Ashwin Gupta, 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.

As healthcare costs rise, physicians and other stakeholders are now seeking innovative and effective ways to reduce the provision of low-value services.^1,2 The Choosing Wisely^® campaign aims to further this goal by promoting lists of specific procedures, tests, and treatments that providers should avoid in selected clinical settings.³ On February 21, 2013, the Society of Hospital Medicine (SHM) released 2 Choosing Wisely^® lists consisting of adult and pediatric services that are seen as costly to consumers and to the healthcare system, but which are often nonbeneficial or even harmful.^4,5 A total of 80 physician and nurse specialty societies have joined in submitting additional lists.

Despite the growing enthusiasm for this effort, questions remain regarding the Choosing Wisely^® campaign’s ability to initiate the meaningful de-adoption of low-value services. Specifically, prior efforts to reduce the use of services deemed to be of questionable benefit have met several challenges.^2,6 Early analyses of the Choosing Wisely^® recommendations reveal similar roadblocks and variable uptakes of several recommendations.^7-10 While the reasons for difficulties in achieving de-adoption are broad, one important factor in whether clinicians are willing to follow guideline recommendations from such initiatives as Choosing Wisely^®is the extent to which they believe in the underlying evidence.¹¹ The current work seeks to formally evaluate the evidence supporting the Choosing Wisely^® recommendations, and to compare the quality of evidence supporting SHM lists to other published Choosing Wisely^® lists.

Data Sources

Using the online listing of published Choosing Wisely^® recommendations, a dataset was generated incorporating all 320 recommendations comprising the 58 lists published through August, 2014; these include both the adult and pediatric hospital medicine lists released by the SHM.^4,5,12 Although data collection ended at this point, this represents a majority of all 81 lists and 535 recommendations published through December, 2017. The reviewers (A.J.A., A.G., M.W., T.S.V., M.S., and C.R.C) extracted information about the references cited for each recommendation.

Data Analysis

The reviewers obtained each reference cited by a Choosing Wisely^® recommendation and categorized it by evidence strength along the following hierarchy: clinical practice guideline (CPG), primary research, review article, expert opinion, book, or others/unknown. CPGs were used as the highest level of evidence based on standard expectations for methodological rigor.¹³ Primary research was further rated as follows: systematic reviews and meta-analyses, randomized controlled trials (RCTs), observational studies, and case series. Each recommendation was graded using only the strongest piece of evidence cited.

Guideline Appraisal

We further sought to evaluate the strength of referenced CPGs. To accomplish this, a 10% random sample of the Choosing Wisely^® recommendations citing CPGs was selected, and the referenced CPGs were obtained. Separately, CPGs referenced by the SHM-published adult and pediatric lists were also obtained. For both groups, one CPG was randomly selected when a recommendation cited more than one CPG. These guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, a widely used instrument designed to assess CPG quality.^14,15 AGREE II consists of 25 questions categorized into 6 domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Guidelines are also assigned an overall score. Two trained reviewers (A.J.A. and A.G.) assessed each of the sampled CPGs using a standardized form. Scores were then standardized using the method recommended by the instrument and reported as a percentage of available points. Although a standard interpretation of scores is not provided by the instrument, prior applications deemed scores below 50% as deficient^16,17. When a recommendation item cited multiple CPGs, one was randomly selected. We also abstracted data on the year of publication, the evidence grade assigned to specific items recommended by Choosing Wisely^®, and whether the CPG addressed the referring recommendation. All data management and analysis were conducted using Stata (V14.2, StataCorp, College Station, Texas).

A total of 320 recommendations were considered in our analysis, including 10 published across the 2 hospital medicine lists. When limited to the highest quality citation for each of the recommendations, 225 (70.3%) cited CPGs, whereas 71 (22.2%) cited primary research articles (Table 1). Specifically, 29 (9.1%) cited systematic reviews and meta-analyses, 28 (8.8%) cited observational studies, and 13 (4.1%) cited RCTs. One recommendation (0.3%) cited a case series as its highest level of evidence, 7 (2.2%) cited review articles, 7 (2.2%) cited editorials or opinion pieces, and 10 (3.1%) cited other types of documents, such as websites or books. Among hospital medicine recommendations, 9 (90%) referenced CPGs and 1 (10%) cited an observational study.

For the AGREE II assessment, we included 23 CPGs from the 225 referenced across all recommendations, after which we separately selected 6 CPGs from the hospital medicine recommendations. There was no overlap. Notably, 4 hospital medicine recommendations referenced a common CPG. Among the random sample of referenced CPGs, the median overall score obtained by using AGREE II was 54.2% (IQR 33.3%-70.8%, Table 2). This was similar to the median overall among hospital medicine guidelines (58.2%, IQR 50.0%-83.3%). Both hospital medicine and other sampled guidelines tended to score poorly in stakeholder involvement (48.6%, IQR 44.1%-61.1% and 47.2%, IQR 38.9%-61.1%, respectively). There were no significant differences between hospital medicine-referenced CPGs and the larger sample of CPGs in any AGREE II subdomains. The median age from the CPG publication to the list publication was 7 years (IQR 4–7) for hospital medicine recommendations and 3 years (IQR 2–6) for the nonhospital medicine recommendations. Substantial agreement was found between raters on the overall guideline assessment (ICC 0.80, 95% CI 0.58-0.91; Supplementary Table 1).

