. 2011;139:802-809. TH

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Clinical question: What is the effect of corticosteroid therapy on survival in severe alcoholic hepatitis?

Background: Previous meta-analyses have suggested a survival benefit of corticosteroid treatment restricted only to those patients with severe alcoholic hepatitis (AH), with little or no benefit in less severe disease. Other meta-analyses, however, have questioned the efficacy in AH regardless of disease severity.

Study design: Meta-analysis of individual patient data.

Setting: Five randomized controlled trials (RCT) enrolling 418 patients.

Synopsis: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n3), enteral nutrition (n1), or an antioxidant cocktail (n1). Researchers analyzed 221 patients allocated to corticosteroid treatment and 197 allocated to noncorticosteroid treatment. Twenty-eight-day survival was higher in corticosteroid treated patients than in noncorticosteroid-treated patients (79.97% vs. 65.76%, P=0.0005). A subgroup analysis was performed according to the Lille score. Patients were classified as complete responders, partial responders, and null responders. Corticosteroids had a significant effect on 28-day survival in complete responders and in partial responders, but not in null responders (91.16% vs. 79.46% vs. 53.36%, P<0.0001)

Bottom line: Corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Citation: Mathurin P, O'Grady J, Carithers RL et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-260.

For more physician reviews of HM-related research, visit our website.

Literature at a Glance

A guide to this month’s studies

1. Risks of preoperative tobacco use
2. Timing of perioperative beta-blocker use and outcomes
3. Continuous vs. bolus dose diuretics in CHF
4. Outcomes of carotid endearterectomy and carotid artery stenting
5. Protocol for low-risk chest pain
6. Effect of esomeprazole on recurrent ulcer rates in clopidogrel users
7. Effect of ICU QI project on hospital mortality
8. Acute kidney injury risks after coronary angiography

Smokers Have Worse Perioperative Outcomes

Clinical question: Do current smokers have worse 30-day postoperative outcomes than nonsmokers after noncardiac surgery?

Background: Approximately 20% of adults in the U.S. smoke cigarettes, and a significant fraction of surgical patients are current smokers. Despite concerns that smoking is associated with worse postoperative outcomes, these increased risks have not been quantified across multiple outcomes.

Study design: Retrospective cohort study.

Setting: Surgical patients in 200 centers throughout the United States.

Synopsis: Data from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2008 were acquired, and 391,006 patient records were reviewed. Postoperative morbidity and mortality were significantly greater in smokers. Current smokers had a 40% increased odds of death at 30 days compared to people who had never smoked (OR 1.38, 95% CI, 1.11-1.72). Current smokers also had significantly greater odds of pulmonary complications, including pneumonia (OR 2.09, 95% CI, 1.80-2.43), unplanned intubation (OR 1.87, 95% CI, 1.58-2.21), and mechanical ventilation (OR 1.53, 95% CI, 1.31-1.79).

Furthermore, current smokers had significantly greater odds of postoperative cardiac arrest (OR 1.57, 95% CI, 1.10-2.25), myocardial infarction (OR 1.80, 95% CI, 1.11-2.25), and stroke (OR 1.73, 95% CI, 1.18-2.53). Odds of infectious complications were increased in current smokers, including deep incisional infections (OR 1.42, 95% CI, 1.21-1.68), sepsis (OR 1.30, 95% CI, 1.20-1.60), and septic shock (OR 1.55, 95% CI, 1.29-1.87).

Limitations of this study include self-reporting of smoking habits and absence of detailed smoking history just before and after surgery.

Bottom line: Current smokers have significantly increased postoperative morbidity and mortality after noncardiac surgery.

Citation: Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology. 2011;114(4):837-846.

Chronic Beta-Blockade Reduces Postoperative Myocardial Ischemia

Clinical question: Does the timing of beta-blocker exposure affect cardiovascular outcomes in patients undergoing elective, noncardiac surgery?

Background: Several studies have demonstrated that beta-blockers are associated with decreased perioperative cardiovascular morbidity and mortality. Study designs have varied greatly, and differences in dosing and timing of beta-blocker administration have caused conflicting results. The question of when to initiate beta-blockers prior to surgery remains controversial.

Study design: Prospective cohort study.

Setting: Three academic medical centers in Canada.

Synopsis: Data from 1,398 patients who had elective, noncardiac surgery with either acute (n=436) or chronic (n=962) beta-blocker exposure were analyzed. Acute exposure was defined as receiving a beta-blocker for the first time within 48 hours after surgery, whereas chronic beta-blocker exposure was defined as receiving a beta-blocker seven to 10 days prior to surgery.

Patients with chronic beta-blocker exposure were more likely to have a history of coronary disease, heart failure, or hypertension and were more likely to be receiving statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors. The primary outcome was a composite of major cardiac events, including myocardial infarction, nonfatal cardiac arrest, and 30-day mortality.

Major cardiac events occurred more often in patients with acute versus chronic beta-blocker exposure in both the entire cohort (8.3% vs. 4.7%) and in the propensity-matched cohort (8.0% vs. 3.0%). Myocardial infarction accounted for the majority of cardiac events.

There are several limitations of this study: The sample size was small, the beta-blocker and dosage used varied, and the indication and exact duration of chronic beta-blocker therapy was unknown.

Bottom line: Chronic beta-blocker therapy reduces major cardiac events compared with acute beta-blocker therapy in patients undergoing elective, noncardiac surgery.

Citation: Ellenberger C, Tait G, Beattie WS. Chronic beta-blockade is associated with a better outcome after elective noncardiac surgery than acute beta-blockade: a single-center propensity-matched cohort study. Anesthesiology. 2011;114(4):817-823.

Continuous and Bolus Dosing of Furosemide Provides Similar Outcomes in Heart Failure

Clinical question: Does continuous infusion compared to bolus dosing of furosemide improve clinical outcomes in patients with acute decompensated heart failure?

Background: Diuresis with furosemide is commonly used to manage acute decompensated heart failure, but it is uncertain which dosing strategy is optimal. Continuous infusion of furosemide has been proposed as a more effective method of diuresis compared with bolus dosing, especially when higher doses are required, but data comparing the two strategies are limited.

Study design: Randomized, double-blind, controlled trial.

Setting: Twenty-six clinical sites in the U.S. and Canada.

Synopsis: Researchers randomized 308 patients with acute decompensated heart failure to either continuous or bolus intravenous dosing, which was calculated as either the equivalent of their daily oral dose (low-dose strategy) or 2.5 times their daily dose (high-dose strategy). Mean ejection fraction was 35%. Primary endpoints were patients’ assessment of symptoms based on a visual-analogue scale quantified as area under the curve, as well as change in serum creatinine level at 72 hours.

No significant differences between the continuous and bolus dosing groups were evidenced in primary endpoints at 72 hours. Patients in the bolus group had more dose increases at 48 hours (21% vs. 11%, P=0.01). Patients in the high-dose group were more likely to change from intravenous to oral doses at 48 hours (31% vs. 17%, P<0.001) and had greater net fluid loss (4.9L vs. 3.6L, P=0.01). More patients in the high-dose versus low-dose group had an increase in creatinine ≥0.3 mg/dL (23% vs. 14%, P=0.04). Hospital length of stay, readmission, and mortality rates were similar between the groups.

Bottom line: Diuretic therapy administered by continuous infusion or bolus dosing in patients with acute decompensated heart failure have equivocal effects on patients’ symptoms and kidney function.

Citation: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805.

Carotid Endarterectomy Is Better than Carotid Artery Stenting

Clinical question: How do the clinical outcomes of carotid artery stenting compare with those of carotid endarterectomy?

Background: Whether carotid artery stenting or carotid endarterectomy is the preferred therapy for patients with carotid artery stenosis has been highly controversial. This study was a meta-analysis of all available data from randomized trials comparing carotid endarterectomy to carotid artery stenting.

Study design: Meta-analysis.

Setting: Teaching and nonteaching hospitals.

Synopsis: Thirteen randomized trials were identified with 3,723 patients who had undergone endarterectomy and 3,754 patients who had undergone carotid artery stenting. Outcomes included stroke, myocardial infarction, cranial nerve injury, and death or stroke, and these outcomes were divided as either short-term (<30 days) or long-term (>1 year) outcomes.

Patients who had undergone carotid artery stenting had less risk of short-term myocardial infarction (OR 0.48, 95% CI, 0.29–9.78, P=0.003) and less risk of cranial nerve injury (OR 0.09, 95% CI, 0.05–0.16, P<0.001). However, carotid artery stenting had a significantly higher risk of short-term stroke and combined death or stroke, and also significantly higher long-term risk of stroke and combined death or stroke. The association between carotid artery stenting and stroke was stronger in the subgroup of patients >68 years but not in patients <68 years. There was no significant heterogeneity, and no significant modifying associations were revealed by meta-regression analysis.

Limitations include potentially unpublished small studies favoring carotid endarterectomy and a significant publication bias regarding short-term death.

Bottom line: Although carotid artery stenting has less short-term risk of myocardial infarction and cranial nerve injury, carotid endarterectomy has less short-term and long-term risks of stroke and death.

Citation: Economopoulus KP, Sergentanis TN, Tsivgoulis G, Mariolis AD, Stefanadis C. Carotid artery stenting versus carotid endarterectomy: a comprehensive meta-analysis of short-term and long-term outcomes. Stroke. 2011;42:687-692.

Chest Pain Protocol Can Identify Low-Risk Chest Pain in Emergency Departments

Clinical question: Can a two-hour accelerated diagnostic protocol (ADP) based on electrocardiogram, point-of-care biomarkers, and Thrombolysis in Myocardial Infarction (TIMI) score safely identify patients with chest pain at very low short-term risk of major cardiac events?

Background: Evaluation of patients presenting to EDs with chest pain utilize significant amounts of hospital resources. A safe, reproducible, and expeditious process to identify patients at low risk for short-term cardiac events is desired.

Study design: Prospective cohort study.

Setting: Fourteen urban EDs in nine countries across the Asia-Pacific region.

Synopsis: The study included 3,582 patients presenting to an ED with at least five minutes of chest pain suggestive of an acute coronary syndrome and for whom further evaluation with serial cardiac biomarkers was planned. A negative ADP was defined as TIMI score of 0, no new ischemic changes on initial electrocardiogram, and normal cardiac biomarkers at zero and two hours after arrival.

All components of the ADP were negative for 352 patients (9.8%). Only three low-risk patients (0.9%) by ADP had a major cardiac event during the 30-day follow-up period, yielding a negative predictive value of 99.1% (95% CI, 97.3-99.8%). Mean hospital stay for the low-risk group with a negative ADP was 43 hours with a median of 26 hours. The authors suggest that a 10% reduction in prolonged workups of patients with chest pain could be seen with implementation of this protocol.

Potential limitations include applicability only to a select cohort of patients with chest pain and the low specificity of the protocol.

Bottom line: A two-hour diagnostic protocol can help expedite discharge of patients with very-low-risk chest pain.

Citation: Than T, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;337:1077-1084.

Esomeprazole Reduces Peptic Ulcer Recurrence in Patients on Clopidogrel

Clinical question: Does esomeprazole prevent recurrent peptic ulcers in patients with atherosclerosis on clopidogrel?

Background: Although clopidogrel is sometimes used as an alternative antiplatelet agent to aspirin, a significant rate of recurrent ulcer bleeding on clopidogrel has been described. No previous prospective trial has studied whether a proton-pump inhibitor (PPI) can reduce the risk of peptic ulcer recurrence or bleeding in atherosclerotic patients on clopidogrel.

Study design: Randomized controlled trial.

Setting: A single veterans hospital in Taiwan.

Synopsis: One hundred sixty-five patients were enrolled with a past history of peptic ulcer disease, no signs of ulcer recurrence by endoscopy, and current use of clopidogrel 37.5 mg to 75 mg per day. All patients had atherosclerosis and had been on clopidogrel for at least two weeks, without aspirin, corticosteroids, anticoagulants, or recent treatment with a PPI. Patients were randomized to clopidogrel 75 mg at night (n=82) or clopidogrel 75 mg at night plus esomeprazole 20 mg before breakfast. Follow-up endoscopy was performed at six months or as needed for symptoms.

Recurrence of ulcer was found in 1.2% of patients on clopidogrel plus esomeprazole versus 11.0% in patients on clopidogrel alone (95% CI, 2.6-17.0%; P=0.009). The pharmacodynamic study revealed no significant differences in platelet aggregation within or between treatment groups on day 1 or day 28. No significant differences were seen on the incidence of ischemic events in this setting, but the trial was underpowered to draw conclusions on this outcome.

An important limitation is that the findings of this study are applicable only to patients on clopidogrel monotherapy and not dual antiplatelet therapy.

Bottom line: A significant reduction in recurrent peptic ulcers is seen with the combination of esomeprazole plus clopidogrel, versus clopidogrel alone, in patients with atherosclerosis and a history of peptic ulcer disease.

Citation: Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology. 2011;140:791-798.

ICU Quality-Improvement Project Reduces Hospital Mortality

Clinical question: Does a quality-improvement (QI) project in the ICU reduce in-hospital mortality and length of stay among elderly adults?

Background: Previous studies have shown that ICU-acquired infections are associated with increased morbidity and mortality, and QI initiatives reduce hospital-acquired infections. However, it has not been demonstrated that QI projects in the ICU reduce in-hospital mortality or length of stay.

Study design: Retrospective cohort study.

Setting: Four hundred fifty-nine Midwestern hospitals.

Synopsis: This study included 238,937 adults age >65 who were hospitalized in an ICU from 2001 to 2006 at one of 95 hospitals invited to implement the Keystone ICU Project. The control group included 1,091,547 elderly adults at one of 364 hospitals not invited to participate in the project. The Keystone ICU Project implements evidence-based practices to reduce rates of catheter-related bloodstream infections and ventilator-associated pneumonia.

