Robert Chang, MD

A 21-year-old man with a history of hypertension presented to the emergency department with four days of generalized abdominal pain, nausea, and vomiting as well as one month of loose stools. He also had a headache (not further specified) for one day. Due to his nausea, he had been unable to take his medications for two days. Home blood pressure measurements over the preceding two days revealed systolic pressures exceeding 200 mm Hg. He did not experience fever, dyspnea, chest pain, vision changes, numbness, weakness, diaphoresis, or palpitations.

Abdominal pain with vomiting and diarrhea is often caused by a self-limited gastroenteritis. However, the priority initially is to exclude serious intraabdominal processes including arterial insufficiency, bowel obstruction, organ perforation, or organ-based infection or inflammation (eg, appendicitis, cholecystitis, pancreatitis). Essential hypertension accounts for 95% of cases of hypertension in the United States, but given this patient’s young age, secondary causes should be evaluated. These include primary aldosteronism (the most common endocrine cause for hypertension in young patients), chronic kidney disease, fibromuscular dysplasia, illicit drug use, hypercortisolism, pheochromocytoma, and coarctation of the aorta. Thyrotoxicosis can elevate blood pressure (although usually not to this extent) and cause hyperdefecation. While the etiology of the chronic hypertension is uncertain, the proximate cause of the acute rise in blood pressure is likely the stress of his acute illness and the inability to take his prescribed antihypertensive medications. In the setting of severe hypertension, his headache may reflect an intracranial hemorrhage and his abdominal pain could signal an aortic dissection.

His medical history included hypertension diagnosed at age 16 as well as anxiety diagnosed following a panic attack at age 19. Over the past year, he had also developed persistent nausea, which was attributed to gastroesophageal reflux disease. His medications included metoprolol 50 mg daily, amlodipine 5 mg daily, hydrochlorothiazide 12.5 mg daily, escitalopram 20 mg daily, and omeprazole 20 mg daily. His father and 15-year-old brother also had hypertension. He was a part-time student while working at a car dealership. He did not smoke or use drugs and he rarely drank alcohol.

The need for three antihypertensive medications (albeit at submaximal doses) reflects the severity of his hypertension (provided challenges with medication adherence have been excluded). His family history, especially that of his brother who was diagnosed with hypertension at an early age, and the patient’s own early onset hypertension point toward an inherited form of hypertension. Autosomal dominant polycystic kidney disease often results in hypertension before chronic kidney disease develops. Rare inherited forms of hypertension include familial hyperaldosteronism, apparent mineralocorticoid excess, Liddle syndrome, or a hereditary endocrine tumor syndrome predisposing to pheochromocytoma. Even among patients who report classic pheochromocytoma symptoms, such as headache and anxiety, the diagnosis remains unlikely as these symptoms are nonspecific and highly prevalent in the general population. However, once secondary hypertension is plausible or suspected, testing for hyperadrenergic states, which can also cause nausea and vomiting during times of catecholamine excess, should be pursued.

His temperature was 97.5°F, heart rate 95 beats per minute and regular, respiratory rate 18 breaths per minute, blood pressure 181/118 mm Hg (systolic and diastolic pressures in each arm were within 10 mm Hg), and oxygen saturation 100% on room air. Systolic and diastolic pressures did not decrease by more than 20 mm Hg and 10 mm Hg, respectively, after he stood for two minutes. His body mass index was 24 kg/m². He was alert and appeared slightly anxious. There was a bounding point of maximal impulse in the fifth intercostal space at the midclavicular line and a 3/6 systolic murmur at the left upper sternal border with radiation to the carotid arteries. His abdomen was soft with generalized tenderness to palpation and without rebound tenderness, masses, organomegaly, or bruits. There was no costovertebral angle tenderness. No lymphadenopathy was present. His fundoscopic, pulmonary, skin and neurologic examinations were normal.

Laboratory studies revealed a white blood cell count of 13.3 × 10³/uL with a normal differential, hemoglobin 13.9 g/dL, platelet count 373 × 10³/uL, sodium 142 mmol/L, potassium 3.8 mmol/L, chloride 103 mmol/L,bicarbonate 25 mmol/L, blood urea nitrogen 12 mg/dL, creatinine 1.3 mg/dL (a baseline creatinine level was not available), glucose 88 mg/dL, calcium 10.6 mg/dL, albumin 4.9 g/dL, aspartate aminotransferase 27 IU/L, alanine aminotransferase 37 IU/L, and lipase 40 IU/L. Urinalysis revealed 5-10 white blood cells per high power field without casts and 10 mg/dL protein. Urine toxicology was not performed. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH). Chest radiography was normal.

The abdominal examination does not suggest peritonitis. The laboratory tests do not suggest inflammation of the liver, pancreas, or biliary tree as the cause of his abdominal pain or diarrhea. The murmur may indicate hypertrophic cardiomyopathy or a congenital anomaly such as bicuspid aortic valve; but neither would explain hypertension unless they were associated with another developmental abnormality, such as coarctation of the aorta. Tricuspid regurgitation is conceivable and if confirmed, might raise concern for carcinoid syndrome, which can cause diarrhea. The normal neurologic examination, including the absence of papilledema, lowers suspicion of intracranial hemorrhage as a cause of his headache.

The albumin of 4.9 g/dL likely reflects hypovolemia resulting from vomiting and diarrhea. Vasoconstriction associated with pheochromocytoma can cause pressure diuresis and resultant hypovolemia. Hyperaldosteronism arising from bilateral adrenal hyperplasia or adrenal adenoma commonly causes hypokalemia, although this is not a universal feature.

The duration of his mildly decreased glomerular filtration rate is uncertain. He may have chronic kidney disease from sustained hypertension, or acute kidney injury from hypovolemia. The mild pyuria could indicate infection or renal calculi, either of which could account for generalized abdominal pain or could reflect an acute renal injury from acute interstitial nephritis from his proton pump inhibitor or hydrochlorothiazide.

LVH on the ECG indicates longstanding hypertension. The chest radiograph does not reveal clues to the etiology of or sequelae from hypertension. In particular, there is no widened aorta to suggest aortic dissection, no pulmonary edema to indicate heart failure, and no rib notching that points toward aortic coarctation. A transthoracic echocardiogram to assess for valvular and other structural abnormalities is warranted.

Tests for secondary hypertension should be sent, including serum aldosterone and renin levels to assess for primary aldosteronism and plasma or 24-hour urine normetanephrine and metanephrine levels to assess for pheochromocytoma. Biochemical evaluation is the mainstay for endocrine hypertension evaluation and should be followed by imaging if abnormal results are found.

Intact parathyroid hormone (PTH) was 78 pg/mL (normal, 10-65 pg/mL), thyroid stimulating hormone 3.6 mIU/L (normal, 0.30-5.50 mIU/L), and morning cortisol 4.1 ug/dL (normal, >7.0 ug/dL). Plasma aldosterone was 14.6 ng/dL (normal, 1-16 ng/dL), plasma renin activity 3.6 ng/mL/hr (normal, 0.5-3.5 ng/mL/hr), and aldosterone-renin ratio 4.1 (normal, <20). Transthoracic echocardiogram showed LVH with normal valves, wall motion, and proximal aorta; the left ventricular ejection fraction was 70%. Magnetic resonance angiography of the renal vessels demonstrated no abnormalities.

Computed tomography (CT) of the abdomen and pelvis with oral and intravenous contrast revealed a 5 cm heterogeneous enhancing mass associated with the prostate gland extending into the base of the bladder. The mass obstructed the right renal collecting system and ureter causing severe right-sided ureterectasis and hydronephrosis. There was also 2.8 cm right-sided paracaval lymph node enlargement and 2.1 cm right-sided and 1.5 cm left-sided external iliac lymph node enlargement (Figure 1). There were no adrenal masses.

He is young for prostate, bladder, or colorectal cancer, but early onset variations of these tumors, along with metastatic testicular cancer, must be considered for the pelvic mass and associated lymphadenopathy. Prostatic masses can be infectious (eg, abscess) or malignant (eg, adenocarcinoma, small cell carcinoma). Additional considerations for abdominopelvic cancer are sarcomas, germ cell tumors, or lymphoma. A low aldosterone-renin ratio coupled with a normal potassium level makes primary aldosteronism unlikely. The normal angiography excludes renovascular hypertension.

His abdominal pain and gastrointestinal symptoms could arise from irritation of the bowel, distension of the right-sided urinary collecting system, or products secreted from the mass (eg, catecholamines). The hyperdynamic precordium, elevated ejection fraction, and murmur may reflect augmented blood flow from a hyperadrenergic state. A unifying diagnosis would be a pheochromocytoma. However, given the normal appearance of the adrenal glands on CT imaging, catecholamines arising from a paraganglioma, a tumor of the autonomic nervous system, is more likely. These tumors often secrete catecholamines and can be metastatic (suggested here by the lymphadenopathy). Functional imaging or biopsy of either the mass or an adjacent lymph node is indicated. However, because of the possibility of a catecholamine-secreting tumor, he should be treated with an alpha-adrenergic receptor antagonist before undergoing a biopsy to prevent unopposed vasoconstriction from catecholamine leakage.

Scrotal ultrasound revealed no evidence of a testicular tumor. Lactate dehydrogenase (LDH) was 179 IU/L (normal, 120-240 IU/L) and prostate specific antigen (PSA) was 0.7 ng/mL (normal, <2.5 ng/mL). The patient was given amlodipine and labetalol with improvement of blood pressures to 160s/100s. His creatinine decreased to 1.1 mg/dL. He underwent CT-guided biopsy of a pelvic lymph node. CT of the head without intravenous contrast demonstrated no intracranial abnormalities. His headache resolved with improvement in blood pressure, and he had minimal gastrointestinal symptoms during his hospitalization. No stool studies were sent. A right-sided percutaneous nephrostomy was placed which yielded >15 L of urine from the tube over the next four days.

Upon the first episode of micturition through the urethra four days after percutaneous nephrostomy placement, he experienced severe lightheadedness, diaphoresis, and palpitations. These symptoms prompted him to recall similar episodes following micturition for several months prior to his hospitalization.

It is likely that contraction of the bladder during episodes of urination caused irritation of the pelvic mass, leading to catecholamine secretion. Another explanation for his recurrent lightheadedness would be a neurocardiogenic reflex with micturition (which when it culminates with loss of consciousness is called micturition syncope), but this would not explain his hypertension or bladder mass.

Biochemical tests that were ordered on admission but sent to a reference lab then returned. Plasma metanephrine was 0.2 nmol/L (normal, <0.5 nmol/L) and plasma normetanephrine 34.6 nmol/L (normal, <0.9 nmol/L). His 24-hour urine metanephrine was 72 ug/24 hr (normal, 0-300 ug/24 hr) and normetanephrine 8,511 ug/24 hr (normal, 50-800 ug/24 hr).

The markedly elevated plasma and urine normetanephrine levels confirm a diagnosis of a catecholamine-secreting tumor (paraganglioma). The tissue obtained from the CT-guided lymph node biopsy should be sent for markers of neuroendocrine tumors including chromogranin.

Lymph node biopsy revealed metastatic paraganglioma that was chromogranin A and synaptophysin positive (Figure 2). A fluorodeoxyglucose positron emission tomography (FDG-PET) scan disclosed skull metastases. He was treated with phenoxybenzamine, amlodipine, and labetalol. Surgical resection of the pelvic mass was discussed, but the patient elected to defer surgery as the location of the primary tumor made it challenging to resect and would have required an ileal conduit.

After the diagnosis was made, the patient’s family recalled that a maternal uncle had been diagnosed with a paraganglioma of the carotid body. Genetic testing of the patient identified a succinate dehydrogenase complex subunit B (SDHB) pathogenic variant and confirmed hereditary paraganglioma syndrome (HPGL). One year after the diagnosis, liver and lung metastases developed. He was treated with lanreotide (somatostatin analogue), capecitabine, and temozolomide, as well as a craniotomy and radiotherapy for palliation of bony metastases. The patient died less than two years after diagnosis.

Most patients with hypertension (defined as blood pressure >130/80 mm Hg¹) do not have an identifiable etiology (primary hypertension). Many components of this patient’s history, however, including his young age of onset, a teenage sibling with hypertension, lack of obesity, hypertension refractory to multiple medications, and LVH suggested secondary hypertension. Hypertension onset at an age less than 30 years, resistance to three or more medications,^1,2 and/or acute onset hypertension at any age should prompt an evaluation for secondary causes.¹ The prevalence of secondary hypertension is approximately 30% in hypertensive patients ages 18 to 40 years compared with 5%-10% in the overall adult population with hypertension.³ Among children and adolescents ages 0 to 19 years with hypertension, the prevalence of secondary hypertension may be as high as 57%.⁴

The most common etiology of secondary hypertension is primary aldosteronism.^5,6 However, in young adults (ages 19 to 39 years), common etiologies also include renovascular disease and renal parenchymal disease.⁷ Other causes include obstructive sleep apnea, medications, stimulants (cocaine and amphetamines),⁸ and endocrinopathies such as thyrotoxicosis, Cushing syndrome, and catecholamine-secreting tumors.⁷ Less than 1% of secondary hypertension in all adults is due to catecholamine-secreting tumors, and the minority of those catecholamine-secreting tumors are paragangliomas.⁹

Paragangliomas are tumors of the peripheral autonomic nervous system. These neoplasms arise in the sympathetic and parasympathetic chains along the paravertebral and paraaortic axes. They are closely related to pheochromocytomas, which arise in the adrenal medulla.⁹ Most head and neck paragangliomas are biochemically silent and are generally discovered due to mass effect.¹⁰ The subset of paragangliomas that secrete catecholamines most often arise in the abdomen and pelvis, and their clinical presentation mimics that of pheochromocytomas, including episodic hypertension, palpitations, pallor, and diaphoresis.

This patient had persistent, nonepisodic hypertension, while palpitations and diaphoresis only manifested following micturition. Other cases of urinary bladder paragangliomas have described micturition-associated symptoms and hypertensive crises. Three-fold increases of catecholamine secretion after micturition have been observed in these patients, likely due to muscle contraction and pressure changes in the bladder leading to the systemic release of catecholamines.¹¹

Epinephrine and norepinephrine are monoamine neurotransmitters that activate alpha-adrenergic and beta-adrenergic receptors. Adrenergic receptors are present in all tissues of the body but have prominent effects on the smooth muscle in the vasculature, gastrointestinal tract, urinary tract, and airways.¹² Alpha-adrenergic vasoconstriction causes hypertension, which is commonly observed in patients with catecholamine-secreting tumors.¹⁰ Catecholamine excess due to secretion from these tumors causes headache in 60%-80% of patients, tachycardia/palpitations in 50%-70%, anxiety in 20%-40%, and nausea in 20%-25%.¹⁰ Other symptoms include sweating, pallor, dyspnea, and vertigo.^9,10 This patient’s chronic nausea, which was attributed to gastroesophageal reflux, and his anxiety, attributed to generalized anxiety disorder, were likely symptoms of catecholamine excess.¹³

The best test for the diagnosis of paragangliomas and pheochromocytomas is the measurement of plasma free or 24-hour urinary fractionated metanephrines (test sensitivity of >90% and >90%, respectively).¹⁴ Screening for pheochromocytoma should be considered in hypertensive patients who have symptoms of catecholamine excess, refractory or paroxysmal hypertension, and/or familial pheochromocytoma/paraganglioma syndromes.¹⁵ Screening for pheochromocytoma should also be performed in children and adolescents with systolic or diastolic blood pressure that is greater than the 95th percentile for their age plus 5 mm Hg.¹⁶

While a typical tumor location and elevated metanephrine levels are sufficient to make the diagnosis of a pheochromocytoma or catecholamine-secreting paraganglioma, functional imaging with FDG-PET, Ga-DOTATATE-PET, or 123I-meta-iodobenzylguanidine (123I-MIBG) can further confirm the diagnosis and detect distant metastases. However, imaging has low sensitivity for these tumors and thus should only be considered for patients in whom metastatic disease is suspected.¹⁴ Biopsy is rarely needed and should be reserved for unusual metastatic locations. Treatment with an alpha-adrenergic receptor antagonist often reduces symptoms and lowers blood pressure. Definitive management typically involves surgical resection for benign disease. Surgery, radionuclide therapy, or chemotherapy is used for malignant disease.

While most pheochromocytomas are sporadic, up to 40% of paragangliomas are due to germline pathogenic variants.¹⁷ Mutations in the succinate dehydrogenase (SDH) group of genes are the most common germline pathogenic variants in the autosomal dominant hereditary paraganglioma syndrome (HPGL). Most paragangliomas and pheochromocytomas are localized and benign, but 10%-15% are metastatic.¹⁸ SDHB mutations are associated with a high risk of metastasis.¹⁹ Thus, genetic testing for patients and subsequent cascade testing to identify at-risk family members is advised in all patients with pheochromocytomas or paragangliomas.²⁰ This patient’s younger brother and mother were both found to carry the same pathogenic SDHB variant, but neither was found to have paragangliomas. Annual metanephrine levels (urine or plasma) and every other year whole-body magnetic resonance imaging (MRI) scans were recommended for tumor surveillance.

The clinician team followed a logical branching algorithm for the diagnosis of severe hypertension with biochemical testing, advanced imaging, histology, and genetic testing to arrive at the final diagnosis of hereditary paraganglioma syndrome. Although this patient presented for urgent care because of the acute effects of catecholamine excess, he suffered from chronic effects (nausea, anxiety, and hypertension) for years. Each symptom had been diagnosed and treated in isolation, but the combination and severity in a young patient suggested a unifying diagnosis. The family history of hypertension (brother and father) suggested an inherited diagnosis from the father’s family, but the final answer rested on the other branch (maternal uncle) of the family tree.

• Hypertension in a young adult is due to a secondary cause in up to 30% of patients.
• Pathologic catecholamine excess leads to hypertension, tachycardia, pallor, sweating, anxiety, and nausea. A sustained and unexplained combination of these symptoms should prompt a biochemical evaluation for pheochromocytoma or paraganglioma.
• Paragangliomas are tumors of the autonomic nervous system. The frequency of catecholamine secretion depends on their location in the body, and they are commonly caused by germline pathogenic variants.

Acknowledgments

This conundrum was presented during a live Grand Rounds with the expert clinician’s responses recorded and edited for space and clarity.

Disclosures

Dr. Dhaliwal reports speaking honoraria from ISMIE Mutual Insurance Company and GE Healthcare. All other authors have nothing to disclose.