Given the rising costs and the potential for iatrogenic harm, curbing ineffective practices has become an urgent concern. To achieve this, the Choosing Wisely^® campaign has taken an important step by targeting certain low-value practices for de-adoption. However, the evidence supporting recommendations is variable. Specifically, 25 recommendations cited case series, review articles, or lower quality evidence as their highest level of support; moreover, among recommendations citing CPGs, quality, timeliness, and support for the recommendation item were variable. Although the hospital medicine lists tended to cite higher-quality evidence in the form of CPGs, these CPGs were often less recent than the guidelines referenced by other lists.

Our findings parallel those of other works that evaluate evidence among Choosing Wisely^® recommendations and, more broadly, among CPGs.^18–21 Lin and Yancey evaluated the quality of primary care-focused Choosing Wisely^® recommendations using the Strength of Recommendation Taxonomy, a ranking system that evaluates evidence quality, consistency, and patient-centeredness.¹⁸ In their analysis, the authors found that many recommendations were based on lower quality evidence or relied on nonpatent-centered intermediate outcomes. Several groups, meanwhile, have evaluated the quality of evidence supporting CPG recommendations, finding them to be highly variable as well.^19–21 These findings likely reflect inherent difficulties in the process, by which guideline development groups distill a broad evidence base into useful clinical recommendations, a reality that may have influenced the Choosing Wisely^® list development groups seeking to make similar recommendations on low-value services.

These data should be taken in context due to several limitations. First, our sample of referenced CPGs includes only a small sample of all CPGs cited; thus, it may not be representative of all referenced guidelines. Second, the AGREE II assessment is inherently subjective, despite the availability of training materials. Third, data collection ended in April, 2014. Although this represents a majority of published lists to date, it is possible that more recent Choosing Wisely^®lists include a stronger focus on evidence quality. Finally, references cited by Choosing Wisely^®may not be representative of the entirety of the dataset that was considered when formulating the recommendations.

Despite these limitations, our findings suggest that Choosing Wisely^®recommendations vary in terms of evidence strength. Although our results reveal that the majority of recommendations cite guidelines or high-quality original research, evidence gaps remain, with a small number citing low-quality evidence or low-quality CPGs as their highest form of support. Given the barriers to the successful de-implementation of low-value services, such campaigns as Choosing Wisely^®face an uphill battle in their attempt to prompt behavior changes among providers and consumers.^6-9 As a result, it is incumbent on funding agencies and medical journals to promote studies evaluating the harms and overall value of the care we deliver.

Although a majority of Choosing Wisely^® recommendations cite high-quality evidence, some reference low-quality evidence or low-quality CPGs as their highest form of support. To overcome clinical inertia and other barriers to the successful de-implementation of low-value services, a clear rationale for the impetus to eradicate entrenched practices is critical.^2,22 Choosing Wisely^® has provided visionary leadership and a powerful platform to question low-value care. To expand the campaign’s efforts, the medical field must be able to generate the high-quality evidence necessary to support these efforts; further, list development groups must consider the availability of strong evidence when targeting services for de-implementation.

This work was supported, in part, by a grant from the Agency for Healthcare Research and Quality (No. K08HS020672, Dr. Cooke).

Disclosures

The authors have nothing to disclose.

As healthcare costs rise, physicians and other stakeholders are now seeking innovative and effective ways to reduce the provision of low-value services.^1,2 The Choosing Wisely^® campaign aims to further this goal by promoting lists of specific procedures, tests, and treatments that providers should avoid in selected clinical settings.³ On February 21, 2013, the Society of Hospital Medicine (SHM) released 2 Choosing Wisely^® lists consisting of adult and pediatric services that are seen as costly to consumers and to the healthcare system, but which are often nonbeneficial or even harmful.^4,5 A total of 80 physician and nurse specialty societies have joined in submitting additional lists.

Despite the growing enthusiasm for this effort, questions remain regarding the Choosing Wisely^® campaign’s ability to initiate the meaningful de-adoption of low-value services. Specifically, prior efforts to reduce the use of services deemed to be of questionable benefit have met several challenges.^2,6 Early analyses of the Choosing Wisely^® recommendations reveal similar roadblocks and variable uptakes of several recommendations.^7-10 While the reasons for difficulties in achieving de-adoption are broad, one important factor in whether clinicians are willing to follow guideline recommendations from such initiatives as Choosing Wisely^®is the extent to which they believe in the underlying evidence.¹¹ The current work seeks to formally evaluate the evidence supporting the Choosing Wisely^® recommendations, and to compare the quality of evidence supporting SHM lists to other published Choosing Wisely^® lists.