Hospital mortality was not significantly reduced during initiation or implementation of the project; however, a significant reduction in hospital mortality occurred in the study group during one to 12 months post-implementation (OR=0.83 vs. 0.88, P=0.041) and 13 to 22 months post-implementation (OR=0.76 vs. 0.84, P=0.007). In contrast, length of stay did not differ significantly between the two groups, but the study was underpowered for this outcome.

The study is limited by the complexity of the Keystone ICU Project, as well as the exclusion of smaller hospitals and nonelderly adults. The study is promising because implementing a QI project in the ICU is associated with no known harms and might confer a mortality benefit at a relatively low cost.

Bottom line: Elderly adults had lower in-hospital mortality after implementation of the Keystone QI project in ICUs.

Citation: Lipitz-Snyderman A, Steinwachs D, Needham DM, Colantuoni E, Morlock LL, Pronovost PJ. Impact of a statewide intensive care unit quality improvement initiative on hospital mortality and length of stay: retrospective comparative analysis. BMJ. 2011;342:d219.

Serious Long-Term Risks with Acute Kidney Injury after Coronary Angiography

Clinical question: Does postcoronary angiography acute kidney injury (AKI) increase the risk of poor long-term clinical outcomes?

Background: Previous studies have shown that AKI following coronary angiography increases the risk of poor short-term clinical outcomes, such as in-hospital myocardial infarction, prolonged hospital stay, and early mortality. Little is known about the long-term cardiovascular and renal outcomes following post-coronary angiography AKI.

Study design: Retrospective cohort study.

Setting: All coronary angiography centers in Alberta, Canada.

Synopsis: The study included 14,782 adults who were ≥18 years of age, underwent coronary angiography, had a baseline creatinine measurement, did not have end-stage renal disease (ESRD), and had a creatinine measurement within seven days after coronary angiography.

During a median follow-up period of 19.7 months, 1,099 (7.4%) patients developed stage 1 AKI and 321 (2.2%) developed stage 2 or 3 AKI. Mortality increased twofold with stage 1 AKI and >3-fold with stage 2 or 3 AKI. Risk of ESRD increased substantially by >11-fold in patients with stage 2 or 3 AKI. Risk of hospitalization for subsequent AKI, myocardial infarction, and heart failure also increased significantly following post-coronary angiography AKI.

Patients who experienced AKI were older, had more severe CAD, were more likely to have such comorbidities as DM, HTN, and heart failure, and had lower baseline GFRs. However, the underlying comorbidities do not completely explain the increased risk of poor long-term outcomes in the adjusted analysis.

Limitations include missing or underestimating mild cases of AKI, residual confounding from unmeasured variables, and inability of retrospective comparative studies to establish causality.

Bottom line: Adults with post-coronary angiography AKI are at increased risk of poor long-term cardiovascular and renal outcomes.

Citation: James MT, Ghali WA, Knudtson ML, et al. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation. 2011;123(4):409-416. TH

Pediatric HM Literature

Proton-Pump Inhibitors Ineffective for Gastroesophageal Reflux Disease in Children

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: What is the efficacy of proton-pump inhibitors (PPIs) in children with gastroesophageal reflux disease (GERD)?

Background: Gastroesophageal reflux is both a common and normal phenomenon in infants. GERD refers to the presence of abnormal symptoms ascribed to the reflux and frequently is treated in children in a manner similar to adults with reflux esophagitis. PPIs often are prescribed as front-line treatment, and their use has increased dramatically in recent years, though their effectiveness in children remains unclear.

Study design: Systematic review of the literature.

Setting: Hawaii’s largest health insurer.

Synopsis: Medline, Embase, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs) and crossover studies performed to evaluate the efficacy of PPIs in children 0-17 years with GERD and no complicating diseases. Ten RCTs and two crossover studies were analyzed and rated independently by two reviewers.

Due to significant heterogeneity between the studies, a meta-analysis was not possible; studies were discussed separately. PPIs offered no advantage when compared with controls (alginates, ranitidine, different dosages of PPIs), and similar rates of adverse events were reported between treatment groups.

This study is hampered by notable heterogeneity of patient type, symptoms, and study design in many of the trials. However, the results are in line with discussions at a recent FDA Gastrointestinal Drugs Advisory Committee meeting, which reviewed the lack of efficacy of PPIs in infants in four recent Phase 3 clinical trials.

Bottom line: Little evidence supports the widespread use of PPIs in children.

Citation: Van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, Tabbers MM, Benninga MA. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935.

Literature at a Glance

A guide to this month’s studies

1. Risks of preoperative tobacco use
2. Timing of perioperative beta-blocker use and outcomes
3. Continuous vs. bolus dose diuretics in CHF
4. Outcomes of carotid endearterectomy and carotid artery stenting
5. Protocol for low-risk chest pain
6. Effect of esomeprazole on recurrent ulcer rates in clopidogrel users
7. Effect of ICU QI project on hospital mortality
8. Acute kidney injury risks after coronary angiography

Smokers Have Worse Perioperative Outcomes

Clinical question: Do current smokers have worse 30-day postoperative outcomes than nonsmokers after noncardiac surgery?

Background: Approximately 20% of adults in the U.S. smoke cigarettes, and a significant fraction of surgical patients are current smokers. Despite concerns that smoking is associated with worse postoperative outcomes, these increased risks have not been quantified across multiple outcomes.

Study design: Retrospective cohort study.

Setting: Surgical patients in 200 centers throughout the United States.

Synopsis: Data from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2008 were acquired, and 391,006 patient records were reviewed. Postoperative morbidity and mortality were significantly greater in smokers. Current smokers had a 40% increased odds of death at 30 days compared to people who had never smoked (OR 1.38, 95% CI, 1.11-1.72). Current smokers also had significantly greater odds of pulmonary complications, including pneumonia (OR 2.09, 95% CI, 1.80-2.43), unplanned intubation (OR 1.87, 95% CI, 1.58-2.21), and mechanical ventilation (OR 1.53, 95% CI, 1.31-1.79).

Furthermore, current smokers had significantly greater odds of postoperative cardiac arrest (OR 1.57, 95% CI, 1.10-2.25), myocardial infarction (OR 1.80, 95% CI, 1.11-2.25), and stroke (OR 1.73, 95% CI, 1.18-2.53). Odds of infectious complications were increased in current smokers, including deep incisional infections (OR 1.42, 95% CI, 1.21-1.68), sepsis (OR 1.30, 95% CI, 1.20-1.60), and septic shock (OR 1.55, 95% CI, 1.29-1.87).

Limitations of this study include self-reporting of smoking habits and absence of detailed smoking history just before and after surgery.

Bottom line: Current smokers have significantly increased postoperative morbidity and mortality after noncardiac surgery.

Citation: Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology. 2011;114(4):837-846.

Chronic Beta-Blockade Reduces Postoperative Myocardial Ischemia

Clinical question: Does the timing of beta-blocker exposure affect cardiovascular outcomes in patients undergoing elective, noncardiac surgery?

Background: Several studies have demonstrated that beta-blockers are associated with decreased perioperative cardiovascular morbidity and mortality. Study designs have varied greatly, and differences in dosing and timing of beta-blocker administration have caused conflicting results. The question of when to initiate beta-blockers prior to surgery remains controversial.

Study design: Prospective cohort study.

Setting: Three academic medical centers in Canada.

Synopsis: Data from 1,398 patients who had elective, noncardiac surgery with either acute (n=436) or chronic (n=962) beta-blocker exposure were analyzed. Acute exposure was defined as receiving a beta-blocker for the first time within 48 hours after surgery, whereas chronic beta-blocker exposure was defined as receiving a beta-blocker seven to 10 days prior to surgery.

Patients with chronic beta-blocker exposure were more likely to have a history of coronary disease, heart failure, or hypertension and were more likely to be receiving statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors. The primary outcome was a composite of major cardiac events, including myocardial infarction, nonfatal cardiac arrest, and 30-day mortality.

Major cardiac events occurred more often in patients with acute versus chronic beta-blocker exposure in both the entire cohort (8.3% vs. 4.7%) and in the propensity-matched cohort (8.0% vs. 3.0%). Myocardial infarction accounted for the majority of cardiac events.

There are several limitations of this study: The sample size was small, the beta-blocker and dosage used varied, and the indication and exact duration of chronic beta-blocker therapy was unknown.

Bottom line: Chronic beta-blocker therapy reduces major cardiac events compared with acute beta-blocker therapy in patients undergoing elective, noncardiac surgery.

Citation: Ellenberger C, Tait G, Beattie WS. Chronic beta-blockade is associated with a better outcome after elective noncardiac surgery than acute beta-blockade: a single-center propensity-matched cohort study. Anesthesiology. 2011;114(4):817-823.

Continuous and Bolus Dosing of Furosemide Provides Similar Outcomes in Heart Failure

Clinical question: Does continuous infusion compared to bolus dosing of furosemide improve clinical outcomes in patients with acute decompensated heart failure?

Background: Diuresis with furosemide is commonly used to manage acute decompensated heart failure, but it is uncertain which dosing strategy is optimal. Continuous infusion of furosemide has been proposed as a more effective method of diuresis compared with bolus dosing, especially when higher doses are required, but data comparing the two strategies are limited.

Study design: Randomized, double-blind, controlled trial.

Setting: Twenty-six clinical sites in the U.S. and Canada.

Synopsis: Researchers randomized 308 patients with acute decompensated heart failure to either continuous or bolus intravenous dosing, which was calculated as either the equivalent of their daily oral dose (low-dose strategy) or 2.5 times their daily dose (high-dose strategy). Mean ejection fraction was 35%. Primary endpoints were patients’ assessment of symptoms based on a visual-analogue scale quantified as area under the curve, as well as change in serum creatinine level at 72 hours.

No significant differences between the continuous and bolus dosing groups were evidenced in primary endpoints at 72 hours. Patients in the bolus group had more dose increases at 48 hours (21% vs. 11%, P=0.01). Patients in the high-dose group were more likely to change from intravenous to oral doses at 48 hours (31% vs. 17%, P<0.001) and had greater net fluid loss (4.9L vs. 3.6L, P=0.01). More patients in the high-dose versus low-dose group had an increase in creatinine ≥0.3 mg/dL (23% vs. 14%, P=0.04). Hospital length of stay, readmission, and mortality rates were similar between the groups.

Bottom line: Diuretic therapy administered by continuous infusion or bolus dosing in patients with acute decompensated heart failure have equivocal effects on patients’ symptoms and kidney function.

Citation: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805.

Carotid Endarterectomy Is Better than Carotid Artery Stenting

Clinical question: How do the clinical outcomes of carotid artery stenting compare with those of carotid endarterectomy?

Background: Whether carotid artery stenting or carotid endarterectomy is the preferred therapy for patients with carotid artery stenosis has been highly controversial. This study was a meta-analysis of all available data from randomized trials comparing carotid endarterectomy to carotid artery stenting.

Study design: Meta-analysis.

Setting: Teaching and nonteaching hospitals.

Synopsis: Thirteen randomized trials were identified with 3,723 patients who had undergone endarterectomy and 3,754 patients who had undergone carotid artery stenting. Outcomes included stroke, myocardial infarction, cranial nerve injury, and death or stroke, and these outcomes were divided as either short-term (<30 days) or long-term (>1 year) outcomes.

Patients who had undergone carotid artery stenting had less risk of short-term myocardial infarction (OR 0.48, 95% CI, 0.29–9.78, P=0.003) and less risk of cranial nerve injury (OR 0.09, 95% CI, 0.05–0.16, P<0.001). However, carotid artery stenting had a significantly higher risk of short-term stroke and combined death or stroke, and also significantly higher long-term risk of stroke and combined death or stroke. The association between carotid artery stenting and stroke was stronger in the subgroup of patients >68 years but not in patients <68 years. There was no significant heterogeneity, and no significant modifying associations were revealed by meta-regression analysis.

Limitations include potentially unpublished small studies favoring carotid endarterectomy and a significant publication bias regarding short-term death.

Bottom line: Although carotid artery stenting has less short-term risk of myocardial infarction and cranial nerve injury, carotid endarterectomy has less short-term and long-term risks of stroke and death.

Citation: Economopoulus KP, Sergentanis TN, Tsivgoulis G, Mariolis AD, Stefanadis C. Carotid artery stenting versus carotid endarterectomy: a comprehensive meta-analysis of short-term and long-term outcomes. Stroke. 2011;42:687-692.

Chest Pain Protocol Can Identify Low-Risk Chest Pain in Emergency Departments

Clinical question: Can a two-hour accelerated diagnostic protocol (ADP) based on electrocardiogram, point-of-care biomarkers, and Thrombolysis in Myocardial Infarction (TIMI) score safely identify patients with chest pain at very low short-term risk of major cardiac events?

Background: Evaluation of patients presenting to EDs with chest pain utilize significant amounts of hospital resources. A safe, reproducible, and expeditious process to identify patients at low risk for short-term cardiac events is desired.

Study design: Prospective cohort study.

Setting: Fourteen urban EDs in nine countries across the Asia-Pacific region.

Synopsis: The study included 3,582 patients presenting to an ED with at least five minutes of chest pain suggestive of an acute coronary syndrome and for whom further evaluation with serial cardiac biomarkers was planned. A negative ADP was defined as TIMI score of 0, no new ischemic changes on initial electrocardiogram, and normal cardiac biomarkers at zero and two hours after arrival.

All components of the ADP were negative for 352 patients (9.8%). Only three low-risk patients (0.9%) by ADP had a major cardiac event during the 30-day follow-up period, yielding a negative predictive value of 99.1% (95% CI, 97.3-99.8%). Mean hospital stay for the low-risk group with a negative ADP was 43 hours with a median of 26 hours. The authors suggest that a 10% reduction in prolonged workups of patients with chest pain could be seen with implementation of this protocol.