Funding

No sources of funding.

A 21-year-old man with a history of hypertension presented to the emergency department with four days of generalized abdominal pain, nausea, and vomiting as well as one month of loose stools. He also had a headache (not further specified) for one day. Due to his nausea, he had been unable to take his medications for two days. Home blood pressure measurements over the preceding two days revealed systolic pressures exceeding 200 mm Hg. He did not experience fever, dyspnea, chest pain, vision changes, numbness, weakness, diaphoresis, or palpitations.

Abdominal pain with vomiting and diarrhea is often caused by a self-limited gastroenteritis. However, the priority initially is to exclude serious intraabdominal processes including arterial insufficiency, bowel obstruction, organ perforation, or organ-based infection or inflammation (eg, appendicitis, cholecystitis, pancreatitis). Essential hypertension accounts for 95% of cases of hypertension in the United States, but given this patient’s young age, secondary causes should be evaluated. These include primary aldosteronism (the most common endocrine cause for hypertension in young patients), chronic kidney disease, fibromuscular dysplasia, illicit drug use, hypercortisolism, pheochromocytoma, and coarctation of the aorta. Thyrotoxicosis can elevate blood pressure (although usually not to this extent) and cause hyperdefecation. While the etiology of the chronic hypertension is uncertain, the proximate cause of the acute rise in blood pressure is likely the stress of his acute illness and the inability to take his prescribed antihypertensive medications. In the setting of severe hypertension, his headache may reflect an intracranial hemorrhage and his abdominal pain could signal an aortic dissection.

His medical history included hypertension diagnosed at age 16 as well as anxiety diagnosed following a panic attack at age 19. Over the past year, he had also developed persistent nausea, which was attributed to gastroesophageal reflux disease. His medications included metoprolol 50 mg daily, amlodipine 5 mg daily, hydrochlorothiazide 12.5 mg daily, escitalopram 20 mg daily, and omeprazole 20 mg daily. His father and 15-year-old brother also had hypertension. He was a part-time student while working at a car dealership. He did not smoke or use drugs and he rarely drank alcohol.

The need for three antihypertensive medications (albeit at submaximal doses) reflects the severity of his hypertension (provided challenges with medication adherence have been excluded). His family history, especially that of his brother who was diagnosed with hypertension at an early age, and the patient’s own early onset hypertension point toward an inherited form of hypertension. Autosomal dominant polycystic kidney disease often results in hypertension before chronic kidney disease develops. Rare inherited forms of hypertension include familial hyperaldosteronism, apparent mineralocorticoid excess, Liddle syndrome, or a hereditary endocrine tumor syndrome predisposing to pheochromocytoma. Even among patients who report classic pheochromocytoma symptoms, such as headache and anxiety, the diagnosis remains unlikely as these symptoms are nonspecific and highly prevalent in the general population. However, once secondary hypertension is plausible or suspected, testing for hyperadrenergic states, which can also cause nausea and vomiting during times of catecholamine excess, should be pursued.

His temperature was 97.5°F, heart rate 95 beats per minute and regular, respiratory rate 18 breaths per minute, blood pressure 181/118 mm Hg (systolic and diastolic pressures in each arm were within 10 mm Hg), and oxygen saturation 100% on room air. Systolic and diastolic pressures did not decrease by more than 20 mm Hg and 10 mm Hg, respectively, after he stood for two minutes. His body mass index was 24 kg/m². He was alert and appeared slightly anxious. There was a bounding point of maximal impulse in the fifth intercostal space at the midclavicular line and a 3/6 systolic murmur at the left upper sternal border with radiation to the carotid arteries. His abdomen was soft with generalized tenderness to palpation and without rebound tenderness, masses, organomegaly, or bruits. There was no costovertebral angle tenderness. No lymphadenopathy was present. His fundoscopic, pulmonary, skin and neurologic examinations were normal.

Laboratory studies revealed a white blood cell count of 13.3 × 10³/uL with a normal differential, hemoglobin 13.9 g/dL, platelet count 373 × 10³/uL, sodium 142 mmol/L, potassium 3.8 mmol/L, chloride 103 mmol/L,bicarbonate 25 mmol/L, blood urea nitrogen 12 mg/dL, creatinine 1.3 mg/dL (a baseline creatinine level was not available), glucose 88 mg/dL, calcium 10.6 mg/dL, albumin 4.9 g/dL, aspartate aminotransferase 27 IU/L, alanine aminotransferase 37 IU/L, and lipase 40 IU/L. Urinalysis revealed 5-10 white blood cells per high power field without casts and 10 mg/dL protein. Urine toxicology was not performed. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH). Chest radiography was normal.

The abdominal examination does not suggest peritonitis. The laboratory tests do not suggest inflammation of the liver, pancreas, or biliary tree as the cause of his abdominal pain or diarrhea. The murmur may indicate hypertrophic cardiomyopathy or a congenital anomaly such as bicuspid aortic valve; but neither would explain hypertension unless they were associated with another developmental abnormality, such as coarctation of the aorta. Tricuspid regurgitation is conceivable and if confirmed, might raise concern for carcinoid syndrome, which can cause diarrhea. The normal neurologic examination, including the absence of papilledema, lowers suspicion of intracranial hemorrhage as a cause of his headache.

The albumin of 4.9 g/dL likely reflects hypovolemia resulting from vomiting and diarrhea. Vasoconstriction associated with pheochromocytoma can cause pressure diuresis and resultant hypovolemia. Hyperaldosteronism arising from bilateral adrenal hyperplasia or adrenal adenoma commonly causes hypokalemia, although this is not a universal feature.

The duration of his mildly decreased glomerular filtration rate is uncertain. He may have chronic kidney disease from sustained hypertension, or acute kidney injury from hypovolemia. The mild pyuria could indicate infection or renal calculi, either of which could account for generalized abdominal pain or could reflect an acute renal injury from acute interstitial nephritis from his proton pump inhibitor or hydrochlorothiazide.

LVH on the ECG indicates longstanding hypertension. The chest radiograph does not reveal clues to the etiology of or sequelae from hypertension. In particular, there is no widened aorta to suggest aortic dissection, no pulmonary edema to indicate heart failure, and no rib notching that points toward aortic coarctation. A transthoracic echocardiogram to assess for valvular and other structural abnormalities is warranted.

Tests for secondary hypertension should be sent, including serum aldosterone and renin levels to assess for primary aldosteronism and plasma or 24-hour urine normetanephrine and metanephrine levels to assess for pheochromocytoma. Biochemical evaluation is the mainstay for endocrine hypertension evaluation and should be followed by imaging if abnormal results are found.

Intact parathyroid hormone (PTH) was 78 pg/mL (normal, 10-65 pg/mL), thyroid stimulating hormone 3.6 mIU/L (normal, 0.30-5.50 mIU/L), and morning cortisol 4.1 ug/dL (normal, >7.0 ug/dL). Plasma aldosterone was 14.6 ng/dL (normal, 1-16 ng/dL), plasma renin activity 3.6 ng/mL/hr (normal, 0.5-3.5 ng/mL/hr), and aldosterone-renin ratio 4.1 (normal, <20). Transthoracic echocardiogram showed LVH with normal valves, wall motion, and proximal aorta; the left ventricular ejection fraction was 70%. Magnetic resonance angiography of the renal vessels demonstrated no abnormalities.

Computed tomography (CT) of the abdomen and pelvis with oral and intravenous contrast revealed a 5 cm heterogeneous enhancing mass associated with the prostate gland extending into the base of the bladder. The mass obstructed the right renal collecting system and ureter causing severe right-sided ureterectasis and hydronephrosis. There was also 2.8 cm right-sided paracaval lymph node enlargement and 2.1 cm right-sided and 1.5 cm left-sided external iliac lymph node enlargement (Figure 1). There were no adrenal masses.

He is young for prostate, bladder, or colorectal cancer, but early onset variations of these tumors, along with metastatic testicular cancer, must be considered for the pelvic mass and associated lymphadenopathy. Prostatic masses can be infectious (eg, abscess) or malignant (eg, adenocarcinoma, small cell carcinoma). Additional considerations for abdominopelvic cancer are sarcomas, germ cell tumors, or lymphoma. A low aldosterone-renin ratio coupled with a normal potassium level makes primary aldosteronism unlikely. The normal angiography excludes renovascular hypertension.

His abdominal pain and gastrointestinal symptoms could arise from irritation of the bowel, distension of the right-sided urinary collecting system, or products secreted from the mass (eg, catecholamines). The hyperdynamic precordium, elevated ejection fraction, and murmur may reflect augmented blood flow from a hyperadrenergic state. A unifying diagnosis would be a pheochromocytoma. However, given the normal appearance of the adrenal glands on CT imaging, catecholamines arising from a paraganglioma, a tumor of the autonomic nervous system, is more likely. These tumors often secrete catecholamines and can be metastatic (suggested here by the lymphadenopathy). Functional imaging or biopsy of either the mass or an adjacent lymph node is indicated. However, because of the possibility of a catecholamine-secreting tumor, he should be treated with an alpha-adrenergic receptor antagonist before undergoing a biopsy to prevent unopposed vasoconstriction from catecholamine leakage.

Scrotal ultrasound revealed no evidence of a testicular tumor. Lactate dehydrogenase (LDH) was 179 IU/L (normal, 120-240 IU/L) and prostate specific antigen (PSA) was 0.7 ng/mL (normal, <2.5 ng/mL). The patient was given amlodipine and labetalol with improvement of blood pressures to 160s/100s. His creatinine decreased to 1.1 mg/dL. He underwent CT-guided biopsy of a pelvic lymph node. CT of the head without intravenous contrast demonstrated no intracranial abnormalities. His headache resolved with improvement in blood pressure, and he had minimal gastrointestinal symptoms during his hospitalization. No stool studies were sent. A right-sided percutaneous nephrostomy was placed which yielded >15 L of urine from the tube over the next four days.

Upon the first episode of micturition through the urethra four days after percutaneous nephrostomy placement, he experienced severe lightheadedness, diaphoresis, and palpitations. These symptoms prompted him to recall similar episodes following micturition for several months prior to his hospitalization.

It is likely that contraction of the bladder during episodes of urination caused irritation of the pelvic mass, leading to catecholamine secretion. Another explanation for his recurrent lightheadedness would be a neurocardiogenic reflex with micturition (which when it culminates with loss of consciousness is called micturition syncope), but this would not explain his hypertension or bladder mass.

Biochemical tests that were ordered on admission but sent to a reference lab then returned. Plasma metanephrine was 0.2 nmol/L (normal, <0.5 nmol/L) and plasma normetanephrine 34.6 nmol/L (normal, <0.9 nmol/L). His 24-hour urine metanephrine was 72 ug/24 hr (normal, 0-300 ug/24 hr) and normetanephrine 8,511 ug/24 hr (normal, 50-800 ug/24 hr).

The markedly elevated plasma and urine normetanephrine levels confirm a diagnosis of a catecholamine-secreting tumor (paraganglioma). The tissue obtained from the CT-guided lymph node biopsy should be sent for markers of neuroendocrine tumors including chromogranin.

Lymph node biopsy revealed metastatic paraganglioma that was chromogranin A and synaptophysin positive (Figure 2). A fluorodeoxyglucose positron emission tomography (FDG-PET) scan disclosed skull metastases. He was treated with phenoxybenzamine, amlodipine, and labetalol. Surgical resection of the pelvic mass was discussed, but the patient elected to defer surgery as the location of the primary tumor made it challenging to resect and would have required an ileal conduit.

After the diagnosis was made, the patient’s family recalled that a maternal uncle had been diagnosed with a paraganglioma of the carotid body. Genetic testing of the patient identified a succinate dehydrogenase complex subunit B (SDHB) pathogenic variant and confirmed hereditary paraganglioma syndrome (HPGL). One year after the diagnosis, liver and lung metastases developed. He was treated with lanreotide (somatostatin analogue), capecitabine, and temozolomide, as well as a craniotomy and radiotherapy for palliation of bony metastases. The patient died less than two years after diagnosis.

Most patients with hypertension (defined as blood pressure >130/80 mm Hg¹) do not have an identifiable etiology (primary hypertension). Many components of this patient’s history, however, including his young age of onset, a teenage sibling with hypertension, lack of obesity, hypertension refractory to multiple medications, and LVH suggested secondary hypertension. Hypertension onset at an age less than 30 years, resistance to three or more medications,^1,2 and/or acute onset hypertension at any age should prompt an evaluation for secondary causes.¹ The prevalence of secondary hypertension is approximately 30% in hypertensive patients ages 18 to 40 years compared with 5%-10% in the overall adult population with hypertension.³ Among children and adolescents ages 0 to 19 years with hypertension, the prevalence of secondary hypertension may be as high as 57%.⁴

The most common etiology of secondary hypertension is primary aldosteronism.^5,6 However, in young adults (ages 19 to 39 years), common etiologies also include renovascular disease and renal parenchymal disease.⁷ Other causes include obstructive sleep apnea, medications, stimulants (cocaine and amphetamines),⁸ and endocrinopathies such as thyrotoxicosis, Cushing syndrome, and catecholamine-secreting tumors.⁷ Less than 1% of secondary hypertension in all adults is due to catecholamine-secreting tumors, and the minority of those catecholamine-secreting tumors are paragangliomas.⁹

Paragangliomas are tumors of the peripheral autonomic nervous system. These neoplasms arise in the sympathetic and parasympathetic chains along the paravertebral and paraaortic axes. They are closely related to pheochromocytomas, which arise in the adrenal medulla.⁹ Most head and neck paragangliomas are biochemically silent and are generally discovered due to mass effect.¹⁰ The subset of paragangliomas that secrete catecholamines most often arise in the abdomen and pelvis, and their clinical presentation mimics that of pheochromocytomas, including episodic hypertension, palpitations, pallor, and diaphoresis.

This patient had persistent, nonepisodic hypertension, while palpitations and diaphoresis only manifested following micturition. Other cases of urinary bladder paragangliomas have described micturition-associated symptoms and hypertensive crises. Three-fold increases of catecholamine secretion after micturition have been observed in these patients, likely due to muscle contraction and pressure changes in the bladder leading to the systemic release of catecholamines.¹¹

Epinephrine and norepinephrine are monoamine neurotransmitters that activate alpha-adrenergic and beta-adrenergic receptors. Adrenergic receptors are present in all tissues of the body but have prominent effects on the smooth muscle in the vasculature, gastrointestinal tract, urinary tract, and airways.¹² Alpha-adrenergic vasoconstriction causes hypertension, which is commonly observed in patients with catecholamine-secreting tumors.¹⁰ Catecholamine excess due to secretion from these tumors causes headache in 60%-80% of patients, tachycardia/palpitations in 50%-70%, anxiety in 20%-40%, and nausea in 20%-25%.¹⁰ Other symptoms include sweating, pallor, dyspnea, and vertigo.^9,10 This patient’s chronic nausea, which was attributed to gastroesophageal reflux, and his anxiety, attributed to generalized anxiety disorder, were likely symptoms of catecholamine excess.¹³

The best test for the diagnosis of paragangliomas and pheochromocytomas is the measurement of plasma free or 24-hour urinary fractionated metanephrines (test sensitivity of >90% and >90%, respectively).¹⁴ Screening for pheochromocytoma should be considered in hypertensive patients who have symptoms of catecholamine excess, refractory or paroxysmal hypertension, and/or familial pheochromocytoma/paraganglioma syndromes.¹⁵ Screening for pheochromocytoma should also be performed in children and adolescents with systolic or diastolic blood pressure that is greater than the 95th percentile for their age plus 5 mm Hg.¹⁶

While a typical tumor location and elevated metanephrine levels are sufficient to make the diagnosis of a pheochromocytoma or catecholamine-secreting paraganglioma, functional imaging with FDG-PET, Ga-DOTATATE-PET, or 123I-meta-iodobenzylguanidine (123I-MIBG) can further confirm the diagnosis and detect distant metastases. However, imaging has low sensitivity for these tumors and thus should only be considered for patients in whom metastatic disease is suspected.¹⁴ Biopsy is rarely needed and should be reserved for unusual metastatic locations. Treatment with an alpha-adrenergic receptor antagonist often reduces symptoms and lowers blood pressure. Definitive management typically involves surgical resection for benign disease. Surgery, radionuclide therapy, or chemotherapy is used for malignant disease.

While most pheochromocytomas are sporadic, up to 40% of paragangliomas are due to germline pathogenic variants.¹⁷ Mutations in the succinate dehydrogenase (SDH) group of genes are the most common germline pathogenic variants in the autosomal dominant hereditary paraganglioma syndrome (HPGL). Most paragangliomas and pheochromocytomas are localized and benign, but 10%-15% are metastatic.¹⁸ SDHB mutations are associated with a high risk of metastasis.¹⁹ Thus, genetic testing for patients and subsequent cascade testing to identify at-risk family members is advised in all patients with pheochromocytomas or paragangliomas.²⁰ This patient’s younger brother and mother were both found to carry the same pathogenic SDHB variant, but neither was found to have paragangliomas. Annual metanephrine levels (urine or plasma) and every other year whole-body magnetic resonance imaging (MRI) scans were recommended for tumor surveillance.

The clinician team followed a logical branching algorithm for the diagnosis of severe hypertension with biochemical testing, advanced imaging, histology, and genetic testing to arrive at the final diagnosis of hereditary paraganglioma syndrome. Although this patient presented for urgent care because of the acute effects of catecholamine excess, he suffered from chronic effects (nausea, anxiety, and hypertension) for years. Each symptom had been diagnosed and treated in isolation, but the combination and severity in a young patient suggested a unifying diagnosis. The family history of hypertension (brother and father) suggested an inherited diagnosis from the father’s family, but the final answer rested on the other branch (maternal uncle) of the family tree.

• Hypertension in a young adult is due to a secondary cause in up to 30% of patients.
• Pathologic catecholamine excess leads to hypertension, tachycardia, pallor, sweating, anxiety, and nausea. A sustained and unexplained combination of these symptoms should prompt a biochemical evaluation for pheochromocytoma or paraganglioma.
• Paragangliomas are tumors of the autonomic nervous system. The frequency of catecholamine secretion depends on their location in the body, and they are commonly caused by germline pathogenic variants.

Acknowledgments

This conundrum was presented during a live Grand Rounds with the expert clinician’s responses recorded and edited for space and clarity.

Disclosures

Dr. Dhaliwal reports speaking honoraria from ISMIE Mutual Insurance Company and GE Healthcare. All other authors have nothing to disclose.

Funding

No sources of funding.

A 21-year-old man with a history of hypertension presented to the emergency department with four days of generalized abdominal pain, nausea, and vomiting as well as one month of loose stools. He also had a headache (not further specified) for one day. Due to his nausea, he had been unable to take his medications for two days. Home blood pressure measurements over the preceding two days revealed systolic pressures exceeding 200 mm Hg. He did not experience fever, dyspnea, chest pain, vision changes, numbness, weakness, diaphoresis, or palpitations.

Abdominal pain with vomiting and diarrhea is often caused by a self-limited gastroenteritis. However, the priority initially is to exclude serious intraabdominal processes including arterial insufficiency, bowel obstruction, organ perforation, or organ-based infection or inflammation (eg, appendicitis, cholecystitis, pancreatitis). Essential hypertension accounts for 95% of cases of hypertension in the United States, but given this patient’s young age, secondary causes should be evaluated. These include primary aldosteronism (the most common endocrine cause for hypertension in young patients), chronic kidney disease, fibromuscular dysplasia, illicit drug use, hypercortisolism, pheochromocytoma, and coarctation of the aorta. Thyrotoxicosis can elevate blood pressure (although usually not to this extent) and cause hyperdefecation. While the etiology of the chronic hypertension is uncertain, the proximate cause of the acute rise in blood pressure is likely the stress of his acute illness and the inability to take his prescribed antihypertensive medications. In the setting of severe hypertension, his headache may reflect an intracranial hemorrhage and his abdominal pain could signal an aortic dissection.

His medical history included hypertension diagnosed at age 16 as well as anxiety diagnosed following a panic attack at age 19. Over the past year, he had also developed persistent nausea, which was attributed to gastroesophageal reflux disease. His medications included metoprolol 50 mg daily, amlodipine 5 mg daily, hydrochlorothiazide 12.5 mg daily, escitalopram 20 mg daily, and omeprazole 20 mg daily. His father and 15-year-old brother also had hypertension. He was a part-time student while working at a car dealership. He did not smoke or use drugs and he rarely drank alcohol.

The need for three antihypertensive medications (albeit at submaximal doses) reflects the severity of his hypertension (provided challenges with medication adherence have been excluded). His family history, especially that of his brother who was diagnosed with hypertension at an early age, and the patient’s own early onset hypertension point toward an inherited form of hypertension. Autosomal dominant polycystic kidney disease often results in hypertension before chronic kidney disease develops. Rare inherited forms of hypertension include familial hyperaldosteronism, apparent mineralocorticoid excess, Liddle syndrome, or a hereditary endocrine tumor syndrome predisposing to pheochromocytoma. Even among patients who report classic pheochromocytoma symptoms, such as headache and anxiety, the diagnosis remains unlikely as these symptoms are nonspecific and highly prevalent in the general population. However, once secondary hypertension is plausible or suspected, testing for hyperadrenergic states, which can also cause nausea and vomiting during times of catecholamine excess, should be pursued.

His temperature was 97.5°F, heart rate 95 beats per minute and regular, respiratory rate 18 breaths per minute, blood pressure 181/118 mm Hg (systolic and diastolic pressures in each arm were within 10 mm Hg), and oxygen saturation 100% on room air. Systolic and diastolic pressures did not decrease by more than 20 mm Hg and 10 mm Hg, respectively, after he stood for two minutes. His body mass index was 24 kg/m². He was alert and appeared slightly anxious. There was a bounding point of maximal impulse in the fifth intercostal space at the midclavicular line and a 3/6 systolic murmur at the left upper sternal border with radiation to the carotid arteries. His abdomen was soft with generalized tenderness to palpation and without rebound tenderness, masses, organomegaly, or bruits. There was no costovertebral angle tenderness. No lymphadenopathy was present. His fundoscopic, pulmonary, skin and neurologic examinations were normal.

Laboratory studies revealed a white blood cell count of 13.3 × 10³/uL with a normal differential, hemoglobin 13.9 g/dL, platelet count 373 × 10³/uL, sodium 142 mmol/L, potassium 3.8 mmol/L, chloride 103 mmol/L,bicarbonate 25 mmol/L, blood urea nitrogen 12 mg/dL, creatinine 1.3 mg/dL (a baseline creatinine level was not available), glucose 88 mg/dL, calcium 10.6 mg/dL, albumin 4.9 g/dL, aspartate aminotransferase 27 IU/L, alanine aminotransferase 37 IU/L, and lipase 40 IU/L. Urinalysis revealed 5-10 white blood cells per high power field without casts and 10 mg/dL protein. Urine toxicology was not performed. Electrocardiogram (ECG) showed left ventricular hypertrophy (LVH). Chest radiography was normal.

The abdominal examination does not suggest peritonitis. The laboratory tests do not suggest inflammation of the liver, pancreas, or biliary tree as the cause of his abdominal pain or diarrhea. The murmur may indicate hypertrophic cardiomyopathy or a congenital anomaly such as bicuspid aortic valve; but neither would explain hypertension unless they were associated with another developmental abnormality, such as coarctation of the aorta. Tricuspid regurgitation is conceivable and if confirmed, might raise concern for carcinoid syndrome, which can cause diarrhea. The normal neurologic examination, including the absence of papilledema, lowers suspicion of intracranial hemorrhage as a cause of his headache.

The albumin of 4.9 g/dL likely reflects hypovolemia resulting from vomiting and diarrhea. Vasoconstriction associated with pheochromocytoma can cause pressure diuresis and resultant hypovolemia. Hyperaldosteronism arising from bilateral adrenal hyperplasia or adrenal adenoma commonly causes hypokalemia, although this is not a universal feature.

The duration of his mildly decreased glomerular filtration rate is uncertain. He may have chronic kidney disease from sustained hypertension, or acute kidney injury from hypovolemia. The mild pyuria could indicate infection or renal calculi, either of which could account for generalized abdominal pain or could reflect an acute renal injury from acute interstitial nephritis from his proton pump inhibitor or hydrochlorothiazide.

LVH on the ECG indicates longstanding hypertension. The chest radiograph does not reveal clues to the etiology of or sequelae from hypertension. In particular, there is no widened aorta to suggest aortic dissection, no pulmonary edema to indicate heart failure, and no rib notching that points toward aortic coarctation. A transthoracic echocardiogram to assess for valvular and other structural abnormalities is warranted.

Tests for secondary hypertension should be sent, including serum aldosterone and renin levels to assess for primary aldosteronism and plasma or 24-hour urine normetanephrine and metanephrine levels to assess for pheochromocytoma. Biochemical evaluation is the mainstay for endocrine hypertension evaluation and should be followed by imaging if abnormal results are found.

Intact parathyroid hormone (PTH) was 78 pg/mL (normal, 10-65 pg/mL), thyroid stimulating hormone 3.6 mIU/L (normal, 0.30-5.50 mIU/L), and morning cortisol 4.1 ug/dL (normal, >7.0 ug/dL). Plasma aldosterone was 14.6 ng/dL (normal, 1-16 ng/dL), plasma renin activity 3.6 ng/mL/hr (normal, 0.5-3.5 ng/mL/hr), and aldosterone-renin ratio 4.1 (normal, <20). Transthoracic echocardiogram showed LVH with normal valves, wall motion, and proximal aorta; the left ventricular ejection fraction was 70%. Magnetic resonance angiography of the renal vessels demonstrated no abnormalities.

Computed tomography (CT) of the abdomen and pelvis with oral and intravenous contrast revealed a 5 cm heterogeneous enhancing mass associated with the prostate gland extending into the base of the bladder. The mass obstructed the right renal collecting system and ureter causing severe right-sided ureterectasis and hydronephrosis. There was also 2.8 cm right-sided paracaval lymph node enlargement and 2.1 cm right-sided and 1.5 cm left-sided external iliac lymph node enlargement (Figure 1). There were no adrenal masses.

He is young for prostate, bladder, or colorectal cancer, but early onset variations of these tumors, along with metastatic testicular cancer, must be considered for the pelvic mass and associated lymphadenopathy. Prostatic masses can be infectious (eg, abscess) or malignant (eg, adenocarcinoma, small cell carcinoma). Additional considerations for abdominopelvic cancer are sarcomas, germ cell tumors, or lymphoma. A low aldosterone-renin ratio coupled with a normal potassium level makes primary aldosteronism unlikely. The normal angiography excludes renovascular hypertension.

His abdominal pain and gastrointestinal symptoms could arise from irritation of the bowel, distension of the right-sided urinary collecting system, or products secreted from the mass (eg, catecholamines). The hyperdynamic precordium, elevated ejection fraction, and murmur may reflect augmented blood flow from a hyperadrenergic state. A unifying diagnosis would be a pheochromocytoma. However, given the normal appearance of the adrenal glands on CT imaging, catecholamines arising from a paraganglioma, a tumor of the autonomic nervous system, is more likely. These tumors often secrete catecholamines and can be metastatic (suggested here by the lymphadenopathy). Functional imaging or biopsy of either the mass or an adjacent lymph node is indicated. However, because of the possibility of a catecholamine-secreting tumor, he should be treated with an alpha-adrenergic receptor antagonist before undergoing a biopsy to prevent unopposed vasoconstriction from catecholamine leakage.

Scrotal ultrasound revealed no evidence of a testicular tumor. Lactate dehydrogenase (LDH) was 179 IU/L (normal, 120-240 IU/L) and prostate specific antigen (PSA) was 0.7 ng/mL (normal, <2.5 ng/mL). The patient was given amlodipine and labetalol with improvement of blood pressures to 160s/100s. His creatinine decreased to 1.1 mg/dL. He underwent CT-guided biopsy of a pelvic lymph node. CT of the head without intravenous contrast demonstrated no intracranial abnormalities. His headache resolved with improvement in blood pressure, and he had minimal gastrointestinal symptoms during his hospitalization. No stool studies were sent. A right-sided percutaneous nephrostomy was placed which yielded >15 L of urine from the tube over the next four days.

Upon the first episode of micturition through the urethra four days after percutaneous nephrostomy placement, he experienced severe lightheadedness, diaphoresis, and palpitations. These symptoms prompted him to recall similar episodes following micturition for several months prior to his hospitalization.

It is likely that contraction of the bladder during episodes of urination caused irritation of the pelvic mass, leading to catecholamine secretion. Another explanation for his recurrent lightheadedness would be a neurocardiogenic reflex with micturition (which when it culminates with loss of consciousness is called micturition syncope), but this would not explain his hypertension or bladder mass.

Biochemical tests that were ordered on admission but sent to a reference lab then returned. Plasma metanephrine was 0.2 nmol/L (normal, <0.5 nmol/L) and plasma normetanephrine 34.6 nmol/L (normal, <0.9 nmol/L). His 24-hour urine metanephrine was 72 ug/24 hr (normal, 0-300 ug/24 hr) and normetanephrine 8,511 ug/24 hr (normal, 50-800 ug/24 hr).

The markedly elevated plasma and urine normetanephrine levels confirm a diagnosis of a catecholamine-secreting tumor (paraganglioma). The tissue obtained from the CT-guided lymph node biopsy should be sent for markers of neuroendocrine tumors including chromogranin.

Lymph node biopsy revealed metastatic paraganglioma that was chromogranin A and synaptophysin positive (Figure 2). A fluorodeoxyglucose positron emission tomography (FDG-PET) scan disclosed skull metastases. He was treated with phenoxybenzamine, amlodipine, and labetalol. Surgical resection of the pelvic mass was discussed, but the patient elected to defer surgery as the location of the primary tumor made it challenging to resect and would have required an ileal conduit.

After the diagnosis was made, the patient’s family recalled that a maternal uncle had been diagnosed with a paraganglioma of the carotid body. Genetic testing of the patient identified a succinate dehydrogenase complex subunit B (SDHB) pathogenic variant and confirmed hereditary paraganglioma syndrome (HPGL). One year after the diagnosis, liver and lung metastases developed. He was treated with lanreotide (somatostatin analogue), capecitabine, and temozolomide, as well as a craniotomy and radiotherapy for palliation of bony metastases. The patient died less than two years after diagnosis.

Most patients with hypertension (defined as blood pressure >130/80 mm Hg¹) do not have an identifiable etiology (primary hypertension). Many components of this patient’s history, however, including his young age of onset, a teenage sibling with hypertension, lack of obesity, hypertension refractory to multiple medications, and LVH suggested secondary hypertension. Hypertension onset at an age less than 30 years, resistance to three or more medications,^1,2 and/or acute onset hypertension at any age should prompt an evaluation for secondary causes.¹ The prevalence of secondary hypertension is approximately 30% in hypertensive patients ages 18 to 40 years compared with 5%-10% in the overall adult population with hypertension.³ Among children and adolescents ages 0 to 19 years with hypertension, the prevalence of secondary hypertension may be as high as 57%.⁴

The most common etiology of secondary hypertension is primary aldosteronism.^5,6 However, in young adults (ages 19 to 39 years), common etiologies also include renovascular disease and renal parenchymal disease.⁷ Other causes include obstructive sleep apnea, medications, stimulants (cocaine and amphetamines),⁸ and endocrinopathies such as thyrotoxicosis, Cushing syndrome, and catecholamine-secreting tumors.⁷ Less than 1% of secondary hypertension in all adults is due to catecholamine-secreting tumors, and the minority of those catecholamine-secreting tumors are paragangliomas.⁹

Paragangliomas are tumors of the peripheral autonomic nervous system. These neoplasms arise in the sympathetic and parasympathetic chains along the paravertebral and paraaortic axes. They are closely related to pheochromocytomas, which arise in the adrenal medulla.⁹ Most head and neck paragangliomas are biochemically silent and are generally discovered due to mass effect.¹⁰ The subset of paragangliomas that secrete catecholamines most often arise in the abdomen and pelvis, and their clinical presentation mimics that of pheochromocytomas, including episodic hypertension, palpitations, pallor, and diaphoresis.

This patient had persistent, nonepisodic hypertension, while palpitations and diaphoresis only manifested following micturition. Other cases of urinary bladder paragangliomas have described micturition-associated symptoms and hypertensive crises. Three-fold increases of catecholamine secretion after micturition have been observed in these patients, likely due to muscle contraction and pressure changes in the bladder leading to the systemic release of catecholamines.¹¹

Epinephrine and norepinephrine are monoamine neurotransmitters that activate alpha-adrenergic and beta-adrenergic receptors. Adrenergic receptors are present in all tissues of the body but have prominent effects on the smooth muscle in the vasculature, gastrointestinal tract, urinary tract, and airways.¹² Alpha-adrenergic vasoconstriction causes hypertension, which is commonly observed in patients with catecholamine-secreting tumors.¹⁰ Catecholamine excess due to secretion from these tumors causes headache in 60%-80% of patients, tachycardia/palpitations in 50%-70%, anxiety in 20%-40%, and nausea in 20%-25%.¹⁰ Other symptoms include sweating, pallor, dyspnea, and vertigo.^9,10 This patient’s chronic nausea, which was attributed to gastroesophageal reflux, and his anxiety, attributed to generalized anxiety disorder, were likely symptoms of catecholamine excess.¹³

The best test for the diagnosis of paragangliomas and pheochromocytomas is the measurement of plasma free or 24-hour urinary fractionated metanephrines (test sensitivity of >90% and >90%, respectively).¹⁴ Screening for pheochromocytoma should be considered in hypertensive patients who have symptoms of catecholamine excess, refractory or paroxysmal hypertension, and/or familial pheochromocytoma/paraganglioma syndromes.¹⁵ Screening for pheochromocytoma should also be performed in children and adolescents with systolic or diastolic blood pressure that is greater than the 95th percentile for their age plus 5 mm Hg.¹⁶

While a typical tumor location and elevated metanephrine levels are sufficient to make the diagnosis of a pheochromocytoma or catecholamine-secreting paraganglioma, functional imaging with FDG-PET, Ga-DOTATATE-PET, or 123I-meta-iodobenzylguanidine (123I-MIBG) can further confirm the diagnosis and detect distant metastases. However, imaging has low sensitivity for these tumors and thus should only be considered for patients in whom metastatic disease is suspected.¹⁴ Biopsy is rarely needed and should be reserved for unusual metastatic locations. Treatment with an alpha-adrenergic receptor antagonist often reduces symptoms and lowers blood pressure. Definitive management typically involves surgical resection for benign disease. Surgery, radionuclide therapy, or chemotherapy is used for malignant disease.

While most pheochromocytomas are sporadic, up to 40% of paragangliomas are due to germline pathogenic variants.¹⁷ Mutations in the succinate dehydrogenase (SDH) group of genes are the most common germline pathogenic variants in the autosomal dominant hereditary paraganglioma syndrome (HPGL). Most paragangliomas and pheochromocytomas are localized and benign, but 10%-15% are metastatic.¹⁸ SDHB mutations are associated with a high risk of metastasis.¹⁹ Thus, genetic testing for patients and subsequent cascade testing to identify at-risk family members is advised in all patients with pheochromocytomas or paragangliomas.²⁰ This patient’s younger brother and mother were both found to carry the same pathogenic SDHB variant, but neither was found to have paragangliomas. Annual metanephrine levels (urine or plasma) and every other year whole-body magnetic resonance imaging (MRI) scans were recommended for tumor surveillance.

The clinician team followed a logical branching algorithm for the diagnosis of severe hypertension with biochemical testing, advanced imaging, histology, and genetic testing to arrive at the final diagnosis of hereditary paraganglioma syndrome. Although this patient presented for urgent care because of the acute effects of catecholamine excess, he suffered from chronic effects (nausea, anxiety, and hypertension) for years. Each symptom had been diagnosed and treated in isolation, but the combination and severity in a young patient suggested a unifying diagnosis. The family history of hypertension (brother and father) suggested an inherited diagnosis from the father’s family, but the final answer rested on the other branch (maternal uncle) of the family tree.

• Hypertension in a young adult is due to a secondary cause in up to 30% of patients.
• Pathologic catecholamine excess leads to hypertension, tachycardia, pallor, sweating, anxiety, and nausea. A sustained and unexplained combination of these symptoms should prompt a biochemical evaluation for pheochromocytoma or paraganglioma.
• Paragangliomas are tumors of the autonomic nervous system. The frequency of catecholamine secretion depends on their location in the body, and they are commonly caused by germline pathogenic variants.

Acknowledgments

This conundrum was presented during a live Grand Rounds with the expert clinician’s responses recorded and edited for space and clarity.

Disclosures

Dr. Dhaliwal reports speaking honoraria from ISMIE Mutual Insurance Company and GE Healthcare. All other authors have nothing to disclose.