Potential limitations include applicability only to a select cohort of patients with chest pain and the low specificity of the protocol.

Bottom line: A two-hour diagnostic protocol can help expedite discharge of patients with very-low-risk chest pain.

Citation: Than T, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;337:1077-1084.

Esomeprazole Reduces Peptic Ulcer Recurrence in Patients on Clopidogrel

Clinical question: Does esomeprazole prevent recurrent peptic ulcers in patients with atherosclerosis on clopidogrel?

Background: Although clopidogrel is sometimes used as an alternative antiplatelet agent to aspirin, a significant rate of recurrent ulcer bleeding on clopidogrel has been described. No previous prospective trial has studied whether a proton-pump inhibitor (PPI) can reduce the risk of peptic ulcer recurrence or bleeding in atherosclerotic patients on clopidogrel.

Study design: Randomized controlled trial.

Setting: A single veterans hospital in Taiwan.

Synopsis: One hundred sixty-five patients were enrolled with a past history of peptic ulcer disease, no signs of ulcer recurrence by endoscopy, and current use of clopidogrel 37.5 mg to 75 mg per day. All patients had atherosclerosis and had been on clopidogrel for at least two weeks, without aspirin, corticosteroids, anticoagulants, or recent treatment with a PPI. Patients were randomized to clopidogrel 75 mg at night (n=82) or clopidogrel 75 mg at night plus esomeprazole 20 mg before breakfast. Follow-up endoscopy was performed at six months or as needed for symptoms.

Recurrence of ulcer was found in 1.2% of patients on clopidogrel plus esomeprazole versus 11.0% in patients on clopidogrel alone (95% CI, 2.6-17.0%; P=0.009). The pharmacodynamic study revealed no significant differences in platelet aggregation within or between treatment groups on day 1 or day 28. No significant differences were seen on the incidence of ischemic events in this setting, but the trial was underpowered to draw conclusions on this outcome.

An important limitation is that the findings of this study are applicable only to patients on clopidogrel monotherapy and not dual antiplatelet therapy.

Bottom line: A significant reduction in recurrent peptic ulcers is seen with the combination of esomeprazole plus clopidogrel, versus clopidogrel alone, in patients with atherosclerosis and a history of peptic ulcer disease.

Citation: Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology. 2011;140:791-798.

ICU Quality-Improvement Project Reduces Hospital Mortality

Clinical question: Does a quality-improvement (QI) project in the ICU reduce in-hospital mortality and length of stay among elderly adults?

Background: Previous studies have shown that ICU-acquired infections are associated with increased morbidity and mortality, and QI initiatives reduce hospital-acquired infections. However, it has not been demonstrated that QI projects in the ICU reduce in-hospital mortality or length of stay.

Study design: Retrospective cohort study.

Setting: Four hundred fifty-nine Midwestern hospitals.

Synopsis: This study included 238,937 adults age >65 who were hospitalized in an ICU from 2001 to 2006 at one of 95 hospitals invited to implement the Keystone ICU Project. The control group included 1,091,547 elderly adults at one of 364 hospitals not invited to participate in the project. The Keystone ICU Project implements evidence-based practices to reduce rates of catheter-related bloodstream infections and ventilator-associated pneumonia.

Hospital mortality was not significantly reduced during initiation or implementation of the project; however, a significant reduction in hospital mortality occurred in the study group during one to 12 months post-implementation (OR=0.83 vs. 0.88, P=0.041) and 13 to 22 months post-implementation (OR=0.76 vs. 0.84, P=0.007). In contrast, length of stay did not differ significantly between the two groups, but the study was underpowered for this outcome.

The study is limited by the complexity of the Keystone ICU Project, as well as the exclusion of smaller hospitals and nonelderly adults. The study is promising because implementing a QI project in the ICU is associated with no known harms and might confer a mortality benefit at a relatively low cost.

Bottom line: Elderly adults had lower in-hospital mortality after implementation of the Keystone QI project in ICUs.

Citation: Lipitz-Snyderman A, Steinwachs D, Needham DM, Colantuoni E, Morlock LL, Pronovost PJ. Impact of a statewide intensive care unit quality improvement initiative on hospital mortality and length of stay: retrospective comparative analysis. BMJ. 2011;342:d219.

Serious Long-Term Risks with Acute Kidney Injury after Coronary Angiography

Clinical question: Does postcoronary angiography acute kidney injury (AKI) increase the risk of poor long-term clinical outcomes?

Background: Previous studies have shown that AKI following coronary angiography increases the risk of poor short-term clinical outcomes, such as in-hospital myocardial infarction, prolonged hospital stay, and early mortality. Little is known about the long-term cardiovascular and renal outcomes following post-coronary angiography AKI.

Study design: Retrospective cohort study.

Setting: All coronary angiography centers in Alberta, Canada.

Synopsis: The study included 14,782 adults who were ≥18 years of age, underwent coronary angiography, had a baseline creatinine measurement, did not have end-stage renal disease (ESRD), and had a creatinine measurement within seven days after coronary angiography.

During a median follow-up period of 19.7 months, 1,099 (7.4%) patients developed stage 1 AKI and 321 (2.2%) developed stage 2 or 3 AKI. Mortality increased twofold with stage 1 AKI and >3-fold with stage 2 or 3 AKI. Risk of ESRD increased substantially by >11-fold in patients with stage 2 or 3 AKI. Risk of hospitalization for subsequent AKI, myocardial infarction, and heart failure also increased significantly following post-coronary angiography AKI.

Patients who experienced AKI were older, had more severe CAD, were more likely to have such comorbidities as DM, HTN, and heart failure, and had lower baseline GFRs. However, the underlying comorbidities do not completely explain the increased risk of poor long-term outcomes in the adjusted analysis.

Limitations include missing or underestimating mild cases of AKI, residual confounding from unmeasured variables, and inability of retrospective comparative studies to establish causality.

Bottom line: Adults with post-coronary angiography AKI are at increased risk of poor long-term cardiovascular and renal outcomes.

Citation: James MT, Ghali WA, Knudtson ML, et al. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation. 2011;123(4):409-416. TH

Pediatric HM Literature

Proton-Pump Inhibitors Ineffective for Gastroesophageal Reflux Disease in Children

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: What is the efficacy of proton-pump inhibitors (PPIs) in children with gastroesophageal reflux disease (GERD)?

Background: Gastroesophageal reflux is both a common and normal phenomenon in infants. GERD refers to the presence of abnormal symptoms ascribed to the reflux and frequently is treated in children in a manner similar to adults with reflux esophagitis. PPIs often are prescribed as front-line treatment, and their use has increased dramatically in recent years, though their effectiveness in children remains unclear.

Study design: Systematic review of the literature.

Setting: Hawaii’s largest health insurer.

Synopsis: Medline, Embase, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs) and crossover studies performed to evaluate the efficacy of PPIs in children 0-17 years with GERD and no complicating diseases. Ten RCTs and two crossover studies were analyzed and rated independently by two reviewers.

Due to significant heterogeneity between the studies, a meta-analysis was not possible; studies were discussed separately. PPIs offered no advantage when compared with controls (alginates, ranitidine, different dosages of PPIs), and similar rates of adverse events were reported between treatment groups.

This study is hampered by notable heterogeneity of patient type, symptoms, and study design in many of the trials. However, the results are in line with discussions at a recent FDA Gastrointestinal Drugs Advisory Committee meeting, which reviewed the lack of efficacy of PPIs in infants in four recent Phase 3 clinical trials.

Bottom line: Little evidence supports the widespread use of PPIs in children.

Citation: Van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, Tabbers MM, Benninga MA. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935.

Literature at a Glance

A guide to this month’s studies

1. Risks of preoperative tobacco use
2. Timing of perioperative beta-blocker use and outcomes
3. Continuous vs. bolus dose diuretics in CHF
4. Outcomes of carotid endearterectomy and carotid artery stenting
5. Protocol for low-risk chest pain
6. Effect of esomeprazole on recurrent ulcer rates in clopidogrel users
7. Effect of ICU QI project on hospital mortality
8. Acute kidney injury risks after coronary angiography

Smokers Have Worse Perioperative Outcomes

Clinical question: Do current smokers have worse 30-day postoperative outcomes than nonsmokers after noncardiac surgery?

Background: Approximately 20% of adults in the U.S. smoke cigarettes, and a significant fraction of surgical patients are current smokers. Despite concerns that smoking is associated with worse postoperative outcomes, these increased risks have not been quantified across multiple outcomes.

Study design: Retrospective cohort study.

Setting: Surgical patients in 200 centers throughout the United States.

Synopsis: Data from the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2008 were acquired, and 391,006 patient records were reviewed. Postoperative morbidity and mortality were significantly greater in smokers. Current smokers had a 40% increased odds of death at 30 days compared to people who had never smoked (OR 1.38, 95% CI, 1.11-1.72). Current smokers also had significantly greater odds of pulmonary complications, including pneumonia (OR 2.09, 95% CI, 1.80-2.43), unplanned intubation (OR 1.87, 95% CI, 1.58-2.21), and mechanical ventilation (OR 1.53, 95% CI, 1.31-1.79).

Furthermore, current smokers had significantly greater odds of postoperative cardiac arrest (OR 1.57, 95% CI, 1.10-2.25), myocardial infarction (OR 1.80, 95% CI, 1.11-2.25), and stroke (OR 1.73, 95% CI, 1.18-2.53). Odds of infectious complications were increased in current smokers, including deep incisional infections (OR 1.42, 95% CI, 1.21-1.68), sepsis (OR 1.30, 95% CI, 1.20-1.60), and septic shock (OR 1.55, 95% CI, 1.29-1.87).

Limitations of this study include self-reporting of smoking habits and absence of detailed smoking history just before and after surgery.

Bottom line: Current smokers have significantly increased postoperative morbidity and mortality after noncardiac surgery.

Citation: Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology. 2011;114(4):837-846.

Chronic Beta-Blockade Reduces Postoperative Myocardial Ischemia

Clinical question: Does the timing of beta-blocker exposure affect cardiovascular outcomes in patients undergoing elective, noncardiac surgery?

Background: Several studies have demonstrated that beta-blockers are associated with decreased perioperative cardiovascular morbidity and mortality. Study designs have varied greatly, and differences in dosing and timing of beta-blocker administration have caused conflicting results. The question of when to initiate beta-blockers prior to surgery remains controversial.

Study design: Prospective cohort study.

Setting: Three academic medical centers in Canada.

Synopsis: Data from 1,398 patients who had elective, noncardiac surgery with either acute (n=436) or chronic (n=962) beta-blocker exposure were analyzed. Acute exposure was defined as receiving a beta-blocker for the first time within 48 hours after surgery, whereas chronic beta-blocker exposure was defined as receiving a beta-blocker seven to 10 days prior to surgery.

Patients with chronic beta-blocker exposure were more likely to have a history of coronary disease, heart failure, or hypertension and were more likely to be receiving statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors. The primary outcome was a composite of major cardiac events, including myocardial infarction, nonfatal cardiac arrest, and 30-day mortality.

Major cardiac events occurred more often in patients with acute versus chronic beta-blocker exposure in both the entire cohort (8.3% vs. 4.7%) and in the propensity-matched cohort (8.0% vs. 3.0%). Myocardial infarction accounted for the majority of cardiac events.

There are several limitations of this study: The sample size was small, the beta-blocker and dosage used varied, and the indication and exact duration of chronic beta-blocker therapy was unknown.

Bottom line: Chronic beta-blocker therapy reduces major cardiac events compared with acute beta-blocker therapy in patients undergoing elective, noncardiac surgery.

Citation: Ellenberger C, Tait G, Beattie WS. Chronic beta-blockade is associated with a better outcome after elective noncardiac surgery than acute beta-blockade: a single-center propensity-matched cohort study. Anesthesiology. 2011;114(4):817-823.

Continuous and Bolus Dosing of Furosemide Provides Similar Outcomes in Heart Failure

Clinical question: Does continuous infusion compared to bolus dosing of furosemide improve clinical outcomes in patients with acute decompensated heart failure?

Background: Diuresis with furosemide is commonly used to manage acute decompensated heart failure, but it is uncertain which dosing strategy is optimal. Continuous infusion of furosemide has been proposed as a more effective method of diuresis compared with bolus dosing, especially when higher doses are required, but data comparing the two strategies are limited.

Study design: Randomized, double-blind, controlled trial.

Setting: Twenty-six clinical sites in the U.S. and Canada.

Synopsis: Researchers randomized 308 patients with acute decompensated heart failure to either continuous or bolus intravenous dosing, which was calculated as either the equivalent of their daily oral dose (low-dose strategy) or 2.5 times their daily dose (high-dose strategy). Mean ejection fraction was 35%. Primary endpoints were patients’ assessment of symptoms based on a visual-analogue scale quantified as area under the curve, as well as change in serum creatinine level at 72 hours.

No significant differences between the continuous and bolus dosing groups were evidenced in primary endpoints at 72 hours. Patients in the bolus group had more dose increases at 48 hours (21% vs. 11%, P=0.01). Patients in the high-dose group were more likely to change from intravenous to oral doses at 48 hours (31% vs. 17%, P<0.001) and had greater net fluid loss (4.9L vs. 3.6L, P=0.01). More patients in the high-dose versus low-dose group had an increase in creatinine ≥0.3 mg/dL (23% vs. 14%, P=0.04). Hospital length of stay, readmission, and mortality rates were similar between the groups.

Bottom line: Diuretic therapy administered by continuous infusion or bolus dosing in patients with acute decompensated heart failure have equivocal effects on patients’ symptoms and kidney function.

Citation: Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364(9):797-805.

Carotid Endarterectomy Is Better than Carotid Artery Stenting

Clinical question: How do the clinical outcomes of carotid artery stenting compare with those of carotid endarterectomy?

Background: Whether carotid artery stenting or carotid endarterectomy is the preferred therapy for patients with carotid artery stenosis has been highly controversial. This study was a meta-analysis of all available data from randomized trials comparing carotid endarterectomy to carotid artery stenting.

Study design: Meta-analysis.

Setting: Teaching and nonteaching hospitals.

Synopsis: Thirteen randomized trials were identified with 3,723 patients who had undergone endarterectomy and 3,754 patients who had undergone carotid artery stenting. Outcomes included stroke, myocardial infarction, cranial nerve injury, and death or stroke, and these outcomes were divided as either short-term (<30 days) or long-term (>1 year) outcomes.

Patients who had undergone carotid artery stenting had less risk of short-term myocardial infarction (OR 0.48, 95% CI, 0.29–9.78, P=0.003) and less risk of cranial nerve injury (OR 0.09, 95% CI, 0.05–0.16, P<0.001). However, carotid artery stenting had a significantly higher risk of short-term stroke and combined death or stroke, and also significantly higher long-term risk of stroke and combined death or stroke. The association between carotid artery stenting and stroke was stronger in the subgroup of patients >68 years but not in patients <68 years. There was no significant heterogeneity, and no significant modifying associations were revealed by meta-regression analysis.

Limitations include potentially unpublished small studies favoring carotid endarterectomy and a significant publication bias regarding short-term death.

Bottom line: Although carotid artery stenting has less short-term risk of myocardial infarction and cranial nerve injury, carotid endarterectomy has less short-term and long-term risks of stroke and death.

Citation: Economopoulus KP, Sergentanis TN, Tsivgoulis G, Mariolis AD, Stefanadis C. Carotid artery stenting versus carotid endarterectomy: a comprehensive meta-analysis of short-term and long-term outcomes. Stroke. 2011;42:687-692.

Chest Pain Protocol Can Identify Low-Risk Chest Pain in Emergency Departments

Clinical question: Can a two-hour accelerated diagnostic protocol (ADP) based on electrocardiogram, point-of-care biomarkers, and Thrombolysis in Myocardial Infarction (TIMI) score safely identify patients with chest pain at very low short-term risk of major cardiac events?

Background: Evaluation of patients presenting to EDs with chest pain utilize significant amounts of hospital resources. A safe, reproducible, and expeditious process to identify patients at low risk for short-term cardiac events is desired.

Study design: Prospective cohort study.

Setting: Fourteen urban EDs in nine countries across the Asia-Pacific region.

Synopsis: The study included 3,582 patients presenting to an ED with at least five minutes of chest pain suggestive of an acute coronary syndrome and for whom further evaluation with serial cardiac biomarkers was planned. A negative ADP was defined as TIMI score of 0, no new ischemic changes on initial electrocardiogram, and normal cardiac biomarkers at zero and two hours after arrival.

All components of the ADP were negative for 352 patients (9.8%). Only three low-risk patients (0.9%) by ADP had a major cardiac event during the 30-day follow-up period, yielding a negative predictive value of 99.1% (95% CI, 97.3-99.8%). Mean hospital stay for the low-risk group with a negative ADP was 43 hours with a median of 26 hours. The authors suggest that a 10% reduction in prolonged workups of patients with chest pain could be seen with implementation of this protocol.

Potential limitations include applicability only to a select cohort of patients with chest pain and the low specificity of the protocol.

Bottom line: A two-hour diagnostic protocol can help expedite discharge of patients with very-low-risk chest pain.

Citation: Than T, Cullen L, Reid CM, et al. A 2-h diagnostic protocol to assess patients with chest pain symptoms in the Asia-Pacific region (ASPECT): a prospective observational validation study. Lancet. 2011;337:1077-1084.

Esomeprazole Reduces Peptic Ulcer Recurrence in Patients on Clopidogrel

Clinical question: Does esomeprazole prevent recurrent peptic ulcers in patients with atherosclerosis on clopidogrel?

Background: Although clopidogrel is sometimes used as an alternative antiplatelet agent to aspirin, a significant rate of recurrent ulcer bleeding on clopidogrel has been described. No previous prospective trial has studied whether a proton-pump inhibitor (PPI) can reduce the risk of peptic ulcer recurrence or bleeding in atherosclerotic patients on clopidogrel.

Study design: Randomized controlled trial.

Setting: A single veterans hospital in Taiwan.

Synopsis: One hundred sixty-five patients were enrolled with a past history of peptic ulcer disease, no signs of ulcer recurrence by endoscopy, and current use of clopidogrel 37.5 mg to 75 mg per day. All patients had atherosclerosis and had been on clopidogrel for at least two weeks, without aspirin, corticosteroids, anticoagulants, or recent treatment with a PPI. Patients were randomized to clopidogrel 75 mg at night (n=82) or clopidogrel 75 mg at night plus esomeprazole 20 mg before breakfast. Follow-up endoscopy was performed at six months or as needed for symptoms.

Recurrence of ulcer was found in 1.2% of patients on clopidogrel plus esomeprazole versus 11.0% in patients on clopidogrel alone (95% CI, 2.6-17.0%; P=0.009). The pharmacodynamic study revealed no significant differences in platelet aggregation within or between treatment groups on day 1 or day 28. No significant differences were seen on the incidence of ischemic events in this setting, but the trial was underpowered to draw conclusions on this outcome.

An important limitation is that the findings of this study are applicable only to patients on clopidogrel monotherapy and not dual antiplatelet therapy.

Bottom line: A significant reduction in recurrent peptic ulcers is seen with the combination of esomeprazole plus clopidogrel, versus clopidogrel alone, in patients with atherosclerosis and a history of peptic ulcer disease.

Citation: Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology. 2011;140:791-798.

ICU Quality-Improvement Project Reduces Hospital Mortality

Clinical question: Does a quality-improvement (QI) project in the ICU reduce in-hospital mortality and length of stay among elderly adults?

Background: Previous studies have shown that ICU-acquired infections are associated with increased morbidity and mortality, and QI initiatives reduce hospital-acquired infections. However, it has not been demonstrated that QI projects in the ICU reduce in-hospital mortality or length of stay.

Study design: Retrospective cohort study.

Setting: Four hundred fifty-nine Midwestern hospitals.

Synopsis: This study included 238,937 adults age >65 who were hospitalized in an ICU from 2001 to 2006 at one of 95 hospitals invited to implement the Keystone ICU Project. The control group included 1,091,547 elderly adults at one of 364 hospitals not invited to participate in the project. The Keystone ICU Project implements evidence-based practices to reduce rates of catheter-related bloodstream infections and ventilator-associated pneumonia.

Hospital mortality was not significantly reduced during initiation or implementation of the project; however, a significant reduction in hospital mortality occurred in the study group during one to 12 months post-implementation (OR=0.83 vs. 0.88, P=0.041) and 13 to 22 months post-implementation (OR=0.76 vs. 0.84, P=0.007). In contrast, length of stay did not differ significantly between the two groups, but the study was underpowered for this outcome.

The study is limited by the complexity of the Keystone ICU Project, as well as the exclusion of smaller hospitals and nonelderly adults. The study is promising because implementing a QI project in the ICU is associated with no known harms and might confer a mortality benefit at a relatively low cost.

Bottom line: Elderly adults had lower in-hospital mortality after implementation of the Keystone QI project in ICUs.

Citation: Lipitz-Snyderman A, Steinwachs D, Needham DM, Colantuoni E, Morlock LL, Pronovost PJ. Impact of a statewide intensive care unit quality improvement initiative on hospital mortality and length of stay: retrospective comparative analysis. BMJ. 2011;342:d219.

Serious Long-Term Risks with Acute Kidney Injury after Coronary Angiography

Clinical question: Does postcoronary angiography acute kidney injury (AKI) increase the risk of poor long-term clinical outcomes?

Background: Previous studies have shown that AKI following coronary angiography increases the risk of poor short-term clinical outcomes, such as in-hospital myocardial infarction, prolonged hospital stay, and early mortality. Little is known about the long-term cardiovascular and renal outcomes following post-coronary angiography AKI.

Study design: Retrospective cohort study.

Setting: All coronary angiography centers in Alberta, Canada.

Synopsis: The study included 14,782 adults who were ≥18 years of age, underwent coronary angiography, had a baseline creatinine measurement, did not have end-stage renal disease (ESRD), and had a creatinine measurement within seven days after coronary angiography.

During a median follow-up period of 19.7 months, 1,099 (7.4%) patients developed stage 1 AKI and 321 (2.2%) developed stage 2 or 3 AKI. Mortality increased twofold with stage 1 AKI and >3-fold with stage 2 or 3 AKI. Risk of ESRD increased substantially by >11-fold in patients with stage 2 or 3 AKI. Risk of hospitalization for subsequent AKI, myocardial infarction, and heart failure also increased significantly following post-coronary angiography AKI.

Patients who experienced AKI were older, had more severe CAD, were more likely to have such comorbidities as DM, HTN, and heart failure, and had lower baseline GFRs. However, the underlying comorbidities do not completely explain the increased risk of poor long-term outcomes in the adjusted analysis.

Limitations include missing or underestimating mild cases of AKI, residual confounding from unmeasured variables, and inability of retrospective comparative studies to establish causality.

Bottom line: Adults with post-coronary angiography AKI are at increased risk of poor long-term cardiovascular and renal outcomes.

Citation: James MT, Ghali WA, Knudtson ML, et al. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation. 2011;123(4):409-416. TH

Pediatric HM Literature

Proton-Pump Inhibitors Ineffective for Gastroesophageal Reflux Disease in Children

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: What is the efficacy of proton-pump inhibitors (PPIs) in children with gastroesophageal reflux disease (GERD)?

Background: Gastroesophageal reflux is both a common and normal phenomenon in infants. GERD refers to the presence of abnormal symptoms ascribed to the reflux and frequently is treated in children in a manner similar to adults with reflux esophagitis. PPIs often are prescribed as front-line treatment, and their use has increased dramatically in recent years, though their effectiveness in children remains unclear.

Study design: Systematic review of the literature.

Setting: Hawaii’s largest health insurer.

Synopsis: Medline, Embase, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs) and crossover studies performed to evaluate the efficacy of PPIs in children 0-17 years with GERD and no complicating diseases. Ten RCTs and two crossover studies were analyzed and rated independently by two reviewers.

Due to significant heterogeneity between the studies, a meta-analysis was not possible; studies were discussed separately. PPIs offered no advantage when compared with controls (alginates, ranitidine, different dosages of PPIs), and similar rates of adverse events were reported between treatment groups.

This study is hampered by notable heterogeneity of patient type, symptoms, and study design in many of the trials. However, the results are in line with discussions at a recent FDA Gastrointestinal Drugs Advisory Committee meeting, which reviewed the lack of efficacy of PPIs in infants in four recent Phase 3 clinical trials.

Bottom line: Little evidence supports the widespread use of PPIs in children.

Citation: Van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, Tabbers MM, Benninga MA. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935.

Clinical question: Does the mortality rate differ between patients treated perioperatively with atenolol versus metoprolol?

Background: Perioperative beta-blockers have been shown to reduce mortality in patients with significant cardiac risk factors. Different beta-blockers have been used in the studies demonstrating benefit, and it is uncertain which beta-blocker is the preferred agent. The purpose of this study was to compare the perioperative benefits of metoprolol versus atenolol.

Study design: Retrospective cohort study.

Setting: San Francisco Veterans Affairs Medical Center.

Synopsis: Computerized records of patients who underwent surgery from 1996 to 2008 were extracted into a database, and patients who received inpatient beta-blockers after surgery were included. Of these patients, 3,787 received beta-blockade exclusively with either atenolol (n=1,011) or metoprolol (n=2,776) during hospitalization. Perioperative risk reduction was better with atenolol versus metoprolol. Mortality rates were 1% versus 3% at 30 days (P=0.0008), and 7% versus 13% at one year (P=<0.0001) with atenolol and metoprolol, respectively. Similar results were found in the analysis of 1,871 patients who were on their respective beta-blocker as an outpatient before surgery.

Because the metoprolol group had higher prevalence of risk factors, such as coronary artery disease, peripheral vascular disease, and congestive heart failure, a propensity-matched analysis was performed to remove differences in risk factors between the groups. After propensity matching, the metoprolol group still had statistically significant higher mortality at 30 days and one year, even though causality cannot be established in this retrospective study.

Bottom line: Atenolol was associated with fewer cases of perioperative mortality compared with metoprolol in patients with cardiac risk factors or established cardiovascular disease.

Citation: Wallace AW, Au S, Cason BA. Perioperative ß-blockade: atenolol is associated with reduced mortality when compared to metoprolol. Anesthesiology. 2011;114:824-836.

For more physician reviews of HM-related research, visit our website.

Clinical question: Does the mortality rate differ between patients treated perioperatively with atenolol versus metoprolol?

Background: Perioperative beta-blockers have been shown to reduce mortality in patients with significant cardiac risk factors. Different beta-blockers have been used in the studies demonstrating benefit, and it is uncertain which beta-blocker is the preferred agent. The purpose of this study was to compare the perioperative benefits of metoprolol versus atenolol.

Study design: Retrospective cohort study.

Setting: San Francisco Veterans Affairs Medical Center.

Synopsis: Computerized records of patients who underwent surgery from 1996 to 2008 were extracted into a database, and patients who received inpatient beta-blockers after surgery were included. Of these patients, 3,787 received beta-blockade exclusively with either atenolol (n=1,011) or metoprolol (n=2,776) during hospitalization. Perioperative risk reduction was better with atenolol versus metoprolol. Mortality rates were 1% versus 3% at 30 days (P=0.0008), and 7% versus 13% at one year (P=<0.0001) with atenolol and metoprolol, respectively. Similar results were found in the analysis of 1,871 patients who were on their respective beta-blocker as an outpatient before surgery.