Funding

No sources of funding.

In This Edition

Literature at a Glance

A guide to this month’s studies

• CPOE and quality outcomes
• Outcomes of standardized management of endocarditis
• Effect of tPA three to 4.5 hours after stroke onset
• Failure to notify patients of significant test results
• PFO repair and stroke rate
• Predictors of delay in defibrillation for in-hospital arrest
• H. pylori eradication and risk of future gastric cancer
• Bleeding risk with fondaparinux vs. enoxaparin in ACS
• Perceptions of physician ability to predict medical futility

CPOE Is Associated with Improvement in Quality Measures

Clinical question: Is computerized physician order entry (CPOE) associated with improved outcomes across a large, nationally representative sample of hospitals?

Background: Several single-institution studies suggest CPOE leads to better outcomes in quality measures for heart failure, acute myocardial infarction, and pneumonia as defined by the Hospital Quality Alliance (HQA) initiative, led by the Centers for Medicare and Medicaid Services (CMS). Little systematic information is known about the effects of CPOE on quality of care.

Study design: Cross-sectional study.

Setting: The Health Information Management System Society (HIMSS) analytics database of 3,364 hospitals throughout the U.S.

Synopsis: Of the hospitals that reported CPOE utilization to HIMSS, 264 (7.8%) fully implement CPOE throughout their institutions. These CPOE hospitals outperformed their peers on five of 11 quality measures related to ordering medications, and in one of nine non-medication-related measures. No difference was noted in the other measures, except CPOE hospitals were less effective at providing antibiotics within four hours of pneumonia diagnosis. Hospitals that utilized CPOE were generally academic, larger, and nonprofit. After adjusting for these differences, benefits were still preserved.

The authors indicate that the lack of systematic outperformance by CPOE hospitals in all 20 of the quality categories inherently suggests that other factors (e.g., concomitant QI efforts) are not affecting these results. Given the observational nature of this study, no causal relationship can be established between CPOE and the observed benefits. CPOE might represent the commitment of certain hospitals to quality measures, but further study is needed.

Bottom line: Enhanced compliance in several CMS-established quality measures is seen in hospitals that utilize CPOE throughout their institutions.

Citation: Yu FB, Menachemi N, Berner ES, Allison JJ, Weissman NW, Houston TK. Full implementation of computerized physician order entry and medication-related quality outcomes: a study of 3,364 hospitals. Am J Med Qual. 2009;24(4):278-286.

Standardized Management of Endocarditis Leads to Significant Mortality Benefit

Clinical question: Does a standardized approach to the treatment of infective endocarditis reduce mortality and morbidity?

Background: Despite epidemiological changes to the inciting bacteria and improvements in available antibiotics, mortality and morbidity associated with endocarditis remain high. The contribution of inconsistent or inaccurate treatment of endocarditis is unclear.

Study design: Case series with historical controls from 1994 to 2001, compared with protocolized patients from 2002 to 2006.

Setting: Single teaching tertiary-care hospital in France.

Synopsis: The authors established a diagnostic protocol for infectious endocarditis from 1994 to 2001 (period 1) and established a treatment protocol from 2002 to 2006 (period 2). Despite a statistically significant sicker population (older, higher comorbidities, higher coagulase-negative staphylococcal infections, and fewer healthy valves), the period-2 patients had a dramatically lower mortality rate of 8.2% (P<0.001), compared with 18.5% in period-1 patients. Fewer episodes of renal failure, organ failure, and deaths associated with embolism were noted in period 2.

Whether these results are due to more frequent care, more aggressive care (patients were “summoned” if they did not show for appointments), standardized medication and surgical options, or the effects of long-term collaboration, these results appear durable, remarkable, and reproducible.

This study is limited by its lack of randomization and extensive time frame, with concomitant changes in medical treatment and observed infectious organisms.

Bottom line: Implementation of a standardized approach to endocarditis has significant benefit on mortality and morbidity.

Citation: Botelho-Nevers E, Thuny F, Casalta JP, et al. Dramatic reduction in infective endocarditis-related mortality with a management-based approach. Arch Intern Med. 2009;169(14):1290-1298.

Treatment with tPA in the Three- to 4.5-Hour Time Window after Stroke Is Beneficial

Clinical question: What is the effect of tissue plasminogen activator (tPA) on outcomes in patients treated in the three- to 4.5-hour window after stroke?

Background: The third European Cooperative Acute Stroke Study 3 (ECASS-3) demonstrated benefit of treatment of acute stroke with tPA in the three- to 4.5-hour time window. Prior studies, however, did not show superiority of tPA over placebo, and there is a lack of a confirmatory randomized, controlled trial of tPA in this time frame.

Study design: Meta-analysis of randomized, controlled trials.

Setting: Four studies involving 1,622 patients who were treated with intravenous tPA for acute ischemic stroke from three to 4.5 hours after stroke compared with placebo.

Synopsis: Of the randomized, controlled trials of intravenous tPA for treatment of acute ischemic stroke from three to 4.5 hours after stroke, four trials (ECASS-1, ECASS-2, ECASS-3, and ATLANTIS) were included in the analysis. Treatment with tPA in the three- to 4.5-hour time window is associated with increased favorable outcomes based on the global outcome measure (OR 1.31; 95% CI: 1.10-1.56, P=0.002) and the modified Rankin Scale (OR 1.31; 95% CI: 1.07-1.59, P=0.01), compared with placebo. The 90-day mortality rate was not significantly different between the treatment and placebo groups (OR 1.04; 95% CI 0.75-1.43, P=0.83).

Due to the relatively high dose of tPA (1.1 mg/kg) administered in the ECASS-1 trial, a separate meta-analysis looking at the other three trials (tPA dose of 0.9 mg/kg) was conducted, and the favorable outcome with tPA remained.

Bottom line: Treatment of acute ischemic stroke with tPA in the three- to 4.5-hour time window results in an increased rate of favorable functional outcomes without a significant difference in mortality.

Citation: Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40(7):2438-2441.

Outpatients Often Are Not Notified of Clinically Significant Test Results

Clinical question: How frequently do primary-care physicians (PCPs) fail to inform patients of clinically significant outpatient test results?

Background: Diagnostic errors are the most common cause of malpractice claims in the U.S. It is unclear how often providers fail to either inform patients of abnormal test results or document that patients have been notified.

Study design: Retrospective chart review.

Setting: Twenty-three primary-care practices: 19 private, four academic.

Synopsis: More than 5,400 charts were reviewed, and 1,889 abnormal test results were identified in this study. Failure to inform or document notification was identified in 135 cases (7.1%). The failure rates in the practices ranged from 0.0% to 26.2%. Practices with the best processes for managing test results had the lowest failure rates; these processes included: all results being routed to the responsible physician; the physician signing off on all results; the practice informing patients of all results, both normal and abnormal; documenting when the patient is informed; and instructing patients to call if not notified of test results within a certain time interval.

Limitations of this study include the potential of over- or underreporting of failures to inform as a chart review was used, and only practices that agreed to participate were included.

Bottom line: Failure to notify outpatients of test results is common but can be minimized by creating a systematic management of test results that include best practices.

Citation: Casalino LP, Dunham D, Chin MH, et al. Frequency of failure to inform patients of clinically significant outpatient test results. Arch Intern Med. 2009;169(12):1123-1129.

Repair of Incidental PFO Discovered During Cardiothoracic Surgery Repair Increases Postoperative Stroke Risk

Clinical question: What is the impact of closing incidentally discovered patent foramen ovale (PFO) defects during cardiothoracic surgery?

Background: PFO’s role in cryptogenic stroke remains controversial. Incidental PFO is commonly detected by transesophageal echocardiography (TEE) during cardiothoracic surgery. Routine PFO closure has been recommended when almost no alteration of the surgical plan is required.

Study design: Retrospective chart review.

Setting: The Cleveland Clinic.

Synopsis: Between 1995 and 2006, 13,092 patients undergoing cardiothoracic surgery had TEE data with no previous diagnosis of PFO, but the review found that 2,277 (17%) had PFO discovered intraoperatively. Of these, 639 (28%) had the PFO repaired.

Patients with an intraoperative diagnosis of PFO had similar rates of in-hospital stroke and hospital death compared with those without PFO. Patients who had their PFO repaired had a greater in-hospital stroke risk (2.8% vs. 1.2%; P=0.04) compared with those with a non-repaired PFO, representing nearly 2.5 times greater odds of having an in-hospital stroke. No other difference was noted in perioperative outcomes for patients who underwent intraoperative repair compared with those who did not, including risk of in-hospital death, hospital length of stay, ICU length of stay, and time on cardiopulmonary bypass. Long-term analysis demonstrated that PFO repair was associated with no survival difference.

The study is limited by its retrospective nature.

Bottom line: Routine surgical closure of incidental PFO detected during intraoperative imaging should be discouraged.

Citation: Krasuski RA, Hart SA, Allen D, et al. Prevalence and repair of interoperatively diagnosed patent foramen ovale and association with perioperative outcomes and long-term survival. JAMA. 2009;302(3):290-297.

Hospital-Level Differences Are Strong Predictors of Time to Defibrillation Delay In Cardiac Arrest

Clinical question: What are the predictors of delay in the time to defibrillation after in-hospital cardiac arrest?

Background: Thirty percent of in-hospital cardiac arrests from ventricular arrhythmias are not treated within the American Heart Association’s recommendation of two minutes. This delay is associated with a 50% lower rate of in-hospital survival. Exploring the hospital-level variation in delays to defibrillation is a critical step toward sharing the best practices.

Study design: Retrospective review of registry data.

Setting: The National Registry of Cardiopulmonary Resuscitation (NRCPR) survey of 200 acute-care, nonpediatric hospitals.

Synopsis: The registry identified 7,479 patients who experienced cardiac arrest from ventricular tachycardia or pulseless ventricular fibrillation. The primary outcome was the hospital rate of delayed defibrillation (time to defibrillation > two minutes), which ranged from 2% to 51%.

Time to defibrillation was found to be a major predictor of survival after a cardiac arrest. Only bed volume and arrest location were associated with differences in rates of delayed defibrillation (lower rates in larger hospitals and in ICUs). The variability was not due to differences in patient characteristics, but was due to hospital-level effects. Academic status, geographical location, arrest volume, and daily admission volume did not affect the time to defibrillation.

The study was able to identify only a few facility characteristics that account for the variability between hospitals in the rate of delayed defibrillation. The study emphasizes the need for new approaches to identifying hospital innovations in process-of-care measures that are associated with improved performance in defibrillation times.

Bottom Line: Future research is needed to better understand the reason for the wide variation between hospitals in the rate of delayed defibrillation after in-hospital cardiac arrest.

Citation: Chan PS, Nichol G, Krumholz HM, Spertus JA, Nallamothu BK; American Heart Association National Registry of Cardiopulmonary Resuscitation (NRCPR) Investigators. Hospital variation in time to defibrillation after in-hospital cardiac arrest. Arch Intern Med. 2009;169(14):1265-1273.

Treating for H. Pylori Reduces the Risk for Developing Gastric Cancer in High-Risk Patients

Clinical question: In patients with high-baseline incidence of gastric cancer, does H. pylori eradication reduce the risk for developing gastric cancer?

Background: Gastric cancer remains a major health problem in Asia. The link of H. pylori and gastric cancer has been established, but it remains unclear whether treatment for H. pylori is effective primary prevention for the development of gastric cancer.

Study design: Meta-analysis of six studies.

Setting: All but one trial was performed in Asia.

Synopsis: Seven studies met inclusion criteria, one of which was excluded due to heterogeneity. The six remaining studies were pooled, with 37 of 3,388 (1.1%) treated patients developing a new gastric cancer, compared with 56 of 3,307 (1.7%) patients who received placebo or were in the control group (RR 0.65; 0.43-0.98). Most patients received gastric biopsy prior to enrollment, and most of those demonstrated gastric atrophy or intestinal metaplasia.

These patients, despite more advanced precancerous pathology findings, still benefited from eradication. The seventh study, which was excluded, enrolled patients with early gastric cancer; these patients still benefited from H. pylori eradication and, when included in the meta-analysis, the RR was even lower, 0.57 (0.49-0.81).

Only two trials were double-blinded, but all of the studies employed the same definition of gastric cancer and held to excellent data reporting standards. This study encourages screening and treatment in high-risk patients given the widespread incidence of H. pylori.

Bottom Line: Treatment of H. pylori reduces the risk of gastric cancer in high-risk patients.

Citation: Fuccio L, Zagari RM, Eusebi LH, et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med. 2009;151(2):121-128.

Patients on Anti-Platelet Agents with Acute Coronary Syndrome Have a Lower Bleeding Risk When Treated with Fondaparinux

Clinical question: Is there a difference in bleeding risk with fondaparinux and enoxaparin when used with GPIIb/IIIa inhibitors or thienopyridines in NSTEMI-ACS?

Background: The OASIS 5 study reported a 50% reduction in severe bleeding when comparing fondaparinux to enoxaparin in ACS while maintaining a similar efficacy. This subgroup analysis was performed to evaluate whether reduced bleeding risk with fondaparinux remains in patients treated with additional anti-platelet agents.

Study design: Subgroup analysis of a large, multicenter, randomized, double-blind trial.

Setting: Acute-care hospitals in North America, Eastern and Western Europe, Latin America, Australia, and Asia.

Synopsis: Patients with NSTE-ACS received either fondaparinux or enoxaparin and were treated with GPIIb/IIIa inhibitors or thienopyridines at the discretion of their physician. At 30 days, the fondaparinux group had similar efficacy and decreased bleeding risk in both the GPIIb/IIIa and the thienopyridine groups. Of the 3,630 patients in the GPIIb/IIIa group, the risk for major bleeding with fondaparinux was 5.2%, whereas the risk with enoxaparin was 8.3% (HR 0.61; P<0.001) compared with enoxaparin. Of the 1,352 patients treated with thienopyridines, the risk for major bleeding with fondaparinux was 3.4%, whereas the risk with enoxaparin was 5.4% (HR 0.62; P<0.001).

Bottom Line: This subgroup analysis suggests there are less-severe bleeding complications in patients treated with fondaparinux when compared with enoxaparin in the setting of cotreatment with GPIIb/IIIa inhibitors, thienopyridines, or both.

Citation: Jolly SS, Faxon DP, Fox KA, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors of thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J Am Coll Cardiol. 2009;54(5):468-476.

Surrogate Decision-Makers Frequently Doubt Clinicians’ Ability to Predict Medical Futility

Clinical question: What attitudes do surrogate decision-makers hold toward clinicians’ predictions of medical futility in critically-ill patients?

Background: The clinical judgment of medical futility leading to the withdrawal of life-sustaining treatment—despite the objections of surrogate decision-makers—is controversial. Very little is known about how surrogate decision-makers view the futility rationale when physicians suggest limiting the use of life-sustaining treatment.

Study design: Multicenter, mixed, qualitative and quantitative study.

Setting: Three ICUs in three different California hospitals from 2006 to 2007.

Synopsis: Semi-structured interviews of surrogate decision-makers for 50 incapacitated, critically-ill patients were performed to ascertain their beliefs about medical futility in response to hypothetical situations. Of the surrogates surveyed, 64% expressed doubt about physicians’ futility predictions.

The interviewees gave four main reasons for their doubts. Two reasons not previously described were doubts about the accuracy of physicians’ predictions and the need for surrogates to see futility themselves. Previously described sources of conflict included a misunderstanding about prognosis and religious-based objections. Surrogates with religious objections were more likely to request continuation of life-sustaining treatments than those with secular or experiential objections (OR 4; 95% CI 1.2-14.0; P=0.03). Nearly a third (32%) of surrogates elected to continue life support with a <1% survival estimate; 18% elected to continue life support when physicians thought there was no chance of survival.

This study has several limitations: a small sample size, the use of hypothetical situations, and the inability to assess attitudes as they change over time.

Bottom line: The nature of surrogate decision-makers’ doubts about medical futility can help predict whether they accept predictions of medical futility from physicians.

Citation: Zier LS, Burack JH, Micco G, Chipman AK, Frank JA, White DB. Surrogate decision makers’ responses to physicians’ predictions of medical futility. Chest. 2009;136:110-117. TH

PEDIATRIC HM LITerature

House-Staff Signout Complexities Remain

By Mark Shen, MD

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

Clinical question: What are the characteristics of signout among house staff?

Background: Inadequate signout is a recognized contributor to medical errors. As care has become increasingly fragmented among house staff who must comply with work-hour restrictions, both the absolute number of signouts and the potential for incomplete transfer of information increase. Despite recent Joint Commission requirements to standardize handoffs, comprehensive analyses of the process remain scarce.

Study design: Quantitative and qualitative analysis of audiotaped oral internal-medicine signout.

Setting: Academic teaching hospital.

Synopsis: Audiotaped signout for eight internal-medicine house-staff teams during two time periods in 2006 were analyzed for content, clarity of language, and surrounding environment. Most signout (59.2%) did not include questions, and questioning of patient management was often indirect when it occurred. A spectrum of clarity existed from unclear anticipatory guidance to clear, concise instructions. Interruptions occurred less than 20% of the time. Familiarity with patients, sense of responsibility for patients, sequential signouts, experience, and comprehensiveness of the written form affected the content of the signout.

This study provides insight into the broad array of factors that affect signout. Despite the potential for interactive facilitation of understanding, the process is often one-sided and operator-dependent. Such systems-based factors as familiarity with patients and sequential signouts might affect quality, while cultural norms (such as sense of responsibility) also play a role.

Limitations of this study include the nonblinded observation method and the potential for institution-specific culture to limit applicability. Nonetheless, this study adds to literature painting a broader and complex picture of a routine hospital process often taken for granted.

Bottom line: Improving and standardizing handoffs requires attention to multifaceted domains that commonly affect complex human organizations.

Citation: Horwitz LI, Moin T, Krumholz HM, Wang L, Bradley EH. What are covering doctors told about their patients? Analysis of sign-out among internal medicine house staff. Qual Saf Health Care. 2009;18(4):248-255.

In This Edition

Literature at a Glance

A guide to this month’s studies

• CPOE and quality outcomes
• Outcomes of standardized management of endocarditis
• Effect of tPA three to 4.5 hours after stroke onset
• Failure to notify patients of significant test results
• PFO repair and stroke rate
• Predictors of delay in defibrillation for in-hospital arrest
• H. pylori eradication and risk of future gastric cancer
• Bleeding risk with fondaparinux vs. enoxaparin in ACS
• Perceptions of physician ability to predict medical futility

CPOE Is Associated with Improvement in Quality Measures

Clinical question: Is computerized physician order entry (CPOE) associated with improved outcomes across a large, nationally representative sample of hospitals?