Because the metoprolol group had higher prevalence of risk factors, such as coronary artery disease, peripheral vascular disease, and congestive heart failure, a propensity-matched analysis was performed to remove differences in risk factors between the groups. After propensity matching, the metoprolol group still had statistically significant higher mortality at 30 days and one year, even though causality cannot be established in this retrospective study.

Bottom line: Atenolol was associated with fewer cases of perioperative mortality compared with metoprolol in patients with cardiac risk factors or established cardiovascular disease.

Citation: Wallace AW, Au S, Cason BA. Perioperative ß-blockade: atenolol is associated with reduced mortality when compared to metoprolol. Anesthesiology. 2011;114:824-836.

For more physician reviews of HM-related research, visit our website.

Clinical question: Does the mortality rate differ between patients treated perioperatively with atenolol versus metoprolol?

Background: Perioperative beta-blockers have been shown to reduce mortality in patients with significant cardiac risk factors. Different beta-blockers have been used in the studies demonstrating benefit, and it is uncertain which beta-blocker is the preferred agent. The purpose of this study was to compare the perioperative benefits of metoprolol versus atenolol.

Study design: Retrospective cohort study.

Setting: San Francisco Veterans Affairs Medical Center.

Synopsis: Computerized records of patients who underwent surgery from 1996 to 2008 were extracted into a database, and patients who received inpatient beta-blockers after surgery were included. Of these patients, 3,787 received beta-blockade exclusively with either atenolol (n=1,011) or metoprolol (n=2,776) during hospitalization. Perioperative risk reduction was better with atenolol versus metoprolol. Mortality rates were 1% versus 3% at 30 days (P=0.0008), and 7% versus 13% at one year (P=<0.0001) with atenolol and metoprolol, respectively. Similar results were found in the analysis of 1,871 patients who were on their respective beta-blocker as an outpatient before surgery.

Because the metoprolol group had higher prevalence of risk factors, such as coronary artery disease, peripheral vascular disease, and congestive heart failure, a propensity-matched analysis was performed to remove differences in risk factors between the groups. After propensity matching, the metoprolol group still had statistically significant higher mortality at 30 days and one year, even though causality cannot be established in this retrospective study.

Bottom line: Atenolol was associated with fewer cases of perioperative mortality compared with metoprolol in patients with cardiac risk factors or established cardiovascular disease.

Citation: Wallace AW, Au S, Cason BA. Perioperative ß-blockade: atenolol is associated with reduced mortality when compared to metoprolol. Anesthesiology. 2011;114:824-836.

For more physician reviews of HM-related research, visit our website.

In This Edition

Literature at a Glance

A guide to this month’s studies

1. Eplerenone and heart failure mortality
2. Fidaxomicin for C. difficile diarrhea
3. Guidelines for intensive insulin therapy
4. Benefits of hospitalist comanagement
5. Peritoneal dialysis versus hemodialysis
6. Pneumococcal urinary antigen to guide CAP treatment
7. Race and readmission rate
8. Factors associated with readmission
9. Unplanned transfers to the ICU

Eplerenone Improves Mortality in Patients with Systolic Heart Failure and Mild Symptoms

Clinical question: Does the selective mineralocorticoid antagonist eplerenone improve outcomes in patients with chronic heart failure and mild symptoms?

Background: In prior studies of miner alocorticoid antagonists in systolic heart failure, spironolactone reduced mortality in patients with moderate to severe heart failure symptoms, and eplerenone reduced mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction. The use of eplerenone in patients with systolic heart failure and mild symptoms has not previously been examined.

Study design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: Two hundred seventy-eight centers in 29 countries.

Synopsis: The study authors randomized 2,737 patients with New York Heart Association Class II heart failure and an ejection fraction of no more than 35% to either eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patients with baseline potassium levels >5 mmol/L or estimated GFR <30 were excluded. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.

The trial was stopped early, after a median follow-up period of 21 months, when an interim analysis showed significant benefit with eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.74; P<0.001). All-cause mortality was 12.5% in the eplerenone group and 15.5% in the placebo group (HR 0.76; 95% CI, 0.62 to 0.93; P=0.008). A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).

Bottom line: Eplerenone reduces both the risk of death and the risk of hospitalization in patients with systolic heart failure and mild symptoms.

Citation: Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

Fidaxomicin Noninferior to Vancomycin for C. Difficile Treatment

Clinical question: What is the safety and efficacy of fidaxomicin compared to vancomycin in the treatment of patients with C. difficile infection?

Background: Fidaxomicin, a new macrocyclic antibiotic, has shown high efficacy in vitro against C. diff, minimal systemic absorption, and a narrow-spectrum profile. In previously published Phase 2 trials of fidaxomicin for the treatment of C. diff, it has been associated with good clinical response and low recurrence rates.

Study design: Prospective, multicenter, double-blind, randomized trial.

Setting: Fifty-two sites in the United States and 15 in Canada.

Synopsis: The study included 629 adults with acute symptoms of C. diff and a positive stool toxin test. The patients were randomly assigned to 200-mg twice-daily fidaxomicin or 125-mg four-times-daily vancomycin for a course of 10 days. The primary endpoint was rate of clinical cure (resolution of diarrhea), and secondary endpoints were recurrence of C. diff and global cure (clinical cure and lack of relapse within four weeks of cessation of therapy).

The rate of clinical cure associated with fidaxomicin was noninferior to that associated with vancomycin (88.2% vs. 85.8%, respectively). Patients receiving fidaxomicin had a lower rate of relapse than those receiving vancomycin (15.4% vs. 25.3%, respectively, P=0.005) and a higher global cure rate (74.6 vs. 61.1%, P=0.006). In subgroup analysis, the lower rate of recurrence was seen in patients with non-North American pulsed-field Type 1 strain (NAP1/BI/027 strain), while in patients with the NAP1/BI/027 strain, the recurrence rate was similar for both drugs. There was no difference in adverse event rates.

Bottom line: Clinical cure rates of C. diff with fidaxomicin are noninferior to those with vancomycin; however, fidaxomicin is associated with a significantly lower rate of recurrence among those infected with the non-NAP1/BI/027 strain.

Citation: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

ACP Guideline Discourages Use of Intensive Insulin Therapy in Hospitalized Patients

Clinical question: Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients (whether in the SICU, MICU, or on the general medicine floor) improve important health outcomes?

Background: Hyperglycemia is a common finding in hospitalized patients and is associated with prolonged length of stay (LOS), death, and worsening health outcomes. Despite this, prospective studies have yet to provide consistent evidence that using IIT to achieve strict glycemic control (80 mg/dL-110 mg/dL) improves outcomes in hospitalized patients.

Study design: Systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from 1950 to January 2010.

Setting: Trials included subjects with myocardial infarction, stroke, and brain injury, as well as those in perioperative settings and ICUs.

Synopsis: The review informing this guideline meta-analyzed 21 trials and found that IIT did not improve short-term mortality, long-term mortality, infection rates, LOS, or the need for renal replacement therapy. Furthermore, IIT was associated with a sixfold increase in risk for severe hypoglycemia in all hospital settings.

Based on these findings, the American College of Physicians (ACP) issued three recommendations:

• To not use IIT to strictly control blood glucose in non-SICU/non-MICU patients with or without diabetes (strong recommendation, moderate-quality evidence);
• To not use IIT to normalize blood glucose in SICU or MICU patients with or without diabetes (strong recommendation, high-quality evidence); and
• To consider a target blood glucose level of 140 mg to 200 mg if insulin therapy is used in SICU or MICU patients (weak recommendation, moderate-quality evidence).

Bottom line: The ACP recommends against using IIT to strictly control blood glucose (80 mg/dL-180 mg/dL) in hospitalized patients, whether in the SICU, MICU, or on the general medicine floor.

Citation: Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

Limited Benefits Seen with Hospitalist-Neurosurgeon Comanagement

Clinical question: Does hospitalist-neurosurgeon comanagement improve patient outcomes?

Background: The shared management of surgical patients between surgeons and hospitalists is increasingly common despite limited data supporting its effectiveness in reducing costs or improving patient outcomes.

Study design: Single-center, retrospective study.

Setting: Tertiary-care academic medical center.

Synopsis: Data were collected on the 7,596 patients who were admitted to the neurosurgical service of the University of California San Francisco Medical Center from June 1, 2005, to December 31, 2008. The study looked at 4,203 patients (55.3%) admitted before July 1, 2007, when hospitalist comanagement was implemented, and 3,393 patients (44.7%) after comanagement began. Of those admitted during the post-implementation period, 988 (29.1%) were comanaged.

After adjusting for patient characteristics and background trends, and accounting for clustering at the physician level, no differences were found in patient mortality rate, readmissions, or LOS after implementation of comanagement. No consistent improvements were seen in patient satisfaction.

However, physician and staff perceptions of safety and quality of care were significantly better after comanagement. There was a moderate decrease in adjusted hospital costs after implementation (adjusted cost ratio 0.94, range 0.88-1.00) equivalent to a cost savings of about $1,439 per hospitalization.

Bottom line: The implementation of a hospitalist-neurosurgery comanagement service did not improve patient outcomes or satisfaction, but it did appear to improve providers’ perception of care quality and reduce hospital costs.

Citation: Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010.

Comparable Mortality Between Hemodialysis and Peritoneal Dialysis

Clinical question: What effect does the initial dialysis modality used have on mortality for patients with end-stage renal disease (ESRD)?

Background: Despite the substantially lower annual per-person costs of peritoneal dialysis (PD) as compared with hemodialysis (HD), only 7% of dialysis patients were treated with PD in 2008. It is unknown whether there are differences in mortality between those using PD and HD when examined in contemporary cohorts.

Study design: Retrospective cohort study.

Setting: National cohort.

Synopsis: Data for patients with incident ESRD over a nine-year period were obtained from the U.S. Renal Data Systems (USRDS), a national registry of all patients with ESRD. Initial dialysis modality was defined as the dialysis modality used 90 days after initiation of dialysis. Patients were divided into three three-year cohorts (1996-1998, 1999-2001, and 2002-2004) based on the date dialysis was initiated and followed for up to five years.

A substantial and consistent reduction in mortality was seen for PD patients across the three time periods. No such improvements were observed across the time periods for the HD patients. PD patients were, on average, younger, healthier, and more likely to be white. In an analysis of the most recent cohort adjusting for these factors, there was no significant difference in the risk of death between HD and PD patients. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively.

Limitations of the study include a lack of randomization and failure to consider switches from one dialysis modality to the other.

Bottom line: Patients beginning their renal replacement therapy with PD had similar mortality after five years compared to patients using in-center HD.

Citation: Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171(2):110-118.

Pneumococcal Urinary Antigen Test Might Guide Community-Acquired Pneumonia Treatment

Clinical question: What is the diagnostic accuracy and clinical utility of pneumococcal urinary antigen testing in adult patients hospitalized with community-acquired pneumonia (CAP)?

Background: Although CAP is common, our ability to determine its etiology is limited, and empirical broad-spectrum antibiotic therapy is the norm. Pneumococcal urinary antigen testing could allow for the more frequent use of narrow-spectrum pathogen-focused antibiotic therapy.

Study design: Prospective cohort study.

Setting: University-affiliated hospital in Spain.

Synopsis: This study included consecutive adult patients hospitalized with CAP from February 2007 though January 2008. A total of 464 patients with 474 episodes of CAP were included. Pneumococcal urinary antigen testing was performed in 383 (80.8%) episodes of CAP. Streptococcus pneumoniae was felt to be the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 of those cases (43.8%).

For the urine antigen test, specificity was 96% (95% CI, 86.5 to 99.5), and the positive predictive value was 96.5% (95% CI, 87.9 to 99.5). The results of the test led clinicians to reduce the spectrum of antibiotics in 41 patients, and pneumonia was cured in all 41 of these patients. Treatment was not modified despite positive antigen test results in 89 patients.

Limitations of this study include a lack of complete microbiological data for all patients. The study also highlighted the difficulty in changing clinicians’ prescribing patterns, even when test results indicate the need for treatment modification.

Bottom line: A positive pneumococcal urinary antigen test result in adult patients hospitalized with CAP can help clinicians narrow antimicrobial therapy with good clinical outcomes.

Citation: Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med. 2011;171(2):166-172.

Racial Disparities Detected in Hospital Readmission Rates

Clinical question: Do black patients have higher odds of readmission than white patients, and, if so, are these disparities related to where black patients receive care?

Background: Racial disparities in healthcare are well documented. Understanding and eliminating those disparities remains a national priority. Reducing hospital readmissions also is a policy focus, as it represents an opportunity to improve quality while reducing costs. Whether there are racial disparities in hospital readmissions at the national level is unknown.

Study design: Retrospective cohort study.

Setting: Medicare fee-for-service beneficiaries from 2006 to 2008.

Synopsis: Medicare discharge data for more than 3 million Medicare fee-for-service beneficiaries aged 65 years or older discharged from January 1, 2006, to November 30, 2008, with the primary discharge diagnosis of acute myocardial infarction (MI), congestive heart failure, or pneumonia were used to calculate risk-adjusted odds of readmission within 30 days of discharge. Hospitals in the highest decile of proportion of black patients were categorized as minority-serving.