Background: Several single-institution studies suggest CPOE leads to better outcomes in quality measures for heart failure, acute myocardial infarction, and pneumonia as defined by the Hospital Quality Alliance (HQA) initiative, led by the Centers for Medicare and Medicaid Services (CMS). Little systematic information is known about the effects of CPOE on quality of care.

Study design: Cross-sectional study.

Setting: The Health Information Management System Society (HIMSS) analytics database of 3,364 hospitals throughout the U.S.

Synopsis: Of the hospitals that reported CPOE utilization to HIMSS, 264 (7.8%) fully implement CPOE throughout their institutions. These CPOE hospitals outperformed their peers on five of 11 quality measures related to ordering medications, and in one of nine non-medication-related measures. No difference was noted in the other measures, except CPOE hospitals were less effective at providing antibiotics within four hours of pneumonia diagnosis. Hospitals that utilized CPOE were generally academic, larger, and nonprofit. After adjusting for these differences, benefits were still preserved.

The authors indicate that the lack of systematic outperformance by CPOE hospitals in all 20 of the quality categories inherently suggests that other factors (e.g., concomitant QI efforts) are not affecting these results. Given the observational nature of this study, no causal relationship can be established between CPOE and the observed benefits. CPOE might represent the commitment of certain hospitals to quality measures, but further study is needed.

Bottom line: Enhanced compliance in several CMS-established quality measures is seen in hospitals that utilize CPOE throughout their institutions.

Citation: Yu FB, Menachemi N, Berner ES, Allison JJ, Weissman NW, Houston TK. Full implementation of computerized physician order entry and medication-related quality outcomes: a study of 3,364 hospitals. Am J Med Qual. 2009;24(4):278-286.

Standardized Management of Endocarditis Leads to Significant Mortality Benefit

Clinical question: Does a standardized approach to the treatment of infective endocarditis reduce mortality and morbidity?

Background: Despite epidemiological changes to the inciting bacteria and improvements in available antibiotics, mortality and morbidity associated with endocarditis remain high. The contribution of inconsistent or inaccurate treatment of endocarditis is unclear.

Study design: Case series with historical controls from 1994 to 2001, compared with protocolized patients from 2002 to 2006.

Setting: Single teaching tertiary-care hospital in France.

Synopsis: The authors established a diagnostic protocol for infectious endocarditis from 1994 to 2001 (period 1) and established a treatment protocol from 2002 to 2006 (period 2). Despite a statistically significant sicker population (older, higher comorbidities, higher coagulase-negative staphylococcal infections, and fewer healthy valves), the period-2 patients had a dramatically lower mortality rate of 8.2% (P<0.001), compared with 18.5% in period-1 patients. Fewer episodes of renal failure, organ failure, and deaths associated with embolism were noted in period 2.

Whether these results are due to more frequent care, more aggressive care (patients were “summoned” if they did not show for appointments), standardized medication and surgical options, or the effects of long-term collaboration, these results appear durable, remarkable, and reproducible.

This study is limited by its lack of randomization and extensive time frame, with concomitant changes in medical treatment and observed infectious organisms.

Bottom line: Implementation of a standardized approach to endocarditis has significant benefit on mortality and morbidity.

Citation: Botelho-Nevers E, Thuny F, Casalta JP, et al. Dramatic reduction in infective endocarditis-related mortality with a management-based approach. Arch Intern Med. 2009;169(14):1290-1298.

Treatment with tPA in the Three- to 4.5-Hour Time Window after Stroke Is Beneficial

Clinical question: What is the effect of tissue plasminogen activator (tPA) on outcomes in patients treated in the three- to 4.5-hour window after stroke?

Background: The third European Cooperative Acute Stroke Study 3 (ECASS-3) demonstrated benefit of treatment of acute stroke with tPA in the three- to 4.5-hour time window. Prior studies, however, did not show superiority of tPA over placebo, and there is a lack of a confirmatory randomized, controlled trial of tPA in this time frame.

Study design: Meta-analysis of randomized, controlled trials.

Setting: Four studies involving 1,622 patients who were treated with intravenous tPA for acute ischemic stroke from three to 4.5 hours after stroke compared with placebo.

Synopsis: Of the randomized, controlled trials of intravenous tPA for treatment of acute ischemic stroke from three to 4.5 hours after stroke, four trials (ECASS-1, ECASS-2, ECASS-3, and ATLANTIS) were included in the analysis. Treatment with tPA in the three- to 4.5-hour time window is associated with increased favorable outcomes based on the global outcome measure (OR 1.31; 95% CI: 1.10-1.56, P=0.002) and the modified Rankin Scale (OR 1.31; 95% CI: 1.07-1.59, P=0.01), compared with placebo. The 90-day mortality rate was not significantly different between the treatment and placebo groups (OR 1.04; 95% CI 0.75-1.43, P=0.83).

Due to the relatively high dose of tPA (1.1 mg/kg) administered in the ECASS-1 trial, a separate meta-analysis looking at the other three trials (tPA dose of 0.9 mg/kg) was conducted, and the favorable outcome with tPA remained.

Bottom line: Treatment of acute ischemic stroke with tPA in the three- to 4.5-hour time window results in an increased rate of favorable functional outcomes without a significant difference in mortality.

Citation: Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40(7):2438-2441.

Outpatients Often Are Not Notified of Clinically Significant Test Results

Clinical question: How frequently do primary-care physicians (PCPs) fail to inform patients of clinically significant outpatient test results?

Background: Diagnostic errors are the most common cause of malpractice claims in the U.S. It is unclear how often providers fail to either inform patients of abnormal test results or document that patients have been notified.

Study design: Retrospective chart review.

Setting: Twenty-three primary-care practices: 19 private, four academic.

Synopsis: More than 5,400 charts were reviewed, and 1,889 abnormal test results were identified in this study. Failure to inform or document notification was identified in 135 cases (7.1%). The failure rates in the practices ranged from 0.0% to 26.2%. Practices with the best processes for managing test results had the lowest failure rates; these processes included: all results being routed to the responsible physician; the physician signing off on all results; the practice informing patients of all results, both normal and abnormal; documenting when the patient is informed; and instructing patients to call if not notified of test results within a certain time interval.

Limitations of this study include the potential of over- or underreporting of failures to inform as a chart review was used, and only practices that agreed to participate were included.

Bottom line: Failure to notify outpatients of test results is common but can be minimized by creating a systematic management of test results that include best practices.

Citation: Casalino LP, Dunham D, Chin MH, et al. Frequency of failure to inform patients of clinically significant outpatient test results. Arch Intern Med. 2009;169(12):1123-1129.

Repair of Incidental PFO Discovered During Cardiothoracic Surgery Repair Increases Postoperative Stroke Risk

Clinical question: What is the impact of closing incidentally discovered patent foramen ovale (PFO) defects during cardiothoracic surgery?

Background: PFO’s role in cryptogenic stroke remains controversial. Incidental PFO is commonly detected by transesophageal echocardiography (TEE) during cardiothoracic surgery. Routine PFO closure has been recommended when almost no alteration of the surgical plan is required.

Study design: Retrospective chart review.

Setting: The Cleveland Clinic.

Synopsis: Between 1995 and 2006, 13,092 patients undergoing cardiothoracic surgery had TEE data with no previous diagnosis of PFO, but the review found that 2,277 (17%) had PFO discovered intraoperatively. Of these, 639 (28%) had the PFO repaired.

Patients with an intraoperative diagnosis of PFO had similar rates of in-hospital stroke and hospital death compared with those without PFO. Patients who had their PFO repaired had a greater in-hospital stroke risk (2.8% vs. 1.2%; P=0.04) compared with those with a non-repaired PFO, representing nearly 2.5 times greater odds of having an in-hospital stroke. No other difference was noted in perioperative outcomes for patients who underwent intraoperative repair compared with those who did not, including risk of in-hospital death, hospital length of stay, ICU length of stay, and time on cardiopulmonary bypass. Long-term analysis demonstrated that PFO repair was associated with no survival difference.

The study is limited by its retrospective nature.

Bottom line: Routine surgical closure of incidental PFO detected during intraoperative imaging should be discouraged.

Citation: Krasuski RA, Hart SA, Allen D, et al. Prevalence and repair of interoperatively diagnosed patent foramen ovale and association with perioperative outcomes and long-term survival. JAMA. 2009;302(3):290-297.

Hospital-Level Differences Are Strong Predictors of Time to Defibrillation Delay In Cardiac Arrest

Clinical question: What are the predictors of delay in the time to defibrillation after in-hospital cardiac arrest?

Background: Thirty percent of in-hospital cardiac arrests from ventricular arrhythmias are not treated within the American Heart Association’s recommendation of two minutes. This delay is associated with a 50% lower rate of in-hospital survival. Exploring the hospital-level variation in delays to defibrillation is a critical step toward sharing the best practices.

Study design: Retrospective review of registry data.

Setting: The National Registry of Cardiopulmonary Resuscitation (NRCPR) survey of 200 acute-care, nonpediatric hospitals.

Synopsis: The registry identified 7,479 patients who experienced cardiac arrest from ventricular tachycardia or pulseless ventricular fibrillation. The primary outcome was the hospital rate of delayed defibrillation (time to defibrillation > two minutes), which ranged from 2% to 51%.

Time to defibrillation was found to be a major predictor of survival after a cardiac arrest. Only bed volume and arrest location were associated with differences in rates of delayed defibrillation (lower rates in larger hospitals and in ICUs). The variability was not due to differences in patient characteristics, but was due to hospital-level effects. Academic status, geographical location, arrest volume, and daily admission volume did not affect the time to defibrillation.

The study was able to identify only a few facility characteristics that account for the variability between hospitals in the rate of delayed defibrillation. The study emphasizes the need for new approaches to identifying hospital innovations in process-of-care measures that are associated with improved performance in defibrillation times.

Bottom Line: Future research is needed to better understand the reason for the wide variation between hospitals in the rate of delayed defibrillation after in-hospital cardiac arrest.

Citation: Chan PS, Nichol G, Krumholz HM, Spertus JA, Nallamothu BK; American Heart Association National Registry of Cardiopulmonary Resuscitation (NRCPR) Investigators. Hospital variation in time to defibrillation after in-hospital cardiac arrest. Arch Intern Med. 2009;169(14):1265-1273.

Treating for H. Pylori Reduces the Risk for Developing Gastric Cancer in High-Risk Patients

Clinical question: In patients with high-baseline incidence of gastric cancer, does H. pylori eradication reduce the risk for developing gastric cancer?

Background: Gastric cancer remains a major health problem in Asia. The link of H. pylori and gastric cancer has been established, but it remains unclear whether treatment for H. pylori is effective primary prevention for the development of gastric cancer.

Study design: Meta-analysis of six studies.

Setting: All but one trial was performed in Asia.

Synopsis: Seven studies met inclusion criteria, one of which was excluded due to heterogeneity. The six remaining studies were pooled, with 37 of 3,388 (1.1%) treated patients developing a new gastric cancer, compared with 56 of 3,307 (1.7%) patients who received placebo or were in the control group (RR 0.65; 0.43-0.98). Most patients received gastric biopsy prior to enrollment, and most of those demonstrated gastric atrophy or intestinal metaplasia.

These patients, despite more advanced precancerous pathology findings, still benefited from eradication. The seventh study, which was excluded, enrolled patients with early gastric cancer; these patients still benefited from H. pylori eradication and, when included in the meta-analysis, the RR was even lower, 0.57 (0.49-0.81).

Only two trials were double-blinded, but all of the studies employed the same definition of gastric cancer and held to excellent data reporting standards. This study encourages screening and treatment in high-risk patients given the widespread incidence of H. pylori.

Bottom Line: Treatment of H. pylori reduces the risk of gastric cancer in high-risk patients.

Citation: Fuccio L, Zagari RM, Eusebi LH, et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med. 2009;151(2):121-128.

Patients on Anti-Platelet Agents with Acute Coronary Syndrome Have a Lower Bleeding Risk When Treated with Fondaparinux

Clinical question: Is there a difference in bleeding risk with fondaparinux and enoxaparin when used with GPIIb/IIIa inhibitors or thienopyridines in NSTEMI-ACS?

Background: The OASIS 5 study reported a 50% reduction in severe bleeding when comparing fondaparinux to enoxaparin in ACS while maintaining a similar efficacy. This subgroup analysis was performed to evaluate whether reduced bleeding risk with fondaparinux remains in patients treated with additional anti-platelet agents.

Study design: Subgroup analysis of a large, multicenter, randomized, double-blind trial.

Setting: Acute-care hospitals in North America, Eastern and Western Europe, Latin America, Australia, and Asia.

Synopsis: Patients with NSTE-ACS received either fondaparinux or enoxaparin and were treated with GPIIb/IIIa inhibitors or thienopyridines at the discretion of their physician. At 30 days, the fondaparinux group had similar efficacy and decreased bleeding risk in both the GPIIb/IIIa and the thienopyridine groups. Of the 3,630 patients in the GPIIb/IIIa group, the risk for major bleeding with fondaparinux was 5.2%, whereas the risk with enoxaparin was 8.3% (HR 0.61; P<0.001) compared with enoxaparin. Of the 1,352 patients treated with thienopyridines, the risk for major bleeding with fondaparinux was 3.4%, whereas the risk with enoxaparin was 5.4% (HR 0.62; P<0.001).

Bottom Line: This subgroup analysis suggests there are less-severe bleeding complications in patients treated with fondaparinux when compared with enoxaparin in the setting of cotreatment with GPIIb/IIIa inhibitors, thienopyridines, or both.

Citation: Jolly SS, Faxon DP, Fox KA, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors of thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J Am Coll Cardiol. 2009;54(5):468-476.

Surrogate Decision-Makers Frequently Doubt Clinicians’ Ability to Predict Medical Futility

Clinical question: What attitudes do surrogate decision-makers hold toward clinicians’ predictions of medical futility in critically-ill patients?

Background: The clinical judgment of medical futility leading to the withdrawal of life-sustaining treatment—despite the objections of surrogate decision-makers—is controversial. Very little is known about how surrogate decision-makers view the futility rationale when physicians suggest limiting the use of life-sustaining treatment.

Study design: Multicenter, mixed, qualitative and quantitative study.

Setting: Three ICUs in three different California hospitals from 2006 to 2007.

Synopsis: Semi-structured interviews of surrogate decision-makers for 50 incapacitated, critically-ill patients were performed to ascertain their beliefs about medical futility in response to hypothetical situations. Of the surrogates surveyed, 64% expressed doubt about physicians’ futility predictions.

The interviewees gave four main reasons for their doubts. Two reasons not previously described were doubts about the accuracy of physicians’ predictions and the need for surrogates to see futility themselves. Previously described sources of conflict included a misunderstanding about prognosis and religious-based objections. Surrogates with religious objections were more likely to request continuation of life-sustaining treatments than those with secular or experiential objections (OR 4; 95% CI 1.2-14.0; P=0.03). Nearly a third (32%) of surrogates elected to continue life support with a <1% survival estimate; 18% elected to continue life support when physicians thought there was no chance of survival.

This study has several limitations: a small sample size, the use of hypothetical situations, and the inability to assess attitudes as they change over time.

Bottom line: The nature of surrogate decision-makers’ doubts about medical futility can help predict whether they accept predictions of medical futility from physicians.

Citation: Zier LS, Burack JH, Micco G, Chipman AK, Frank JA, White DB. Surrogate decision makers’ responses to physicians’ predictions of medical futility. Chest. 2009;136:110-117. TH

PEDIATRIC HM LITerature

House-Staff Signout Complexities Remain

By Mark Shen, MD

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

Clinical question: What are the characteristics of signout among house staff?

Background: Inadequate signout is a recognized contributor to medical errors. As care has become increasingly fragmented among house staff who must comply with work-hour restrictions, both the absolute number of signouts and the potential for incomplete transfer of information increase. Despite recent Joint Commission requirements to standardize handoffs, comprehensive analyses of the process remain scarce.

Study design: Quantitative and qualitative analysis of audiotaped oral internal-medicine signout.

Setting: Academic teaching hospital.

Synopsis: Audiotaped signout for eight internal-medicine house-staff teams during two time periods in 2006 were analyzed for content, clarity of language, and surrounding environment. Most signout (59.2%) did not include questions, and questioning of patient management was often indirect when it occurred. A spectrum of clarity existed from unclear anticipatory guidance to clear, concise instructions. Interruptions occurred less than 20% of the time. Familiarity with patients, sense of responsibility for patients, sequential signouts, experience, and comprehensiveness of the written form affected the content of the signout.

This study provides insight into the broad array of factors that affect signout. Despite the potential for interactive facilitation of understanding, the process is often one-sided and operator-dependent. Such systems-based factors as familiarity with patients and sequential signouts might affect quality, while cultural norms (such as sense of responsibility) also play a role.

Limitations of this study include the nonblinded observation method and the potential for institution-specific culture to limit applicability. Nonetheless, this study adds to literature painting a broader and complex picture of a routine hospital process often taken for granted.

Bottom line: Improving and standardizing handoffs requires attention to multifaceted domains that commonly affect complex human organizations.

Citation: Horwitz LI, Moin T, Krumholz HM, Wang L, Bradley EH. What are covering doctors told about their patients? Analysis of sign-out among internal medicine house staff. Qual Saf Health Care. 2009;18(4):248-255.

In This Edition

Literature at a Glance

A guide to this month’s studies

• CPOE and quality outcomes
• Outcomes of standardized management of endocarditis
• Effect of tPA three to 4.5 hours after stroke onset
• Failure to notify patients of significant test results
• PFO repair and stroke rate
• Predictors of delay in defibrillation for in-hospital arrest
• H. pylori eradication and risk of future gastric cancer
• Bleeding risk with fondaparinux vs. enoxaparin in ACS
• Perceptions of physician ability to predict medical futility

CPOE Is Associated with Improvement in Quality Measures

Clinical question: Is computerized physician order entry (CPOE) associated with improved outcomes across a large, nationally representative sample of hospitals?

Background: Several single-institution studies suggest CPOE leads to better outcomes in quality measures for heart failure, acute myocardial infarction, and pneumonia as defined by the Hospital Quality Alliance (HQA) initiative, led by the Centers for Medicare and Medicaid Services (CMS). Little systematic information is known about the effects of CPOE on quality of care.