Overall, black patients had 13% higher odds of all-cause 30-day readmission than white patients (24.8% vs. 22.6%, OR 1.13, 95% CI, 1.11-1.14), and patients discharged from minority-serving hospitals had 23% higher odds of readmission than patients from non-minority-serving hospitals (25.5% vs. 22.0%, OR 1.23, 95% CI, 1.20-1.27). Among those with acute MI, black patients had 13% higher odds of readmission (OR 1.13, 95% CI, 1.10-1.16), irrespective of the site of care, while patients from minority-serving hospitals had 22% higher odds of readmissions (OR 1.22, 95% CI, 1.17-1.27), even after adjusting for patient race. Similar disparities were seen for CHF and pneumonia. Results were unchanged after adjusting for hospital characteristics, including markers of caring for poor patients.

Bottom line: Compared with white patients, elderly black Medicare patients have a higher 30-day hospital readmission rate for MI, CHF, and pneumonia that is not fully explained by the higher readmission rates seen among hospitals that disproportionately care for black patients.

Citation: Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by race and site of care. JAMA. 2011;305(7):675-681.

Easily Identifiable Clinical and Demographic Factors Associated with Hospital Readmission

Clinical question: Which clinical, operational, or demographic factors are associated with 30-day readmission for general medicine patients?

Background: While a few clinical risk factors for hospital readmission have been well defined in subgroups of inpatients, there are still limited data regarding readmission risk that might be associated with a broad range of operational, demographic, and clinical factors in a heterogeneous population of general medicine patients.

Study design: Retrospective observational study.

Setting: Single academic medical center.

Synopsis: The study examined more than 10,300 consecutive admissions (6,805 patients) discharged over a two-year period from 2006 to 2008 from the general medicine service of an urban academic medical center. The 30-day readmission rate was 17.0%.

In multivariate analysis, factors associated with readmission included black race (OR 1.43, 95% CI, 1.24-1.65), inpatient use of narcotics (OR 1.33, 95% CI, 1.16-1.53) and corticosteroids (OR 1.24, 95% CI, 1.09-1.42), and the disease states of cancer (with metastasis 1.61, 95% CI, 1.33-1.95; without metastasis 1.95, 95% CI 1.54-2.47), renal failure (OR 1.19, 95% CI 1.05-1.36), congestive heart failure (OR 1.30, 95% CI, 1.09-1.56), and weight loss (OR 1.26, 95% CI, 1.09-1.47). Medicaid payor status (OR 1.15, 95% CI, 0.97-1.36) had a trend toward readmission. None of the operational factors were significantly associated with readmission, including discharge to skilled nursing facility or weekend discharge.

A major limitation of the study was its inability to capture readmissions to hospitals other than the study hospital, which, based on prior studies, could have accounted for nearly a quarter of readmissions.

Bottom line: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors.

Citation: Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining readmission risk factors for general medicine patients. J Hosp Med. 2011;6(2):54-60.

Unplanned Medical ICU Transfers Tied to Preventable Errors

Clinical question: What fraction of unplanned medical ICU (MICU) transfers result from errors in care and why do they occur?

Background: Prior studies have suggested that 14% to 28% of patients admitted to the MICU are unplanned transfers. It is not known what fraction of these transfers result from errors in care, and whether these transfers could be prevented.

Study design: Retrospective cohort study.

Setting: University-affiliated academic medical center.

Synopsis: All unplanned transfers to the MICU from June 1, 2005, to May 30, 2006, were included in the study. Three independent observers, all hospitalists for more than three years, reviewed patient records to determine the cause of unplanned transfers according to a taxonomy the researchers developed for classifying the transfers. They also determined whether the transfer could have been prevented.

Of the 4,468 general medicine admissions during the study period, 152 met inclusion criteria for an unplanned MICU transfer. Errors in care were judged to account for 19% (n=29) of unplanned transfers, 15 of which were due to incorrect triage at admission and 14 to iatrogenic errors, such as opiate overdose during pain treatment or delayed treatment. All 15 triage errors were considered preventable. Of the iatrogenic errors, eight were considered preventable through an earlier intervention. Overall, 23 errors (15%) were thought to be preventable. Observer agreement was moderate to almost perfect (κ0.55-0.90).

Bottom line: Nearly 1 in 7 unplanned transfers to the medical ICU are associated with preventable errors in care, with the most common error being inappropriate admission triage.

Citation: Bapoje SR, Gaudiani JL, Narayanan V, Albert RK. Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. J Hosp Med. 2011;6(2):68-72. TH

Pediatric HM Literature

Well Visits Prevent Ambulatory-Care-Sensitive Hospitalizations

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: Is routine well-child care visit adherence associated with a decreased risk of ambulatory-care-sensitive hospitalizations?

Background: Ambulatory-care-sensitive hospitalizations (ACSHs) represent admissions that might have been prevented by quality outpatient care. They are an improvement opportunity for healthcare systems; thus, it is important to characterize factors associated with increased ACSH. Although continuity of care (COC) with the same provider has been associated with reduced hospitalizations, the relationship between regularly scheduled well-child care (WCC) and ACSH is less clear.

Study design: Population-based, retrospective cohort study.

Setting: Hawaii’s largest health insurer.

Synopsis: Young children with the highest likelihood of ACSH (two months to 3.5 years old) who were continuously enrolled in coverage by Hawaii’s largest health insurer (representing 70% of the civilian population) were included. Ultimately, administrative data on 36,944 children were analyzed for WCC adherence rate and a nonlinear COC index, both of which were modeled as time-varying categorical variables.

ACSH were defined by conditions, and notably included acute respiratory-tract infections. Both high WCC visit adherence and COC index were independently associated with decreased risk of ACSH and were modified significantly by chronic-disease status.

This study examines a somewhat unique population: insured children in Hawaii with a relatively high degree of consistency in care. Thus, it is not applicable to the most vulnerable Medicaid and uninsured groups of children. In addition, the relationship between WCC visit adherence and ACSH seemed to disappear in healthy children, further limiting generalizability. Nevertheless, it appears that WCC visits without provider continuity might still be protective for ACSH. It will be important to replicate these findings in a population served by safety-net clinics: children who most often have WCC without continuity.

Bottom line: WCC visit adherence in insured patients with chronic disease reduces the risk of ACSH.

Citation: Tom JO, Tseng CW, Davis J, Solomon C, Zhou C, Mangione-Smith R. Missed well-child care visits, low continuity of care, and risk of ambulatory care-sensitive hospitalizations in young children. Arch Pediatr Adolesc Med. 2010;164(11):1052-1058.

In This Edition

Literature at a Glance

A guide to this month’s studies

1. Eplerenone and heart failure mortality
2. Fidaxomicin for C. difficile diarrhea
3. Guidelines for intensive insulin therapy
4. Benefits of hospitalist comanagement
5. Peritoneal dialysis versus hemodialysis
6. Pneumococcal urinary antigen to guide CAP treatment
7. Race and readmission rate
8. Factors associated with readmission
9. Unplanned transfers to the ICU

Eplerenone Improves Mortality in Patients with Systolic Heart Failure and Mild Symptoms

Clinical question: Does the selective mineralocorticoid antagonist eplerenone improve outcomes in patients with chronic heart failure and mild symptoms?

Background: In prior studies of miner alocorticoid antagonists in systolic heart failure, spironolactone reduced mortality in patients with moderate to severe heart failure symptoms, and eplerenone reduced mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction. The use of eplerenone in patients with systolic heart failure and mild symptoms has not previously been examined.

Study design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: Two hundred seventy-eight centers in 29 countries.

Synopsis: The study authors randomized 2,737 patients with New York Heart Association Class II heart failure and an ejection fraction of no more than 35% to either eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patients with baseline potassium levels >5 mmol/L or estimated GFR <30 were excluded. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.

The trial was stopped early, after a median follow-up period of 21 months, when an interim analysis showed significant benefit with eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.74; P<0.001). All-cause mortality was 12.5% in the eplerenone group and 15.5% in the placebo group (HR 0.76; 95% CI, 0.62 to 0.93; P=0.008). A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).

Bottom line: Eplerenone reduces both the risk of death and the risk of hospitalization in patients with systolic heart failure and mild symptoms.

Citation: Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

Fidaxomicin Noninferior to Vancomycin for C. Difficile Treatment

Clinical question: What is the safety and efficacy of fidaxomicin compared to vancomycin in the treatment of patients with C. difficile infection?

Background: Fidaxomicin, a new macrocyclic antibiotic, has shown high efficacy in vitro against C. diff, minimal systemic absorption, and a narrow-spectrum profile. In previously published Phase 2 trials of fidaxomicin for the treatment of C. diff, it has been associated with good clinical response and low recurrence rates.

Study design: Prospective, multicenter, double-blind, randomized trial.

Setting: Fifty-two sites in the United States and 15 in Canada.

Synopsis: The study included 629 adults with acute symptoms of C. diff and a positive stool toxin test. The patients were randomly assigned to 200-mg twice-daily fidaxomicin or 125-mg four-times-daily vancomycin for a course of 10 days. The primary endpoint was rate of clinical cure (resolution of diarrhea), and secondary endpoints were recurrence of C. diff and global cure (clinical cure and lack of relapse within four weeks of cessation of therapy).

The rate of clinical cure associated with fidaxomicin was noninferior to that associated with vancomycin (88.2% vs. 85.8%, respectively). Patients receiving fidaxomicin had a lower rate of relapse than those receiving vancomycin (15.4% vs. 25.3%, respectively, P=0.005) and a higher global cure rate (74.6 vs. 61.1%, P=0.006). In subgroup analysis, the lower rate of recurrence was seen in patients with non-North American pulsed-field Type 1 strain (NAP1/BI/027 strain), while in patients with the NAP1/BI/027 strain, the recurrence rate was similar for both drugs. There was no difference in adverse event rates.

Bottom line: Clinical cure rates of C. diff with fidaxomicin are noninferior to those with vancomycin; however, fidaxomicin is associated with a significantly lower rate of recurrence among those infected with the non-NAP1/BI/027 strain.

Citation: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

ACP Guideline Discourages Use of Intensive Insulin Therapy in Hospitalized Patients

Clinical question: Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients (whether in the SICU, MICU, or on the general medicine floor) improve important health outcomes?

Background: Hyperglycemia is a common finding in hospitalized patients and is associated with prolonged length of stay (LOS), death, and worsening health outcomes. Despite this, prospective studies have yet to provide consistent evidence that using IIT to achieve strict glycemic control (80 mg/dL-110 mg/dL) improves outcomes in hospitalized patients.

Study design: Systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from 1950 to January 2010.

Setting: Trials included subjects with myocardial infarction, stroke, and brain injury, as well as those in perioperative settings and ICUs.

Synopsis: The review informing this guideline meta-analyzed 21 trials and found that IIT did not improve short-term mortality, long-term mortality, infection rates, LOS, or the need for renal replacement therapy. Furthermore, IIT was associated with a sixfold increase in risk for severe hypoglycemia in all hospital settings.

Based on these findings, the American College of Physicians (ACP) issued three recommendations:

• To not use IIT to strictly control blood glucose in non-SICU/non-MICU patients with or without diabetes (strong recommendation, moderate-quality evidence);
• To not use IIT to normalize blood glucose in SICU or MICU patients with or without diabetes (strong recommendation, high-quality evidence); and
• To consider a target blood glucose level of 140 mg to 200 mg if insulin therapy is used in SICU or MICU patients (weak recommendation, moderate-quality evidence).

Bottom line: The ACP recommends against using IIT to strictly control blood glucose (80 mg/dL-180 mg/dL) in hospitalized patients, whether in the SICU, MICU, or on the general medicine floor.

Citation: Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

Limited Benefits Seen with Hospitalist-Neurosurgeon Comanagement

Clinical question: Does hospitalist-neurosurgeon comanagement improve patient outcomes?

Background: The shared management of surgical patients between surgeons and hospitalists is increasingly common despite limited data supporting its effectiveness in reducing costs or improving patient outcomes.

Study design: Single-center, retrospective study.

Setting: Tertiary-care academic medical center.

Synopsis: Data were collected on the 7,596 patients who were admitted to the neurosurgical service of the University of California San Francisco Medical Center from June 1, 2005, to December 31, 2008. The study looked at 4,203 patients (55.3%) admitted before July 1, 2007, when hospitalist comanagement was implemented, and 3,393 patients (44.7%) after comanagement began. Of those admitted during the post-implementation period, 988 (29.1%) were comanaged.

After adjusting for patient characteristics and background trends, and accounting for clustering at the physician level, no differences were found in patient mortality rate, readmissions, or LOS after implementation of comanagement. No consistent improvements were seen in patient satisfaction.

However, physician and staff perceptions of safety and quality of care were significantly better after comanagement. There was a moderate decrease in adjusted hospital costs after implementation (adjusted cost ratio 0.94, range 0.88-1.00) equivalent to a cost savings of about $1,439 per hospitalization.

Bottom line: The implementation of a hospitalist-neurosurgery comanagement service did not improve patient outcomes or satisfaction, but it did appear to improve providers’ perception of care quality and reduce hospital costs.

Citation: Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010.

Comparable Mortality Between Hemodialysis and Peritoneal Dialysis

Clinical question: What effect does the initial dialysis modality used have on mortality for patients with end-stage renal disease (ESRD)?

Background: Despite the substantially lower annual per-person costs of peritoneal dialysis (PD) as compared with hemodialysis (HD), only 7% of dialysis patients were treated with PD in 2008. It is unknown whether there are differences in mortality between those using PD and HD when examined in contemporary cohorts.

Study design: Retrospective cohort study.

Setting: National cohort.

Synopsis: Data for patients with incident ESRD over a nine-year period were obtained from the U.S. Renal Data Systems (USRDS), a national registry of all patients with ESRD. Initial dialysis modality was defined as the dialysis modality used 90 days after initiation of dialysis. Patients were divided into three three-year cohorts (1996-1998, 1999-2001, and 2002-2004) based on the date dialysis was initiated and followed for up to five years.

A substantial and consistent reduction in mortality was seen for PD patients across the three time periods. No such improvements were observed across the time periods for the HD patients. PD patients were, on average, younger, healthier, and more likely to be white. In an analysis of the most recent cohort adjusting for these factors, there was no significant difference in the risk of death between HD and PD patients. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively.

Limitations of the study include a lack of randomization and failure to consider switches from one dialysis modality to the other.

Bottom line: Patients beginning their renal replacement therapy with PD had similar mortality after five years compared to patients using in-center HD.

Citation: Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171(2):110-118.

Pneumococcal Urinary Antigen Test Might Guide Community-Acquired Pneumonia Treatment

Clinical question: What is the diagnostic accuracy and clinical utility of pneumococcal urinary antigen testing in adult patients hospitalized with community-acquired pneumonia (CAP)?

Background: Although CAP is common, our ability to determine its etiology is limited, and empirical broad-spectrum antibiotic therapy is the norm. Pneumococcal urinary antigen testing could allow for the more frequent use of narrow-spectrum pathogen-focused antibiotic therapy.

Study design: Prospective cohort study.

Setting: University-affiliated hospital in Spain.

Synopsis: This study included consecutive adult patients hospitalized with CAP from February 2007 though January 2008. A total of 464 patients with 474 episodes of CAP were included. Pneumococcal urinary antigen testing was performed in 383 (80.8%) episodes of CAP. Streptococcus pneumoniae was felt to be the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 of those cases (43.8%).

For the urine antigen test, specificity was 96% (95% CI, 86.5 to 99.5), and the positive predictive value was 96.5% (95% CI, 87.9 to 99.5). The results of the test led clinicians to reduce the spectrum of antibiotics in 41 patients, and pneumonia was cured in all 41 of these patients. Treatment was not modified despite positive antigen test results in 89 patients.

Limitations of this study include a lack of complete microbiological data for all patients. The study also highlighted the difficulty in changing clinicians’ prescribing patterns, even when test results indicate the need for treatment modification.

Bottom line: A positive pneumococcal urinary antigen test result in adult patients hospitalized with CAP can help clinicians narrow antimicrobial therapy with good clinical outcomes.

Citation: Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med. 2011;171(2):166-172.

Racial Disparities Detected in Hospital Readmission Rates

Clinical question: Do black patients have higher odds of readmission than white patients, and, if so, are these disparities related to where black patients receive care?

Background: Racial disparities in healthcare are well documented. Understanding and eliminating those disparities remains a national priority. Reducing hospital readmissions also is a policy focus, as it represents an opportunity to improve quality while reducing costs. Whether there are racial disparities in hospital readmissions at the national level is unknown.

Study design: Retrospective cohort study.

Setting: Medicare fee-for-service beneficiaries from 2006 to 2008.

Synopsis: Medicare discharge data for more than 3 million Medicare fee-for-service beneficiaries aged 65 years or older discharged from January 1, 2006, to November 30, 2008, with the primary discharge diagnosis of acute myocardial infarction (MI), congestive heart failure, or pneumonia were used to calculate risk-adjusted odds of readmission within 30 days of discharge. Hospitals in the highest decile of proportion of black patients were categorized as minority-serving.

Overall, black patients had 13% higher odds of all-cause 30-day readmission than white patients (24.8% vs. 22.6%, OR 1.13, 95% CI, 1.11-1.14), and patients discharged from minority-serving hospitals had 23% higher odds of readmission than patients from non-minority-serving hospitals (25.5% vs. 22.0%, OR 1.23, 95% CI, 1.20-1.27). Among those with acute MI, black patients had 13% higher odds of readmission (OR 1.13, 95% CI, 1.10-1.16), irrespective of the site of care, while patients from minority-serving hospitals had 22% higher odds of readmissions (OR 1.22, 95% CI, 1.17-1.27), even after adjusting for patient race. Similar disparities were seen for CHF and pneumonia. Results were unchanged after adjusting for hospital characteristics, including markers of caring for poor patients.

Bottom line: Compared with white patients, elderly black Medicare patients have a higher 30-day hospital readmission rate for MI, CHF, and pneumonia that is not fully explained by the higher readmission rates seen among hospitals that disproportionately care for black patients.

Citation: Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by race and site of care. JAMA. 2011;305(7):675-681.

Easily Identifiable Clinical and Demographic Factors Associated with Hospital Readmission

Clinical question: Which clinical, operational, or demographic factors are associated with 30-day readmission for general medicine patients?

Background: While a few clinical risk factors for hospital readmission have been well defined in subgroups of inpatients, there are still limited data regarding readmission risk that might be associated with a broad range of operational, demographic, and clinical factors in a heterogeneous population of general medicine patients.

Study design: Retrospective observational study.

Setting: Single academic medical center.

Synopsis: The study examined more than 10,300 consecutive admissions (6,805 patients) discharged over a two-year period from 2006 to 2008 from the general medicine service of an urban academic medical center. The 30-day readmission rate was 17.0%.

In multivariate analysis, factors associated with readmission included black race (OR 1.43, 95% CI, 1.24-1.65), inpatient use of narcotics (OR 1.33, 95% CI, 1.16-1.53) and corticosteroids (OR 1.24, 95% CI, 1.09-1.42), and the disease states of cancer (with metastasis 1.61, 95% CI, 1.33-1.95; without metastasis 1.95, 95% CI 1.54-2.47), renal failure (OR 1.19, 95% CI 1.05-1.36), congestive heart failure (OR 1.30, 95% CI, 1.09-1.56), and weight loss (OR 1.26, 95% CI, 1.09-1.47). Medicaid payor status (OR 1.15, 95% CI, 0.97-1.36) had a trend toward readmission. None of the operational factors were significantly associated with readmission, including discharge to skilled nursing facility or weekend discharge.

A major limitation of the study was its inability to capture readmissions to hospitals other than the study hospital, which, based on prior studies, could have accounted for nearly a quarter of readmissions.

Bottom line: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors.

Citation: Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining readmission risk factors for general medicine patients. J Hosp Med. 2011;6(2):54-60.

Unplanned Medical ICU Transfers Tied to Preventable Errors

Clinical question: What fraction of unplanned medical ICU (MICU) transfers result from errors in care and why do they occur?

Background: Prior studies have suggested that 14% to 28% of patients admitted to the MICU are unplanned transfers. It is not known what fraction of these transfers result from errors in care, and whether these transfers could be prevented.

Study design: Retrospective cohort study.

Setting: University-affiliated academic medical center.

Synopsis: All unplanned transfers to the MICU from June 1, 2005, to May 30, 2006, were included in the study. Three independent observers, all hospitalists for more than three years, reviewed patient records to determine the cause of unplanned transfers according to a taxonomy the researchers developed for classifying the transfers. They also determined whether the transfer could have been prevented.

Of the 4,468 general medicine admissions during the study period, 152 met inclusion criteria for an unplanned MICU transfer. Errors in care were judged to account for 19% (n=29) of unplanned transfers, 15 of which were due to incorrect triage at admission and 14 to iatrogenic errors, such as opiate overdose during pain treatment or delayed treatment. All 15 triage errors were considered preventable. Of the iatrogenic errors, eight were considered preventable through an earlier intervention. Overall, 23 errors (15%) were thought to be preventable. Observer agreement was moderate to almost perfect (κ0.55-0.90).

Bottom line: Nearly 1 in 7 unplanned transfers to the medical ICU are associated with preventable errors in care, with the most common error being inappropriate admission triage.

Citation: Bapoje SR, Gaudiani JL, Narayanan V, Albert RK. Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. J Hosp Med. 2011;6(2):68-72. TH

Pediatric HM Literature

Well Visits Prevent Ambulatory-Care-Sensitive Hospitalizations

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: Is routine well-child care visit adherence associated with a decreased risk of ambulatory-care-sensitive hospitalizations?

Background: Ambulatory-care-sensitive hospitalizations (ACSHs) represent admissions that might have been prevented by quality outpatient care. They are an improvement opportunity for healthcare systems; thus, it is important to characterize factors associated with increased ACSH. Although continuity of care (COC) with the same provider has been associated with reduced hospitalizations, the relationship between regularly scheduled well-child care (WCC) and ACSH is less clear.

Study design: Population-based, retrospective cohort study.

Setting: Hawaii’s largest health insurer.

Synopsis: Young children with the highest likelihood of ACSH (two months to 3.5 years old) who were continuously enrolled in coverage by Hawaii’s largest health insurer (representing 70% of the civilian population) were included. Ultimately, administrative data on 36,944 children were analyzed for WCC adherence rate and a nonlinear COC index, both of which were modeled as time-varying categorical variables.

ACSH were defined by conditions, and notably included acute respiratory-tract infections. Both high WCC visit adherence and COC index were independently associated with decreased risk of ACSH and were modified significantly by chronic-disease status.

This study examines a somewhat unique population: insured children in Hawaii with a relatively high degree of consistency in care. Thus, it is not applicable to the most vulnerable Medicaid and uninsured groups of children. In addition, the relationship between WCC visit adherence and ACSH seemed to disappear in healthy children, further limiting generalizability. Nevertheless, it appears that WCC visits without provider continuity might still be protective for ACSH. It will be important to replicate these findings in a population served by safety-net clinics: children who most often have WCC without continuity.

Bottom line: WCC visit adherence in insured patients with chronic disease reduces the risk of ACSH.

Citation: Tom JO, Tseng CW, Davis J, Solomon C, Zhou C, Mangione-Smith R. Missed well-child care visits, low continuity of care, and risk of ambulatory care-sensitive hospitalizations in young children. Arch Pediatr Adolesc Med. 2010;164(11):1052-1058.

In This Edition

Literature at a Glance

A guide to this month’s studies

1. Eplerenone and heart failure mortality
2. Fidaxomicin for C. difficile diarrhea
3. Guidelines for intensive insulin therapy
4. Benefits of hospitalist comanagement
5. Peritoneal dialysis versus hemodialysis
6. Pneumococcal urinary antigen to guide CAP treatment
7. Race and readmission rate
8. Factors associated with readmission
9. Unplanned transfers to the ICU

Eplerenone Improves Mortality in Patients with Systolic Heart Failure and Mild Symptoms

Clinical question: Does the selective mineralocorticoid antagonist eplerenone improve outcomes in patients with chronic heart failure and mild symptoms?

Background: In prior studies of miner alocorticoid antagonists in systolic heart failure, spironolactone reduced mortality in patients with moderate to severe heart failure symptoms, and eplerenone reduced mortality in patients with acute myocardial infarction complicated by left ventricular dysfunction. The use of eplerenone in patients with systolic heart failure and mild symptoms has not previously been examined.

Study design: Randomized, double-blind, multicenter, placebo-controlled trial.

Setting: Two hundred seventy-eight centers in 29 countries.

Synopsis: The study authors randomized 2,737 patients with New York Heart Association Class II heart failure and an ejection fraction of no more than 35% to either eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patients with baseline potassium levels >5 mmol/L or estimated GFR <30 were excluded. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.

The trial was stopped early, after a median follow-up period of 21 months, when an interim analysis showed significant benefit with eplerenone. The primary outcome occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.74; P<0.001). All-cause mortality was 12.5% in the eplerenone group and 15.5% in the placebo group (HR 0.76; 95% CI, 0.62 to 0.93; P=0.008). A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).

Bottom line: Eplerenone reduces both the risk of death and the risk of hospitalization in patients with systolic heart failure and mild symptoms.

Citation: Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

Fidaxomicin Noninferior to Vancomycin for C. Difficile Treatment

Clinical question: What is the safety and efficacy of fidaxomicin compared to vancomycin in the treatment of patients with C. difficile infection?

Background: Fidaxomicin, a new macrocyclic antibiotic, has shown high efficacy in vitro against C. diff, minimal systemic absorption, and a narrow-spectrum profile. In previously published Phase 2 trials of fidaxomicin for the treatment of C. diff, it has been associated with good clinical response and low recurrence rates.

Study design: Prospective, multicenter, double-blind, randomized trial.

Setting: Fifty-two sites in the United States and 15 in Canada.

Synopsis: The study included 629 adults with acute symptoms of C. diff and a positive stool toxin test. The patients were randomly assigned to 200-mg twice-daily fidaxomicin or 125-mg four-times-daily vancomycin for a course of 10 days. The primary endpoint was rate of clinical cure (resolution of diarrhea), and secondary endpoints were recurrence of C. diff and global cure (clinical cure and lack of relapse within four weeks of cessation of therapy).

The rate of clinical cure associated with fidaxomicin was noninferior to that associated with vancomycin (88.2% vs. 85.8%, respectively). Patients receiving fidaxomicin had a lower rate of relapse than those receiving vancomycin (15.4% vs. 25.3%, respectively, P=0.005) and a higher global cure rate (74.6 vs. 61.1%, P=0.006). In subgroup analysis, the lower rate of recurrence was seen in patients with non-North American pulsed-field Type 1 strain (NAP1/BI/027 strain), while in patients with the NAP1/BI/027 strain, the recurrence rate was similar for both drugs. There was no difference in adverse event rates.

Bottom line: Clinical cure rates of C. diff with fidaxomicin are noninferior to those with vancomycin; however, fidaxomicin is associated with a significantly lower rate of recurrence among those infected with the non-NAP1/BI/027 strain.

Citation: Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

ACP Guideline Discourages Use of Intensive Insulin Therapy in Hospitalized Patients

Clinical question: Does the use of intensive insulin therapy (IIT) to achieve tight glycemic control in hospitalized patients (whether in the SICU, MICU, or on the general medicine floor) improve important health outcomes?

Background: Hyperglycemia is a common finding in hospitalized patients and is associated with prolonged length of stay (LOS), death, and worsening health outcomes. Despite this, prospective studies have yet to provide consistent evidence that using IIT to achieve strict glycemic control (80 mg/dL-110 mg/dL) improves outcomes in hospitalized patients.