Study design: Cross-sectional study.

Setting: The Health Information Management System Society (HIMSS) analytics database of 3,364 hospitals throughout the U.S.

Synopsis: Of the hospitals that reported CPOE utilization to HIMSS, 264 (7.8%) fully implement CPOE throughout their institutions. These CPOE hospitals outperformed their peers on five of 11 quality measures related to ordering medications, and in one of nine non-medication-related measures. No difference was noted in the other measures, except CPOE hospitals were less effective at providing antibiotics within four hours of pneumonia diagnosis. Hospitals that utilized CPOE were generally academic, larger, and nonprofit. After adjusting for these differences, benefits were still preserved.

The authors indicate that the lack of systematic outperformance by CPOE hospitals in all 20 of the quality categories inherently suggests that other factors (e.g., concomitant QI efforts) are not affecting these results. Given the observational nature of this study, no causal relationship can be established between CPOE and the observed benefits. CPOE might represent the commitment of certain hospitals to quality measures, but further study is needed.

Bottom line: Enhanced compliance in several CMS-established quality measures is seen in hospitals that utilize CPOE throughout their institutions.

Citation: Yu FB, Menachemi N, Berner ES, Allison JJ, Weissman NW, Houston TK. Full implementation of computerized physician order entry and medication-related quality outcomes: a study of 3,364 hospitals. Am J Med Qual. 2009;24(4):278-286.

Standardized Management of Endocarditis Leads to Significant Mortality Benefit

Clinical question: Does a standardized approach to the treatment of infective endocarditis reduce mortality and morbidity?

Background: Despite epidemiological changes to the inciting bacteria and improvements in available antibiotics, mortality and morbidity associated with endocarditis remain high. The contribution of inconsistent or inaccurate treatment of endocarditis is unclear.

Study design: Case series with historical controls from 1994 to 2001, compared with protocolized patients from 2002 to 2006.

Setting: Single teaching tertiary-care hospital in France.

Synopsis: The authors established a diagnostic protocol for infectious endocarditis from 1994 to 2001 (period 1) and established a treatment protocol from 2002 to 2006 (period 2). Despite a statistically significant sicker population (older, higher comorbidities, higher coagulase-negative staphylococcal infections, and fewer healthy valves), the period-2 patients had a dramatically lower mortality rate of 8.2% (P<0.001), compared with 18.5% in period-1 patients. Fewer episodes of renal failure, organ failure, and deaths associated with embolism were noted in period 2.

Whether these results are due to more frequent care, more aggressive care (patients were “summoned” if they did not show for appointments), standardized medication and surgical options, or the effects of long-term collaboration, these results appear durable, remarkable, and reproducible.

This study is limited by its lack of randomization and extensive time frame, with concomitant changes in medical treatment and observed infectious organisms.

Bottom line: Implementation of a standardized approach to endocarditis has significant benefit on mortality and morbidity.

Citation: Botelho-Nevers E, Thuny F, Casalta JP, et al. Dramatic reduction in infective endocarditis-related mortality with a management-based approach. Arch Intern Med. 2009;169(14):1290-1298.

Treatment with tPA in the Three- to 4.5-Hour Time Window after Stroke Is Beneficial

Clinical question: What is the effect of tissue plasminogen activator (tPA) on outcomes in patients treated in the three- to 4.5-hour window after stroke?

Background: The third European Cooperative Acute Stroke Study 3 (ECASS-3) demonstrated benefit of treatment of acute stroke with tPA in the three- to 4.5-hour time window. Prior studies, however, did not show superiority of tPA over placebo, and there is a lack of a confirmatory randomized, controlled trial of tPA in this time frame.

Study design: Meta-analysis of randomized, controlled trials.

Setting: Four studies involving 1,622 patients who were treated with intravenous tPA for acute ischemic stroke from three to 4.5 hours after stroke compared with placebo.

Synopsis: Of the randomized, controlled trials of intravenous tPA for treatment of acute ischemic stroke from three to 4.5 hours after stroke, four trials (ECASS-1, ECASS-2, ECASS-3, and ATLANTIS) were included in the analysis. Treatment with tPA in the three- to 4.5-hour time window is associated with increased favorable outcomes based on the global outcome measure (OR 1.31; 95% CI: 1.10-1.56, P=0.002) and the modified Rankin Scale (OR 1.31; 95% CI: 1.07-1.59, P=0.01), compared with placebo. The 90-day mortality rate was not significantly different between the treatment and placebo groups (OR 1.04; 95% CI 0.75-1.43, P=0.83).

Due to the relatively high dose of tPA (1.1 mg/kg) administered in the ECASS-1 trial, a separate meta-analysis looking at the other three trials (tPA dose of 0.9 mg/kg) was conducted, and the favorable outcome with tPA remained.

Bottom line: Treatment of acute ischemic stroke with tPA in the three- to 4.5-hour time window results in an increased rate of favorable functional outcomes without a significant difference in mortality.

Citation: Lansberg MG, Bluhmki E, Thijs VN. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis. Stroke. 2009;40(7):2438-2441.

Outpatients Often Are Not Notified of Clinically Significant Test Results

Clinical question: How frequently do primary-care physicians (PCPs) fail to inform patients of clinically significant outpatient test results?

Background: Diagnostic errors are the most common cause of malpractice claims in the U.S. It is unclear how often providers fail to either inform patients of abnormal test results or document that patients have been notified.

Study design: Retrospective chart review.

Setting: Twenty-three primary-care practices: 19 private, four academic.

Synopsis: More than 5,400 charts were reviewed, and 1,889 abnormal test results were identified in this study. Failure to inform or document notification was identified in 135 cases (7.1%). The failure rates in the practices ranged from 0.0% to 26.2%. Practices with the best processes for managing test results had the lowest failure rates; these processes included: all results being routed to the responsible physician; the physician signing off on all results; the practice informing patients of all results, both normal and abnormal; documenting when the patient is informed; and instructing patients to call if not notified of test results within a certain time interval.

Limitations of this study include the potential of over- or underreporting of failures to inform as a chart review was used, and only practices that agreed to participate were included.

Bottom line: Failure to notify outpatients of test results is common but can be minimized by creating a systematic management of test results that include best practices.

Citation: Casalino LP, Dunham D, Chin MH, et al. Frequency of failure to inform patients of clinically significant outpatient test results. Arch Intern Med. 2009;169(12):1123-1129.

Repair of Incidental PFO Discovered During Cardiothoracic Surgery Repair Increases Postoperative Stroke Risk

Clinical question: What is the impact of closing incidentally discovered patent foramen ovale (PFO) defects during cardiothoracic surgery?

Background: PFO’s role in cryptogenic stroke remains controversial. Incidental PFO is commonly detected by transesophageal echocardiography (TEE) during cardiothoracic surgery. Routine PFO closure has been recommended when almost no alteration of the surgical plan is required.

Study design: Retrospective chart review.

Setting: The Cleveland Clinic.

Synopsis: Between 1995 and 2006, 13,092 patients undergoing cardiothoracic surgery had TEE data with no previous diagnosis of PFO, but the review found that 2,277 (17%) had PFO discovered intraoperatively. Of these, 639 (28%) had the PFO repaired.

Patients with an intraoperative diagnosis of PFO had similar rates of in-hospital stroke and hospital death compared with those without PFO. Patients who had their PFO repaired had a greater in-hospital stroke risk (2.8% vs. 1.2%; P=0.04) compared with those with a non-repaired PFO, representing nearly 2.5 times greater odds of having an in-hospital stroke. No other difference was noted in perioperative outcomes for patients who underwent intraoperative repair compared with those who did not, including risk of in-hospital death, hospital length of stay, ICU length of stay, and time on cardiopulmonary bypass. Long-term analysis demonstrated that PFO repair was associated with no survival difference.

The study is limited by its retrospective nature.

Bottom line: Routine surgical closure of incidental PFO detected during intraoperative imaging should be discouraged.

Citation: Krasuski RA, Hart SA, Allen D, et al. Prevalence and repair of interoperatively diagnosed patent foramen ovale and association with perioperative outcomes and long-term survival. JAMA. 2009;302(3):290-297.

Hospital-Level Differences Are Strong Predictors of Time to Defibrillation Delay In Cardiac Arrest

Clinical question: What are the predictors of delay in the time to defibrillation after in-hospital cardiac arrest?

Background: Thirty percent of in-hospital cardiac arrests from ventricular arrhythmias are not treated within the American Heart Association’s recommendation of two minutes. This delay is associated with a 50% lower rate of in-hospital survival. Exploring the hospital-level variation in delays to defibrillation is a critical step toward sharing the best practices.

Study design: Retrospective review of registry data.

Setting: The National Registry of Cardiopulmonary Resuscitation (NRCPR) survey of 200 acute-care, nonpediatric hospitals.

Synopsis: The registry identified 7,479 patients who experienced cardiac arrest from ventricular tachycardia or pulseless ventricular fibrillation. The primary outcome was the hospital rate of delayed defibrillation (time to defibrillation > two minutes), which ranged from 2% to 51%.

Time to defibrillation was found to be a major predictor of survival after a cardiac arrest. Only bed volume and arrest location were associated with differences in rates of delayed defibrillation (lower rates in larger hospitals and in ICUs). The variability was not due to differences in patient characteristics, but was due to hospital-level effects. Academic status, geographical location, arrest volume, and daily admission volume did not affect the time to defibrillation.

The study was able to identify only a few facility characteristics that account for the variability between hospitals in the rate of delayed defibrillation. The study emphasizes the need for new approaches to identifying hospital innovations in process-of-care measures that are associated with improved performance in defibrillation times.

Bottom Line: Future research is needed to better understand the reason for the wide variation between hospitals in the rate of delayed defibrillation after in-hospital cardiac arrest.

Citation: Chan PS, Nichol G, Krumholz HM, Spertus JA, Nallamothu BK; American Heart Association National Registry of Cardiopulmonary Resuscitation (NRCPR) Investigators. Hospital variation in time to defibrillation after in-hospital cardiac arrest. Arch Intern Med. 2009;169(14):1265-1273.

Treating for H. Pylori Reduces the Risk for Developing Gastric Cancer in High-Risk Patients

Clinical question: In patients with high-baseline incidence of gastric cancer, does H. pylori eradication reduce the risk for developing gastric cancer?

Background: Gastric cancer remains a major health problem in Asia. The link of H. pylori and gastric cancer has been established, but it remains unclear whether treatment for H. pylori is effective primary prevention for the development of gastric cancer.

Study design: Meta-analysis of six studies.

Setting: All but one trial was performed in Asia.

Synopsis: Seven studies met inclusion criteria, one of which was excluded due to heterogeneity. The six remaining studies were pooled, with 37 of 3,388 (1.1%) treated patients developing a new gastric cancer, compared with 56 of 3,307 (1.7%) patients who received placebo or were in the control group (RR 0.65; 0.43-0.98). Most patients received gastric biopsy prior to enrollment, and most of those demonstrated gastric atrophy or intestinal metaplasia.

These patients, despite more advanced precancerous pathology findings, still benefited from eradication. The seventh study, which was excluded, enrolled patients with early gastric cancer; these patients still benefited from H. pylori eradication and, when included in the meta-analysis, the RR was even lower, 0.57 (0.49-0.81).

Only two trials were double-blinded, but all of the studies employed the same definition of gastric cancer and held to excellent data reporting standards. This study encourages screening and treatment in high-risk patients given the widespread incidence of H. pylori.

Bottom Line: Treatment of H. pylori reduces the risk of gastric cancer in high-risk patients.

Citation: Fuccio L, Zagari RM, Eusebi LH, et al. Meta-analysis: can Helicobacter pylori eradication treatment reduce the risk for gastric cancer? Ann Intern Med. 2009;151(2):121-128.

Patients on Anti-Platelet Agents with Acute Coronary Syndrome Have a Lower Bleeding Risk When Treated with Fondaparinux

Clinical question: Is there a difference in bleeding risk with fondaparinux and enoxaparin when used with GPIIb/IIIa inhibitors or thienopyridines in NSTEMI-ACS?

Background: The OASIS 5 study reported a 50% reduction in severe bleeding when comparing fondaparinux to enoxaparin in ACS while maintaining a similar efficacy. This subgroup analysis was performed to evaluate whether reduced bleeding risk with fondaparinux remains in patients treated with additional anti-platelet agents.

Study design: Subgroup analysis of a large, multicenter, randomized, double-blind trial.

Setting: Acute-care hospitals in North America, Eastern and Western Europe, Latin America, Australia, and Asia.

Synopsis: Patients with NSTE-ACS received either fondaparinux or enoxaparin and were treated with GPIIb/IIIa inhibitors or thienopyridines at the discretion of their physician. At 30 days, the fondaparinux group had similar efficacy and decreased bleeding risk in both the GPIIb/IIIa and the thienopyridine groups. Of the 3,630 patients in the GPIIb/IIIa group, the risk for major bleeding with fondaparinux was 5.2%, whereas the risk with enoxaparin was 8.3% (HR 0.61; P<0.001) compared with enoxaparin. Of the 1,352 patients treated with thienopyridines, the risk for major bleeding with fondaparinux was 3.4%, whereas the risk with enoxaparin was 5.4% (HR 0.62; P<0.001).

Bottom Line: This subgroup analysis suggests there are less-severe bleeding complications in patients treated with fondaparinux when compared with enoxaparin in the setting of cotreatment with GPIIb/IIIa inhibitors, thienopyridines, or both.

Citation: Jolly SS, Faxon DP, Fox KA, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors of thienopyridines: results from the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial. J Am Coll Cardiol. 2009;54(5):468-476.

Surrogate Decision-Makers Frequently Doubt Clinicians’ Ability to Predict Medical Futility

Clinical question: What attitudes do surrogate decision-makers hold toward clinicians’ predictions of medical futility in critically-ill patients?

Background: The clinical judgment of medical futility leading to the withdrawal of life-sustaining treatment—despite the objections of surrogate decision-makers—is controversial. Very little is known about how surrogate decision-makers view the futility rationale when physicians suggest limiting the use of life-sustaining treatment.

Study design: Multicenter, mixed, qualitative and quantitative study.

Setting: Three ICUs in three different California hospitals from 2006 to 2007.

Synopsis: Semi-structured interviews of surrogate decision-makers for 50 incapacitated, critically-ill patients were performed to ascertain their beliefs about medical futility in response to hypothetical situations. Of the surrogates surveyed, 64% expressed doubt about physicians’ futility predictions.

The interviewees gave four main reasons for their doubts. Two reasons not previously described were doubts about the accuracy of physicians’ predictions and the need for surrogates to see futility themselves. Previously described sources of conflict included a misunderstanding about prognosis and religious-based objections. Surrogates with religious objections were more likely to request continuation of life-sustaining treatments than those with secular or experiential objections (OR 4; 95% CI 1.2-14.0; P=0.03). Nearly a third (32%) of surrogates elected to continue life support with a <1% survival estimate; 18% elected to continue life support when physicians thought there was no chance of survival.

This study has several limitations: a small sample size, the use of hypothetical situations, and the inability to assess attitudes as they change over time.

Bottom line: The nature of surrogate decision-makers’ doubts about medical futility can help predict whether they accept predictions of medical futility from physicians.

Citation: Zier LS, Burack JH, Micco G, Chipman AK, Frank JA, White DB. Surrogate decision makers’ responses to physicians’ predictions of medical futility. Chest. 2009;136:110-117. TH

PEDIATRIC HM LITerature

House-Staff Signout Complexities Remain

By Mark Shen, MD

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

Clinical question: What are the characteristics of signout among house staff?

Background: Inadequate signout is a recognized contributor to medical errors. As care has become increasingly fragmented among house staff who must comply with work-hour restrictions, both the absolute number of signouts and the potential for incomplete transfer of information increase. Despite recent Joint Commission requirements to standardize handoffs, comprehensive analyses of the process remain scarce.

Study design: Quantitative and qualitative analysis of audiotaped oral internal-medicine signout.

Setting: Academic teaching hospital.

Synopsis: Audiotaped signout for eight internal-medicine house-staff teams during two time periods in 2006 were analyzed for content, clarity of language, and surrounding environment. Most signout (59.2%) did not include questions, and questioning of patient management was often indirect when it occurred. A spectrum of clarity existed from unclear anticipatory guidance to clear, concise instructions. Interruptions occurred less than 20% of the time. Familiarity with patients, sense of responsibility for patients, sequential signouts, experience, and comprehensiveness of the written form affected the content of the signout.

This study provides insight into the broad array of factors that affect signout. Despite the potential for interactive facilitation of understanding, the process is often one-sided and operator-dependent. Such systems-based factors as familiarity with patients and sequential signouts might affect quality, while cultural norms (such as sense of responsibility) also play a role.

Limitations of this study include the nonblinded observation method and the potential for institution-specific culture to limit applicability. Nonetheless, this study adds to literature painting a broader and complex picture of a routine hospital process often taken for granted.

Bottom line: Improving and standardizing handoffs requires attention to multifaceted domains that commonly affect complex human organizations.

Citation: Horwitz LI, Moin T, Krumholz HM, Wang L, Bradley EH. What are covering doctors told about their patients? Analysis of sign-out among internal medicine house staff. Qual Saf Health Care. 2009;18(4):248-255.

Literature at a Glance

A guide to this month’s abstracts

• Steroids reduce mortality only in patients with confirmed bacterial meningitis.
• Probiotics can be useful in the treatment of acute diarrhea in children.
• CT pulmonary angiography is not inferior to V/Q scanning for exclusion of PE.
• Hospitalist care results in shorter LOS compared with care by traditional general internists and family practice physicians.
• The early risk of stroke after TIA is approximately 15% to 20% at 90 days after the sentinel event.
• Different anti-thrombotic strategies produce no difference in outcomes of early acute coronary syndromes.
• The risk of fatal PE is highest in the first year after medication is stopped.
• Beers criteria medications are associated with fewer ED visits by elderly patients compared with warfarin, digoxin, and insulin.

Do Steroids Affect the Outcome in Patients with Meningitis?

Background: Pyogenic (bacterial) meningitis has high morbidity and mortality. Studies suggest some benefit of steroids in children but provide limited evidence for adult use.

Study design: Intention-to-treat, randomized control trial.

Setting: Single hospital in Vietnam.

Synopsis: Of 435 patients older than 14 with suspected meningitis all received lumbar puncture with randomization to IV dexamethasone or placebo for four days. Results showed 69% of patients had definite meningitis, 28.3% were probable, and 2.8% had an alternative diagnosis based on culture results.