Study design: Systematic review of MEDLINE and the Cochrane Database of Systematic Reviews from 1950 to January 2010.

Setting: Trials included subjects with myocardial infarction, stroke, and brain injury, as well as those in perioperative settings and ICUs.

Synopsis: The review informing this guideline meta-analyzed 21 trials and found that IIT did not improve short-term mortality, long-term mortality, infection rates, LOS, or the need for renal replacement therapy. Furthermore, IIT was associated with a sixfold increase in risk for severe hypoglycemia in all hospital settings.

Based on these findings, the American College of Physicians (ACP) issued three recommendations:

• To not use IIT to strictly control blood glucose in non-SICU/non-MICU patients with or without diabetes (strong recommendation, moderate-quality evidence);
• To not use IIT to normalize blood glucose in SICU or MICU patients with or without diabetes (strong recommendation, high-quality evidence); and
• To consider a target blood glucose level of 140 mg to 200 mg if insulin therapy is used in SICU or MICU patients (weak recommendation, moderate-quality evidence).

Bottom line: The ACP recommends against using IIT to strictly control blood glucose (80 mg/dL-180 mg/dL) in hospitalized patients, whether in the SICU, MICU, or on the general medicine floor.

Citation: Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154(4):260-267.

Limited Benefits Seen with Hospitalist-Neurosurgeon Comanagement

Clinical question: Does hospitalist-neurosurgeon comanagement improve patient outcomes?

Background: The shared management of surgical patients between surgeons and hospitalists is increasingly common despite limited data supporting its effectiveness in reducing costs or improving patient outcomes.

Study design: Single-center, retrospective study.

Setting: Tertiary-care academic medical center.

Synopsis: Data were collected on the 7,596 patients who were admitted to the neurosurgical service of the University of California San Francisco Medical Center from June 1, 2005, to December 31, 2008. The study looked at 4,203 patients (55.3%) admitted before July 1, 2007, when hospitalist comanagement was implemented, and 3,393 patients (44.7%) after comanagement began. Of those admitted during the post-implementation period, 988 (29.1%) were comanaged.

After adjusting for patient characteristics and background trends, and accounting for clustering at the physician level, no differences were found in patient mortality rate, readmissions, or LOS after implementation of comanagement. No consistent improvements were seen in patient satisfaction.

However, physician and staff perceptions of safety and quality of care were significantly better after comanagement. There was a moderate decrease in adjusted hospital costs after implementation (adjusted cost ratio 0.94, range 0.88-1.00) equivalent to a cost savings of about $1,439 per hospitalization.

Bottom line: The implementation of a hospitalist-neurosurgery comanagement service did not improve patient outcomes or satisfaction, but it did appear to improve providers’ perception of care quality and reduce hospital costs.

Citation: Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004-2010.

Comparable Mortality Between Hemodialysis and Peritoneal Dialysis

Clinical question: What effect does the initial dialysis modality used have on mortality for patients with end-stage renal disease (ESRD)?

Background: Despite the substantially lower annual per-person costs of peritoneal dialysis (PD) as compared with hemodialysis (HD), only 7% of dialysis patients were treated with PD in 2008. It is unknown whether there are differences in mortality between those using PD and HD when examined in contemporary cohorts.

Study design: Retrospective cohort study.

Setting: National cohort.

Synopsis: Data for patients with incident ESRD over a nine-year period were obtained from the U.S. Renal Data Systems (USRDS), a national registry of all patients with ESRD. Initial dialysis modality was defined as the dialysis modality used 90 days after initiation of dialysis. Patients were divided into three three-year cohorts (1996-1998, 1999-2001, and 2002-2004) based on the date dialysis was initiated and followed for up to five years.

A substantial and consistent reduction in mortality was seen for PD patients across the three time periods. No such improvements were observed across the time periods for the HD patients. PD patients were, on average, younger, healthier, and more likely to be white. In an analysis of the most recent cohort adjusting for these factors, there was no significant difference in the risk of death between HD and PD patients. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively.

Limitations of the study include a lack of randomization and failure to consider switches from one dialysis modality to the other.

Bottom line: Patients beginning their renal replacement therapy with PD had similar mortality after five years compared to patients using in-center HD.

Citation: Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171(2):110-118.

Pneumococcal Urinary Antigen Test Might Guide Community-Acquired Pneumonia Treatment

Clinical question: What is the diagnostic accuracy and clinical utility of pneumococcal urinary antigen testing in adult patients hospitalized with community-acquired pneumonia (CAP)?

Background: Although CAP is common, our ability to determine its etiology is limited, and empirical broad-spectrum antibiotic therapy is the norm. Pneumococcal urinary antigen testing could allow for the more frequent use of narrow-spectrum pathogen-focused antibiotic therapy.

Study design: Prospective cohort study.

Setting: University-affiliated hospital in Spain.

Synopsis: This study included consecutive adult patients hospitalized with CAP from February 2007 though January 2008. A total of 464 patients with 474 episodes of CAP were included. Pneumococcal urinary antigen testing was performed in 383 (80.8%) episodes of CAP. Streptococcus pneumoniae was felt to be the causative pathogen in 171 cases (36.1%). It was detected exclusively by urinary antigen test in 75 of those cases (43.8%).

For the urine antigen test, specificity was 96% (95% CI, 86.5 to 99.5), and the positive predictive value was 96.5% (95% CI, 87.9 to 99.5). The results of the test led clinicians to reduce the spectrum of antibiotics in 41 patients, and pneumonia was cured in all 41 of these patients. Treatment was not modified despite positive antigen test results in 89 patients.

Limitations of this study include a lack of complete microbiological data for all patients. The study also highlighted the difficulty in changing clinicians’ prescribing patterns, even when test results indicate the need for treatment modification.

Bottom line: A positive pneumococcal urinary antigen test result in adult patients hospitalized with CAP can help clinicians narrow antimicrobial therapy with good clinical outcomes.

Citation: Sordé R, Falcó V, Lowak M, et al. Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy. Arch Intern Med. 2011;171(2):166-172.

Racial Disparities Detected in Hospital Readmission Rates

Clinical question: Do black patients have higher odds of readmission than white patients, and, if so, are these disparities related to where black patients receive care?

Background: Racial disparities in healthcare are well documented. Understanding and eliminating those disparities remains a national priority. Reducing hospital readmissions also is a policy focus, as it represents an opportunity to improve quality while reducing costs. Whether there are racial disparities in hospital readmissions at the national level is unknown.

Study design: Retrospective cohort study.

Setting: Medicare fee-for-service beneficiaries from 2006 to 2008.

Synopsis: Medicare discharge data for more than 3 million Medicare fee-for-service beneficiaries aged 65 years or older discharged from January 1, 2006, to November 30, 2008, with the primary discharge diagnosis of acute myocardial infarction (MI), congestive heart failure, or pneumonia were used to calculate risk-adjusted odds of readmission within 30 days of discharge. Hospitals in the highest decile of proportion of black patients were categorized as minority-serving.

Overall, black patients had 13% higher odds of all-cause 30-day readmission than white patients (24.8% vs. 22.6%, OR 1.13, 95% CI, 1.11-1.14), and patients discharged from minority-serving hospitals had 23% higher odds of readmission than patients from non-minority-serving hospitals (25.5% vs. 22.0%, OR 1.23, 95% CI, 1.20-1.27). Among those with acute MI, black patients had 13% higher odds of readmission (OR 1.13, 95% CI, 1.10-1.16), irrespective of the site of care, while patients from minority-serving hospitals had 22% higher odds of readmissions (OR 1.22, 95% CI, 1.17-1.27), even after adjusting for patient race. Similar disparities were seen for CHF and pneumonia. Results were unchanged after adjusting for hospital characteristics, including markers of caring for poor patients.

Bottom line: Compared with white patients, elderly black Medicare patients have a higher 30-day hospital readmission rate for MI, CHF, and pneumonia that is not fully explained by the higher readmission rates seen among hospitals that disproportionately care for black patients.

Citation: Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by race and site of care. JAMA. 2011;305(7):675-681.

Easily Identifiable Clinical and Demographic Factors Associated with Hospital Readmission

Clinical question: Which clinical, operational, or demographic factors are associated with 30-day readmission for general medicine patients?

Background: While a few clinical risk factors for hospital readmission have been well defined in subgroups of inpatients, there are still limited data regarding readmission risk that might be associated with a broad range of operational, demographic, and clinical factors in a heterogeneous population of general medicine patients.

Study design: Retrospective observational study.

Setting: Single academic medical center.

Synopsis: The study examined more than 10,300 consecutive admissions (6,805 patients) discharged over a two-year period from 2006 to 2008 from the general medicine service of an urban academic medical center. The 30-day readmission rate was 17.0%.

In multivariate analysis, factors associated with readmission included black race (OR 1.43, 95% CI, 1.24-1.65), inpatient use of narcotics (OR 1.33, 95% CI, 1.16-1.53) and corticosteroids (OR 1.24, 95% CI, 1.09-1.42), and the disease states of cancer (with metastasis 1.61, 95% CI, 1.33-1.95; without metastasis 1.95, 95% CI 1.54-2.47), renal failure (OR 1.19, 95% CI 1.05-1.36), congestive heart failure (OR 1.30, 95% CI, 1.09-1.56), and weight loss (OR 1.26, 95% CI, 1.09-1.47). Medicaid payor status (OR 1.15, 95% CI, 0.97-1.36) had a trend toward readmission. None of the operational factors were significantly associated with readmission, including discharge to skilled nursing facility or weekend discharge.

A major limitation of the study was its inability to capture readmissions to hospitals other than the study hospital, which, based on prior studies, could have accounted for nearly a quarter of readmissions.

Bottom line: Readmission of general medicine patients within 30 days is common and associated with several easily identifiable clinical and nonclinical factors.

Citation: Allaudeen N, Vidyarthi A, Maselli J, Auerbach A. Redefining readmission risk factors for general medicine patients. J Hosp Med. 2011;6(2):54-60.

Unplanned Medical ICU Transfers Tied to Preventable Errors

Clinical question: What fraction of unplanned medical ICU (MICU) transfers result from errors in care and why do they occur?

Background: Prior studies have suggested that 14% to 28% of patients admitted to the MICU are unplanned transfers. It is not known what fraction of these transfers result from errors in care, and whether these transfers could be prevented.

Study design: Retrospective cohort study.

Setting: University-affiliated academic medical center.

Synopsis: All unplanned transfers to the MICU from June 1, 2005, to May 30, 2006, were included in the study. Three independent observers, all hospitalists for more than three years, reviewed patient records to determine the cause of unplanned transfers according to a taxonomy the researchers developed for classifying the transfers. They also determined whether the transfer could have been prevented.

Of the 4,468 general medicine admissions during the study period, 152 met inclusion criteria for an unplanned MICU transfer. Errors in care were judged to account for 19% (n=29) of unplanned transfers, 15 of which were due to incorrect triage at admission and 14 to iatrogenic errors, such as opiate overdose during pain treatment or delayed treatment. All 15 triage errors were considered preventable. Of the iatrogenic errors, eight were considered preventable through an earlier intervention. Overall, 23 errors (15%) were thought to be preventable. Observer agreement was moderate to almost perfect (κ0.55-0.90).

Bottom line: Nearly 1 in 7 unplanned transfers to the medical ICU are associated with preventable errors in care, with the most common error being inappropriate admission triage.

Citation: Bapoje SR, Gaudiani JL, Narayanan V, Albert RK. Unplanned transfers to a medical intensive care unit: causes and relationship to preventable errors in care. J Hosp Med. 2011;6(2):68-72. TH

Pediatric HM Literature

Well Visits Prevent Ambulatory-Care-Sensitive Hospitalizations

Reviewed by Pediatric Editor Mark Shen, MD, FHM, medical director of hospital medicine at Dell Children’s Medical Center, Austin, Texas.

Clinical question: Is routine well-child care visit adherence associated with a decreased risk of ambulatory-care-sensitive hospitalizations?

Background: Ambulatory-care-sensitive hospitalizations (ACSHs) represent admissions that might have been prevented by quality outpatient care. They are an improvement opportunity for healthcare systems; thus, it is important to characterize factors associated with increased ACSH. Although continuity of care (COC) with the same provider has been associated with reduced hospitalizations, the relationship between regularly scheduled well-child care (WCC) and ACSH is less clear.

Study design: Population-based, retrospective cohort study.

Setting: Hawaii’s largest health insurer.

Synopsis: Young children with the highest likelihood of ACSH (two months to 3.5 years old) who were continuously enrolled in coverage by Hawaii’s largest health insurer (representing 70% of the civilian population) were included. Ultimately, administrative data on 36,944 children were analyzed for WCC adherence rate and a nonlinear COC index, both of which were modeled as time-varying categorical variables.

ACSH were defined by conditions, and notably included acute respiratory-tract infections. Both high WCC visit adherence and COC index were independently associated with decreased risk of ACSH and were modified significantly by chronic-disease status.

This study examines a somewhat unique population: insured children in Hawaii with a relatively high degree of consistency in care. Thus, it is not applicable to the most vulnerable Medicaid and uninsured groups of children. In addition, the relationship between WCC visit adherence and ACSH seemed to disappear in healthy children, further limiting generalizability. Nevertheless, it appears that WCC visits without provider continuity might still be protective for ACSH. It will be important to replicate these findings in a population served by safety-net clinics: children who most often have WCC without continuity.

Bottom line: WCC visit adherence in insured patients with chronic disease reduces the risk of ACSH.

Citation: Tom JO, Tseng CW, Davis J, Solomon C, Zhou C, Mangione-Smith R. Missed well-child care visits, low continuity of care, and risk of ambulatory care-sensitive hospitalizations in young children. Arch Pediatr Adolesc Med. 2010;164(11):1052-1058.