The primary outcome was death after one month, which did not differ among groups (risk ratio [RR] 0.79, confidence interval [CI] 0.45-1.39).

Predefined subgroup analysis of patients with definitive meningitis showed a significant reduction in mortality at one month (RR 0.43, CI 0.2-0.94) and death/disability at six months (odds ratio [OR] 0.56, CI 0.32-0.98).

In patients with probable meningitis, those who received steroids demonstrated a trend toward harm (OR 2.65, CI 0.73-9.63).

Probable versus definite meningitis was determined retrospectively based on cultures. The most common isolate was Streptococcus suis.

Bottom line: This study provides some evidence for using steroids in adults with confirmed bacterial meningitis. Clinical application is limited by bacterial epidemiology and the difficulty of prospectively separating patients who would benefit from those who might be harmed.

Citation: Nguyen TH, Tran TH, Thwaites G, et. al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med. 2007;357:2431-2439.

Which Probiotic Preparations Best Reduce the Duration of Acute Diarrhea in Children?

Background: Probiotics have been suggested as an adjunctive therapy to reduce the severity and duration of acute diarrhea in children. However, there are no clear data to suggest if specific probiotic agents are superior to others.

Study design: Prospective single-blind, randomized, controlled trial.

Setting: Outpatient primary care in Naples, Italy.

Synopsis: This study compared five commercially available probiotic preparations (mix of Lactobacillus delbrueckii var bulgaricus/Streptococcus thermophilus/L. acidophilus/ Bifido-bacterium bifidum; L. rhamnosus strain GG; Saccharomyces boulardii; Bacillus clausii; or Enterococcus faecium SF68) and a control group in the treatment of outpatient acute diarrhea in 571 children age 3 months to 36 months.

The primary outcomes were the duration of diarrhea and the number and consistency of stools. The groups receiving Lactobacillus GG and the mixture had a shorter total duration of diarrhea (78.5 and 70 hours, respectively), decreased total number of stools, and improved stool consistency when compared with the control (115.5 hours). The other therapies showed no improvement over the control group. These data report on products commercially available in Italy, which may differ greatly from products available locally.

Bottom line: Probiotic preparations for the treatment of acute diarrhea in children should be chosen based on effectiveness data.

Citation: Canani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 2007;335:340-345.

Is CTPA a Reliable Alternative to V/Q Scan for Diagnosing PE?

Background: Computed tomography pulmonary angiogram (CTPA) has replaced ventilation/perfusion (V/Q) scanning at many hospitals as the test of choice for ruling out pulmonary embolism (PE). But limited clinical data compare CTPA with V/Q scanning in those suspected of having venous thromboembolism (VTE).

Study design: Randomized, investigator blinded, controlled trial.

Setting: The emergency departments (ED), inpatient wards, and outpatient clinics of five academic centers.

Synopsis: In the study, 1,411 patients were enrolled from five medical centers. Of 694 patients randomized to CTPA, 133 (19.2%) were diagnosed with VTE in the initial evaluation period, while 101 of 712 patients (14.2%) receiving a V/Q scan were diagnosed with VTE.

Patients not initially diagnosed with VTE were monitored. At three-month follow-up, 0.4% of the CTPA group and 1.0% of the V/Q group had a diagnosed VTE.

The overall rate of VTE found in the initial diagnostic period was significantly greater in patients randomized to CTPA (19.2% vs. 14.2%; difference, 5.0%; 95% CI; 1.1% to 8.9% p=.01). This suggests CTPA has a higher false positive rate or detects clinically insignificant thrombi.

Bottom line: CTPA was not inferior to V/Q scanning for excluding clinically meaningful PE, but CTPA diagnosed about 30% more patients with VTE than did V/Q scanning.

Citation: Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA. 2007;298(23):2743-2753.

Does the Hospitalist Model Improve Length of Stay, Quality, and Cost of Care?

Background: The hospitalist model, with increased physician availability and expertise but greater discontinuity of care, is becoming more prevalent in U.S. medicine. What little is known about how this model will affect patient care is derived from a number of small studies.

Study design: Retrospective cohort study.

Setting: 45 small to midsize, predominantly nonteaching hospitals throughout the U.S.

Synopsis: Using the Premier Healthcare Informatics database, this study examined information on 76,926 patients admitted for seven common diagnoses to one of three services: hospitalist, general internist, or family physician. Analysis showed that patients on a hospitalist service had a 0.4-day shorter length of stay (p<0.001) compared with those on a general internist or family physician service.

The cost to patients cared for by a hospitalist was lower than the cost of family physicians ($125 less, p=0.33) and internists ($268 less, p=0.02). There was no difference found in death rate or 14-day readmission rate among the three services.

Given the retrospective design of this study, no causal relationship can be deduced. This study is further limited by its lack of specific data on the physicians categorized into one of the three groups solely by administrative data. The authors had concerns that the biases inherent to the retrospective nature of their work accounted for the significant difference found between hospitalists and internists.

Bottom line: The hospitalist model is associated with modest improvements in length of stay as compared with traditional inpatient approaches.

Citation: Lindenauer PK, Rothberg MB, Pekow PS, et. al. Outcomes of care by hospitalists, general internists, and family physicians. N Engl J Med. 2007;357:2589-2600.

What Is the Stroke Risk Soon after TIA, and What Factors Drive the Variability of Previous Findings?

Background: Many studies have attempted to estimate the risk of stroke in the early period after a transient ischemic attack (TIA). These studies vary widely in their calculation of the estimated risk. Further, the clinical and methodological factors underlying this variability are unclear.

Study design: Systematic review and meta-analysis.

Setting: Community and hospital.

Synopsis: Searching the Coch­rane review database, MEDLINE, EMBASE, CINAHL, and BIOSIS, 11 studies from 1973 to 2006 were included for meta-analysis, selected from 694 potential candidate studies identified on initial screening. The studies ranged in size from 62 to 2,285 patients.

The pooled estimate of risk for stroke following TIA was found to be 3.5%, 8%, and 9.2% at two, 30, and 90 days following TIA, respectively. However, there was significant heterogeneity for all periods considered (p<0.001).

Outcome ascertainment was identified as a major source of methodological heterogeneity. When risk of stroke at follow-up was determined by passive ascertainment (e.g., administrative documentation) the early risk of stroke was 3.1% two days after TIA, 6.4% at 30 days, and 8.7% at 90 days. But active ascertainment (e.g., direct, personal contact with study participants) determined stroke risk to be 9.9%, 13.4%, and 17.4% at two, 30, and 90 days after TIA, respectively.

Bottom line: Based on analysis of completed studies that included directly observed follow-up of study participants, the early risk of stroke after TIA is approximately 15% to 20% at 90 days following the sentinel event.

Citation: Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack. Arch Intern Med. 2007;167:2417-2422.

What Is the 1-year Ischemia and Mortality Rate for Three Anti-thrombotic Therapies for Early Invasive Management of ACS?

Background: Early interventional or surgical revascularization has improved morbidity and mortality in patients with acute coronary syndrome (ACS). The optimal anti-thrombotic regimen to reduce late ischemic and death rates has not been determined.

Study design: Prospective, open-label randomized control trial.

Setting: 450 academic and community-based institutions in 17 countries.

Synopsis: A total of 13,819 patients were enrolled between August 2003 and December 2005. They were assigned to heparin plus glycoprotein (GP) IIb/IIIa inhibitors (n=4,603), bivalirudin (Angiomax) plus IIb/IIIa inhibitors (n=4,604), or bivalirudin monotherapy (n=4,612).

For patients receiving GP IIb/IIIa inhibitors, a 2x2 factorial design assigned half the heparin and bivalirudin groups to routine upstream GP inhibitor administration (4,605 patients). The other half received selective GP IIb/IIIa inhibitors administration if PCI was indicated (4,602 patients).

At one year, there was no statistically significant difference in ischemia or mortality rate among the three therapy groups. No difference in ischemia rate was detected between the two GP IIb/IIIa inhibitor utilization strategies.

Since the hypotheses and the power for the one-year analysis in this trial were not prospectively determined, the results are considered to be exploratory and hypothesis generating.

Bottom line: At one year, there is no statistically significant difference in ischemia or mortality rate for the three antithrombotic regiments and the two glycoprotein utilization strategies.

Citation: Stone GW, Ware JH, Bertrand ME, et. al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management. One-year results from the ACUITY trial. JAMA 2007;298:2497-2505.

What Is the PE Risk after Discontinuing Anticoagulation in Patients with Symptomatic VTE?

Background: The natural history of patients with symptomatic VTE who have completed anticoagulation is not well understood.

Study design: Inception cohort using pooled data from a prospective cohort study and one arm of an open-label randomized trial.

Setting: Academic medical centers in Canada, Sweden, and Italy.

Synopsis: Using pooled data from two previous studies, 2,052 patients with a first diagnosis of symptomatic VTE (lower-extremity deep-vein thrombosis [DVT], PE, or both) were evaluated for fatal PE after a standard course of therapy (mean of six months) with a vitamin K antagonist.

Patients were followed for up to 120 months. The investigators found an annual event risk of 0.19-0.49 per 100 person-years for fatal PE. Patients with prolonged immobility, active cancer, and thrombophilia were excluded, as were those with recurrent acute DVT.

Secondary analysis revealed an incidence of any fatal, definite or probable PE within the first year of discontinuing therapy of 0.35%-0.81%.

After the first year, the annual event risk ranged from 0.15-0.40 events per 100 person-years. Patients with advanced age, idiopathic VTE as well as those presenting with PE had higher rates of fatal PE.

Bottom line: There is a real though small (less than 1%) risk of fatal PE in the first year following discontinuation of anticoagulation for the first VTE episode. The optimal course of treatment for patients with idiopathic VTE is yet to be determined.

Citation: Douketis JD, Gu CS, Schulman S, et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766-774.

Do the Beers Criteria Predict ED Visits Associated with Adverse Drug Events?

Background: Adverse drug events are common in the elderly. The Beers criteria are a consensus-based list of 41 medications that are considered inappropriate for use in older adults and often lead to poor outcomes.

Study design: Retrospective medical record review and data analysis.

Setting: Three nationally representative, U.S. public health surveillance systems: the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance System (NEISS-CADES), 2004-2005; the National Ambulatory Medical Care Survey (NAMCS), 2004; and National Hospital Ambulatory Medical Care Survey (NHAMCS), 2004.

Synopsis: Using data collected from ED visits at 58 hospitals in the NEISS-CADES system, this study estimated that 177,504 visits for adverse drug events occur annually in the United States. Only 8.8% of such visits were attributable to the 41 medications included in the Beers criteria. Three drug classes (anticoagulant and antiplatelet agents, antidiabetic agents, and narrow therapeutic index agents) accounted for nearly half of all such ED visits. Warfarin (17.3%), insulin (13%), and digoxin (3.2%) were the most commonly implicated medications, collectively accounting for 33% of visits (CI, 27.8% to 38.7%).

This study suggests that because of the common use and high risk of adverse events associated with these three drugs, interventions targeting their use may prevent ED visits for adverse drug events in the elderly, compared with interventions aimed at reducing the use of medications identified in the Beers criteria.

This study only included adverse drug events identified in the ED and relied on the diagnosis and documentation of such events by the ED physician.

Bottom line: Beers criteria medications, although considered inappropriate for use in the elderly, were associated with significantly fewer ED visits for adverse events compared with warfarin, digoxin, and insulin.

Citation: Budnitz DS, Shehab N, Kegler SR, et. al. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765. TH

Literature at a Glance

A guide to this month’s abstracts

• Steroids reduce mortality only in patients with confirmed bacterial meningitis.
• Probiotics can be useful in the treatment of acute diarrhea in children.
• CT pulmonary angiography is not inferior to V/Q scanning for exclusion of PE.
• Hospitalist care results in shorter LOS compared with care by traditional general internists and family practice physicians.
• The early risk of stroke after TIA is approximately 15% to 20% at 90 days after the sentinel event.
• Different anti-thrombotic strategies produce no difference in outcomes of early acute coronary syndromes.
• The risk of fatal PE is highest in the first year after medication is stopped.
• Beers criteria medications are associated with fewer ED visits by elderly patients compared with warfarin, digoxin, and insulin.

Do Steroids Affect the Outcome in Patients with Meningitis?

Background: Pyogenic (bacterial) meningitis has high morbidity and mortality. Studies suggest some benefit of steroids in children but provide limited evidence for adult use.

Study design: Intention-to-treat, randomized control trial.

Setting: Single hospital in Vietnam.

Synopsis: Of 435 patients older than 14 with suspected meningitis all received lumbar puncture with randomization to IV dexamethasone or placebo for four days. Results showed 69% of patients had definite meningitis, 28.3% were probable, and 2.8% had an alternative diagnosis based on culture results.

The primary outcome was death after one month, which did not differ among groups (risk ratio [RR] 0.79, confidence interval [CI] 0.45-1.39).

Predefined subgroup analysis of patients with definitive meningitis showed a significant reduction in mortality at one month (RR 0.43, CI 0.2-0.94) and death/disability at six months (odds ratio [OR] 0.56, CI 0.32-0.98).

In patients with probable meningitis, those who received steroids demonstrated a trend toward harm (OR 2.65, CI 0.73-9.63).

Probable versus definite meningitis was determined retrospectively based on cultures. The most common isolate was Streptococcus suis.

Bottom line: This study provides some evidence for using steroids in adults with confirmed bacterial meningitis. Clinical application is limited by bacterial epidemiology and the difficulty of prospectively separating patients who would benefit from those who might be harmed.

Citation: Nguyen TH, Tran TH, Thwaites G, et. al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med. 2007;357:2431-2439.

Which Probiotic Preparations Best Reduce the Duration of Acute Diarrhea in Children?

Background: Probiotics have been suggested as an adjunctive therapy to reduce the severity and duration of acute diarrhea in children. However, there are no clear data to suggest if specific probiotic agents are superior to others.

Study design: Prospective single-blind, randomized, controlled trial.

Setting: Outpatient primary care in Naples, Italy.

Synopsis: This study compared five commercially available probiotic preparations (mix of Lactobacillus delbrueckii var bulgaricus/Streptococcus thermophilus/L. acidophilus/ Bifido-bacterium bifidum; L. rhamnosus strain GG; Saccharomyces boulardii; Bacillus clausii; or Enterococcus faecium SF68) and a control group in the treatment of outpatient acute diarrhea in 571 children age 3 months to 36 months.

The primary outcomes were the duration of diarrhea and the number and consistency of stools. The groups receiving Lactobacillus GG and the mixture had a shorter total duration of diarrhea (78.5 and 70 hours, respectively), decreased total number of stools, and improved stool consistency when compared with the control (115.5 hours). The other therapies showed no improvement over the control group. These data report on products commercially available in Italy, which may differ greatly from products available locally.

Bottom line: Probiotic preparations for the treatment of acute diarrhea in children should be chosen based on effectiveness data.

Citation: Canani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 2007;335:340-345.

Is CTPA a Reliable Alternative to V/Q Scan for Diagnosing PE?

Background: Computed tomography pulmonary angiogram (CTPA) has replaced ventilation/perfusion (V/Q) scanning at many hospitals as the test of choice for ruling out pulmonary embolism (PE). But limited clinical data compare CTPA with V/Q scanning in those suspected of having venous thromboembolism (VTE).

Study design: Randomized, investigator blinded, controlled trial.

Setting: The emergency departments (ED), inpatient wards, and outpatient clinics of five academic centers.

Synopsis: In the study, 1,411 patients were enrolled from five medical centers. Of 694 patients randomized to CTPA, 133 (19.2%) were diagnosed with VTE in the initial evaluation period, while 101 of 712 patients (14.2%) receiving a V/Q scan were diagnosed with VTE.

Patients not initially diagnosed with VTE were monitored. At three-month follow-up, 0.4% of the CTPA group and 1.0% of the V/Q group had a diagnosed VTE.

The overall rate of VTE found in the initial diagnostic period was significantly greater in patients randomized to CTPA (19.2% vs. 14.2%; difference, 5.0%; 95% CI; 1.1% to 8.9% p=.01). This suggests CTPA has a higher false positive rate or detects clinically insignificant thrombi.

Bottom line: CTPA was not inferior to V/Q scanning for excluding clinically meaningful PE, but CTPA diagnosed about 30% more patients with VTE than did V/Q scanning.

Citation: Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA. 2007;298(23):2743-2753.

Does the Hospitalist Model Improve Length of Stay, Quality, and Cost of Care?

Background: The hospitalist model, with increased physician availability and expertise but greater discontinuity of care, is becoming more prevalent in U.S. medicine. What little is known about how this model will affect patient care is derived from a number of small studies.

Study design: Retrospective cohort study.

Setting: 45 small to midsize, predominantly nonteaching hospitals throughout the U.S.

Synopsis: Using the Premier Healthcare Informatics database, this study examined information on 76,926 patients admitted for seven common diagnoses to one of three services: hospitalist, general internist, or family physician. Analysis showed that patients on a hospitalist service had a 0.4-day shorter length of stay (p<0.001) compared with those on a general internist or family physician service.

The cost to patients cared for by a hospitalist was lower than the cost of family physicians ($125 less, p=0.33) and internists ($268 less, p=0.02). There was no difference found in death rate or 14-day readmission rate among the three services.

Given the retrospective design of this study, no causal relationship can be deduced. This study is further limited by its lack of specific data on the physicians categorized into one of the three groups solely by administrative data. The authors had concerns that the biases inherent to the retrospective nature of their work accounted for the significant difference found between hospitalists and internists.

Bottom line: The hospitalist model is associated with modest improvements in length of stay as compared with traditional inpatient approaches.

Citation: Lindenauer PK, Rothberg MB, Pekow PS, et. al. Outcomes of care by hospitalists, general internists, and family physicians. N Engl J Med. 2007;357:2589-2600.

What Is the Stroke Risk Soon after TIA, and What Factors Drive the Variability of Previous Findings?

Background: Many studies have attempted to estimate the risk of stroke in the early period after a transient ischemic attack (TIA). These studies vary widely in their calculation of the estimated risk. Further, the clinical and methodological factors underlying this variability are unclear.

Study design: Systematic review and meta-analysis.

Setting: Community and hospital.

Synopsis: Searching the Coch­rane review database, MEDLINE, EMBASE, CINAHL, and BIOSIS, 11 studies from 1973 to 2006 were included for meta-analysis, selected from 694 potential candidate studies identified on initial screening. The studies ranged in size from 62 to 2,285 patients.

The pooled estimate of risk for stroke following TIA was found to be 3.5%, 8%, and 9.2% at two, 30, and 90 days following TIA, respectively. However, there was significant heterogeneity for all periods considered (p<0.001).

Outcome ascertainment was identified as a major source of methodological heterogeneity. When risk of stroke at follow-up was determined by passive ascertainment (e.g., administrative documentation) the early risk of stroke was 3.1% two days after TIA, 6.4% at 30 days, and 8.7% at 90 days. But active ascertainment (e.g., direct, personal contact with study participants) determined stroke risk to be 9.9%, 13.4%, and 17.4% at two, 30, and 90 days after TIA, respectively.

Bottom line: Based on analysis of completed studies that included directly observed follow-up of study participants, the early risk of stroke after TIA is approximately 15% to 20% at 90 days following the sentinel event.

Citation: Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack. Arch Intern Med. 2007;167:2417-2422.

What Is the 1-year Ischemia and Mortality Rate for Three Anti-thrombotic Therapies for Early Invasive Management of ACS?

Background: Early interventional or surgical revascularization has improved morbidity and mortality in patients with acute coronary syndrome (ACS). The optimal anti-thrombotic regimen to reduce late ischemic and death rates has not been determined.

Study design: Prospective, open-label randomized control trial.

Setting: 450 academic and community-based institutions in 17 countries.

Synopsis: A total of 13,819 patients were enrolled between August 2003 and December 2005. They were assigned to heparin plus glycoprotein (GP) IIb/IIIa inhibitors (n=4,603), bivalirudin (Angiomax) plus IIb/IIIa inhibitors (n=4,604), or bivalirudin monotherapy (n=4,612).

For patients receiving GP IIb/IIIa inhibitors, a 2x2 factorial design assigned half the heparin and bivalirudin groups to routine upstream GP inhibitor administration (4,605 patients). The other half received selective GP IIb/IIIa inhibitors administration if PCI was indicated (4,602 patients).

At one year, there was no statistically significant difference in ischemia or mortality rate among the three therapy groups. No difference in ischemia rate was detected between the two GP IIb/IIIa inhibitor utilization strategies.

Since the hypotheses and the power for the one-year analysis in this trial were not prospectively determined, the results are considered to be exploratory and hypothesis generating.

Bottom line: At one year, there is no statistically significant difference in ischemia or mortality rate for the three antithrombotic regiments and the two glycoprotein utilization strategies.

Citation: Stone GW, Ware JH, Bertrand ME, et. al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management. One-year results from the ACUITY trial. JAMA 2007;298:2497-2505.

What Is the PE Risk after Discontinuing Anticoagulation in Patients with Symptomatic VTE?

Background: The natural history of patients with symptomatic VTE who have completed anticoagulation is not well understood.

Study design: Inception cohort using pooled data from a prospective cohort study and one arm of an open-label randomized trial.

Setting: Academic medical centers in Canada, Sweden, and Italy.

Synopsis: Using pooled data from two previous studies, 2,052 patients with a first diagnosis of symptomatic VTE (lower-extremity deep-vein thrombosis [DVT], PE, or both) were evaluated for fatal PE after a standard course of therapy (mean of six months) with a vitamin K antagonist.

Patients were followed for up to 120 months. The investigators found an annual event risk of 0.19-0.49 per 100 person-years for fatal PE. Patients with prolonged immobility, active cancer, and thrombophilia were excluded, as were those with recurrent acute DVT.

Secondary analysis revealed an incidence of any fatal, definite or probable PE within the first year of discontinuing therapy of 0.35%-0.81%.

After the first year, the annual event risk ranged from 0.15-0.40 events per 100 person-years. Patients with advanced age, idiopathic VTE as well as those presenting with PE had higher rates of fatal PE.

Bottom line: There is a real though small (less than 1%) risk of fatal PE in the first year following discontinuation of anticoagulation for the first VTE episode. The optimal course of treatment for patients with idiopathic VTE is yet to be determined.

Citation: Douketis JD, Gu CS, Schulman S, et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766-774.

Do the Beers Criteria Predict ED Visits Associated with Adverse Drug Events?

Background: Adverse drug events are common in the elderly. The Beers criteria are a consensus-based list of 41 medications that are considered inappropriate for use in older adults and often lead to poor outcomes.

Study design: Retrospective medical record review and data analysis.

Setting: Three nationally representative, U.S. public health surveillance systems: the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance System (NEISS-CADES), 2004-2005; the National Ambulatory Medical Care Survey (NAMCS), 2004; and National Hospital Ambulatory Medical Care Survey (NHAMCS), 2004.

Synopsis: Using data collected from ED visits at 58 hospitals in the NEISS-CADES system, this study estimated that 177,504 visits for adverse drug events occur annually in the United States. Only 8.8% of such visits were attributable to the 41 medications included in the Beers criteria. Three drug classes (anticoagulant and antiplatelet agents, antidiabetic agents, and narrow therapeutic index agents) accounted for nearly half of all such ED visits. Warfarin (17.3%), insulin (13%), and digoxin (3.2%) were the most commonly implicated medications, collectively accounting for 33% of visits (CI, 27.8% to 38.7%).

This study suggests that because of the common use and high risk of adverse events associated with these three drugs, interventions targeting their use may prevent ED visits for adverse drug events in the elderly, compared with interventions aimed at reducing the use of medications identified in the Beers criteria.

This study only included adverse drug events identified in the ED and relied on the diagnosis and documentation of such events by the ED physician.

Bottom line: Beers criteria medications, although considered inappropriate for use in the elderly, were associated with significantly fewer ED visits for adverse events compared with warfarin, digoxin, and insulin.

Citation: Budnitz DS, Shehab N, Kegler SR, et. al. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765. TH

Literature at a Glance

A guide to this month’s abstracts

• Steroids reduce mortality only in patients with confirmed bacterial meningitis.
• Probiotics can be useful in the treatment of acute diarrhea in children.
• CT pulmonary angiography is not inferior to V/Q scanning for exclusion of PE.
• Hospitalist care results in shorter LOS compared with care by traditional general internists and family practice physicians.
• The early risk of stroke after TIA is approximately 15% to 20% at 90 days after the sentinel event.
• Different anti-thrombotic strategies produce no difference in outcomes of early acute coronary syndromes.
• The risk of fatal PE is highest in the first year after medication is stopped.
• Beers criteria medications are associated with fewer ED visits by elderly patients compared with warfarin, digoxin, and insulin.

Do Steroids Affect the Outcome in Patients with Meningitis?

Background: Pyogenic (bacterial) meningitis has high morbidity and mortality. Studies suggest some benefit of steroids in children but provide limited evidence for adult use.

Study design: Intention-to-treat, randomized control trial.

Setting: Single hospital in Vietnam.

Synopsis: Of 435 patients older than 14 with suspected meningitis all received lumbar puncture with randomization to IV dexamethasone or placebo for four days. Results showed 69% of patients had definite meningitis, 28.3% were probable, and 2.8% had an alternative diagnosis based on culture results.

The primary outcome was death after one month, which did not differ among groups (risk ratio [RR] 0.79, confidence interval [CI] 0.45-1.39).

Predefined subgroup analysis of patients with definitive meningitis showed a significant reduction in mortality at one month (RR 0.43, CI 0.2-0.94) and death/disability at six months (odds ratio [OR] 0.56, CI 0.32-0.98).

In patients with probable meningitis, those who received steroids demonstrated a trend toward harm (OR 2.65, CI 0.73-9.63).

Probable versus definite meningitis was determined retrospectively based on cultures. The most common isolate was Streptococcus suis.

Bottom line: This study provides some evidence for using steroids in adults with confirmed bacterial meningitis. Clinical application is limited by bacterial epidemiology and the difficulty of prospectively separating patients who would benefit from those who might be harmed.

Citation: Nguyen TH, Tran TH, Thwaites G, et. al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med. 2007;357:2431-2439.

Which Probiotic Preparations Best Reduce the Duration of Acute Diarrhea in Children?

Background: Probiotics have been suggested as an adjunctive therapy to reduce the severity and duration of acute diarrhea in children. However, there are no clear data to suggest if specific probiotic agents are superior to others.

Study design: Prospective single-blind, randomized, controlled trial.

Setting: Outpatient primary care in Naples, Italy.

Synopsis: This study compared five commercially available probiotic preparations (mix of Lactobacillus delbrueckii var bulgaricus/Streptococcus thermophilus/L. acidophilus/ Bifido-bacterium bifidum; L. rhamnosus strain GG; Saccharomyces boulardii; Bacillus clausii; or Enterococcus faecium SF68) and a control group in the treatment of outpatient acute diarrhea in 571 children age 3 months to 36 months.

The primary outcomes were the duration of diarrhea and the number and consistency of stools. The groups receiving Lactobacillus GG and the mixture had a shorter total duration of diarrhea (78.5 and 70 hours, respectively), decreased total number of stools, and improved stool consistency when compared with the control (115.5 hours). The other therapies showed no improvement over the control group. These data report on products commercially available in Italy, which may differ greatly from products available locally.

Bottom line: Probiotic preparations for the treatment of acute diarrhea in children should be chosen based on effectiveness data.

Citation: Canani RB, Cirillo P, Terrin G, et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 2007;335:340-345.

Is CTPA a Reliable Alternative to V/Q Scan for Diagnosing PE?

Background: Computed tomography pulmonary angiogram (CTPA) has replaced ventilation/perfusion (V/Q) scanning at many hospitals as the test of choice for ruling out pulmonary embolism (PE). But limited clinical data compare CTPA with V/Q scanning in those suspected of having venous thromboembolism (VTE).

Study design: Randomized, investigator blinded, controlled trial.

Setting: The emergency departments (ED), inpatient wards, and outpatient clinics of five academic centers.

Synopsis: In the study, 1,411 patients were enrolled from five medical centers. Of 694 patients randomized to CTPA, 133 (19.2%) were diagnosed with VTE in the initial evaluation period, while 101 of 712 patients (14.2%) receiving a V/Q scan were diagnosed with VTE.

Patients not initially diagnosed with VTE were monitored. At three-month follow-up, 0.4% of the CTPA group and 1.0% of the V/Q group had a diagnosed VTE.

The overall rate of VTE found in the initial diagnostic period was significantly greater in patients randomized to CTPA (19.2% vs. 14.2%; difference, 5.0%; 95% CI; 1.1% to 8.9% p=.01). This suggests CTPA has a higher false positive rate or detects clinically insignificant thrombi.

Bottom line: CTPA was not inferior to V/Q scanning for excluding clinically meaningful PE, but CTPA diagnosed about 30% more patients with VTE than did V/Q scanning.

Citation: Anderson DR, Kahn SR, Rodger MA, et al. Computed tomographic pulmonary angiography vs. ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA. 2007;298(23):2743-2753.

Does the Hospitalist Model Improve Length of Stay, Quality, and Cost of Care?

Background: The hospitalist model, with increased physician availability and expertise but greater discontinuity of care, is becoming more prevalent in U.S. medicine. What little is known about how this model will affect patient care is derived from a number of small studies.

Study design: Retrospective cohort study.

Setting: 45 small to midsize, predominantly nonteaching hospitals throughout the U.S.

Synopsis: Using the Premier Healthcare Informatics database, this study examined information on 76,926 patients admitted for seven common diagnoses to one of three services: hospitalist, general internist, or family physician. Analysis showed that patients on a hospitalist service had a 0.4-day shorter length of stay (p<0.001) compared with those on a general internist or family physician service.

The cost to patients cared for by a hospitalist was lower than the cost of family physicians ($125 less, p=0.33) and internists ($268 less, p=0.02). There was no difference found in death rate or 14-day readmission rate among the three services.

Given the retrospective design of this study, no causal relationship can be deduced. This study is further limited by its lack of specific data on the physicians categorized into one of the three groups solely by administrative data. The authors had concerns that the biases inherent to the retrospective nature of their work accounted for the significant difference found between hospitalists and internists.

Bottom line: The hospitalist model is associated with modest improvements in length of stay as compared with traditional inpatient approaches.

Citation: Lindenauer PK, Rothberg MB, Pekow PS, et. al. Outcomes of care by hospitalists, general internists, and family physicians. N Engl J Med. 2007;357:2589-2600.

What Is the Stroke Risk Soon after TIA, and What Factors Drive the Variability of Previous Findings?

Background: Many studies have attempted to estimate the risk of stroke in the early period after a transient ischemic attack (TIA). These studies vary widely in their calculation of the estimated risk. Further, the clinical and methodological factors underlying this variability are unclear.

Study design: Systematic review and meta-analysis.

Setting: Community and hospital.

Synopsis: Searching the Coch­rane review database, MEDLINE, EMBASE, CINAHL, and BIOSIS, 11 studies from 1973 to 2006 were included for meta-analysis, selected from 694 potential candidate studies identified on initial screening. The studies ranged in size from 62 to 2,285 patients.

The pooled estimate of risk for stroke following TIA was found to be 3.5%, 8%, and 9.2% at two, 30, and 90 days following TIA, respectively. However, there was significant heterogeneity for all periods considered (p<0.001).

Outcome ascertainment was identified as a major source of methodological heterogeneity. When risk of stroke at follow-up was determined by passive ascertainment (e.g., administrative documentation) the early risk of stroke was 3.1% two days after TIA, 6.4% at 30 days, and 8.7% at 90 days. But active ascertainment (e.g., direct, personal contact with study participants) determined stroke risk to be 9.9%, 13.4%, and 17.4% at two, 30, and 90 days after TIA, respectively.

Bottom line: Based on analysis of completed studies that included directly observed follow-up of study participants, the early risk of stroke after TIA is approximately 15% to 20% at 90 days following the sentinel event.

Citation: Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack. Arch Intern Med. 2007;167:2417-2422.

What Is the 1-year Ischemia and Mortality Rate for Three Anti-thrombotic Therapies for Early Invasive Management of ACS?

Background: Early interventional or surgical revascularization has improved morbidity and mortality in patients with acute coronary syndrome (ACS). The optimal anti-thrombotic regimen to reduce late ischemic and death rates has not been determined.

Study design: Prospective, open-label randomized control trial.

Setting: 450 academic and community-based institutions in 17 countries.

Synopsis: A total of 13,819 patients were enrolled between August 2003 and December 2005. They were assigned to heparin plus glycoprotein (GP) IIb/IIIa inhibitors (n=4,603), bivalirudin (Angiomax) plus IIb/IIIa inhibitors (n=4,604), or bivalirudin monotherapy (n=4,612).

For patients receiving GP IIb/IIIa inhibitors, a 2x2 factorial design assigned half the heparin and bivalirudin groups to routine upstream GP inhibitor administration (4,605 patients). The other half received selective GP IIb/IIIa inhibitors administration if PCI was indicated (4,602 patients).

At one year, there was no statistically significant difference in ischemia or mortality rate among the three therapy groups. No difference in ischemia rate was detected between the two GP IIb/IIIa inhibitor utilization strategies.

Since the hypotheses and the power for the one-year analysis in this trial were not prospectively determined, the results are considered to be exploratory and hypothesis generating.

Bottom line: At one year, there is no statistically significant difference in ischemia or mortality rate for the three antithrombotic regiments and the two glycoprotein utilization strategies.

Citation: Stone GW, Ware JH, Bertrand ME, et. al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management. One-year results from the ACUITY trial. JAMA 2007;298:2497-2505.

What Is the PE Risk after Discontinuing Anticoagulation in Patients with Symptomatic VTE?

Background: The natural history of patients with symptomatic VTE who have completed anticoagulation is not well understood.

Study design: Inception cohort using pooled data from a prospective cohort study and one arm of an open-label randomized trial.

Setting: Academic medical centers in Canada, Sweden, and Italy.

Synopsis: Using pooled data from two previous studies, 2,052 patients with a first diagnosis of symptomatic VTE (lower-extremity deep-vein thrombosis [DVT], PE, or both) were evaluated for fatal PE after a standard course of therapy (mean of six months) with a vitamin K antagonist.

Patients were followed for up to 120 months. The investigators found an annual event risk of 0.19-0.49 per 100 person-years for fatal PE. Patients with prolonged immobility, active cancer, and thrombophilia were excluded, as were those with recurrent acute DVT.

Secondary analysis revealed an incidence of any fatal, definite or probable PE within the first year of discontinuing therapy of 0.35%-0.81%.

After the first year, the annual event risk ranged from 0.15-0.40 events per 100 person-years. Patients with advanced age, idiopathic VTE as well as those presenting with PE had higher rates of fatal PE.

Bottom line: There is a real though small (less than 1%) risk of fatal PE in the first year following discontinuation of anticoagulation for the first VTE episode. The optimal course of treatment for patients with idiopathic VTE is yet to be determined.

Citation: Douketis JD, Gu CS, Schulman S, et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147(11):766-774.

Do the Beers Criteria Predict ED Visits Associated with Adverse Drug Events?

Background: Adverse drug events are common in the elderly. The Beers criteria are a consensus-based list of 41 medications that are considered inappropriate for use in older adults and often lead to poor outcomes.

Study design: Retrospective medical record review and data analysis.

Setting: Three nationally representative, U.S. public health surveillance systems: the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance System (NEISS-CADES), 2004-2005; the National Ambulatory Medical Care Survey (NAMCS), 2004; and National Hospital Ambulatory Medical Care Survey (NHAMCS), 2004.

Synopsis: Using data collected from ED visits at 58 hospitals in the NEISS-CADES system, this study estimated that 177,504 visits for adverse drug events occur annually in the United States. Only 8.8% of such visits were attributable to the 41 medications included in the Beers criteria. Three drug classes (anticoagulant and antiplatelet agents, antidiabetic agents, and narrow therapeutic index agents) accounted for nearly half of all such ED visits. Warfarin (17.3%), insulin (13%), and digoxin (3.2%) were the most commonly implicated medications, collectively accounting for 33% of visits (CI, 27.8% to 38.7%).

This study suggests that because of the common use and high risk of adverse events associated with these three drugs, interventions targeting their use may prevent ED visits for adverse drug events in the elderly, compared with interventions aimed at reducing the use of medications identified in the Beers criteria.

This study only included adverse drug events identified in the ED and relied on the diagnosis and documentation of such events by the ED physician.

Bottom line: Beers criteria medications, although considered inappropriate for use in the elderly, were associated with significantly fewer ED visits for adverse events compared with warfarin, digoxin, and insulin.

Citation: Budnitz DS, Shehab N, Kegler SR, et. al. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147:755-765. TH