Data Sources

Using the online listing of published Choosing Wisely^® recommendations, a dataset was generated incorporating all 320 recommendations comprising the 58 lists published through August, 2014; these include both the adult and pediatric hospital medicine lists released by the SHM.^4,5,12 Although data collection ended at this point, this represents a majority of all 81 lists and 535 recommendations published through December, 2017. The reviewers (A.J.A., A.G., M.W., T.S.V., M.S., and C.R.C) extracted information about the references cited for each recommendation.

Data Analysis

The reviewers obtained each reference cited by a Choosing Wisely^® recommendation and categorized it by evidence strength along the following hierarchy: clinical practice guideline (CPG), primary research, review article, expert opinion, book, or others/unknown. CPGs were used as the highest level of evidence based on standard expectations for methodological rigor.¹³ Primary research was further rated as follows: systematic reviews and meta-analyses, randomized controlled trials (RCTs), observational studies, and case series. Each recommendation was graded using only the strongest piece of evidence cited.

Guideline Appraisal

We further sought to evaluate the strength of referenced CPGs. To accomplish this, a 10% random sample of the Choosing Wisely^® recommendations citing CPGs was selected, and the referenced CPGs were obtained. Separately, CPGs referenced by the SHM-published adult and pediatric lists were also obtained. For both groups, one CPG was randomly selected when a recommendation cited more than one CPG. These guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, a widely used instrument designed to assess CPG quality.^14,15 AGREE II consists of 25 questions categorized into 6 domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Guidelines are also assigned an overall score. Two trained reviewers (A.J.A. and A.G.) assessed each of the sampled CPGs using a standardized form. Scores were then standardized using the method recommended by the instrument and reported as a percentage of available points. Although a standard interpretation of scores is not provided by the instrument, prior applications deemed scores below 50% as deficient^16,17. When a recommendation item cited multiple CPGs, one was randomly selected. We also abstracted data on the year of publication, the evidence grade assigned to specific items recommended by Choosing Wisely^®, and whether the CPG addressed the referring recommendation. All data management and analysis were conducted using Stata (V14.2, StataCorp, College Station, Texas).

A total of 320 recommendations were considered in our analysis, including 10 published across the 2 hospital medicine lists. When limited to the highest quality citation for each of the recommendations, 225 (70.3%) cited CPGs, whereas 71 (22.2%) cited primary research articles (Table 1). Specifically, 29 (9.1%) cited systematic reviews and meta-analyses, 28 (8.8%) cited observational studies, and 13 (4.1%) cited RCTs. One recommendation (0.3%) cited a case series as its highest level of evidence, 7 (2.2%) cited review articles, 7 (2.2%) cited editorials or opinion pieces, and 10 (3.1%) cited other types of documents, such as websites or books. Among hospital medicine recommendations, 9 (90%) referenced CPGs and 1 (10%) cited an observational study.

For the AGREE II assessment, we included 23 CPGs from the 225 referenced across all recommendations, after which we separately selected 6 CPGs from the hospital medicine recommendations. There was no overlap. Notably, 4 hospital medicine recommendations referenced a common CPG. Among the random sample of referenced CPGs, the median overall score obtained by using AGREE II was 54.2% (IQR 33.3%-70.8%, Table 2). This was similar to the median overall among hospital medicine guidelines (58.2%, IQR 50.0%-83.3%). Both hospital medicine and other sampled guidelines tended to score poorly in stakeholder involvement (48.6%, IQR 44.1%-61.1% and 47.2%, IQR 38.9%-61.1%, respectively). There were no significant differences between hospital medicine-referenced CPGs and the larger sample of CPGs in any AGREE II subdomains. The median age from the CPG publication to the list publication was 7 years (IQR 4–7) for hospital medicine recommendations and 3 years (IQR 2–6) for the nonhospital medicine recommendations. Substantial agreement was found between raters on the overall guideline assessment (ICC 0.80, 95% CI 0.58-0.91; Supplementary Table 1).

Given the rising costs and the potential for iatrogenic harm, curbing ineffective practices has become an urgent concern. To achieve this, the Choosing Wisely^® campaign has taken an important step by targeting certain low-value practices for de-adoption. However, the evidence supporting recommendations is variable. Specifically, 25 recommendations cited case series, review articles, or lower quality evidence as their highest level of support; moreover, among recommendations citing CPGs, quality, timeliness, and support for the recommendation item were variable. Although the hospital medicine lists tended to cite higher-quality evidence in the form of CPGs, these CPGs were often less recent than the guidelines referenced by other lists.

Our findings parallel those of other works that evaluate evidence among Choosing Wisely^® recommendations and, more broadly, among CPGs.^18–21 Lin and Yancey evaluated the quality of primary care-focused Choosing Wisely^® recommendations using the Strength of Recommendation Taxonomy, a ranking system that evaluates evidence quality, consistency, and patient-centeredness.¹⁸ In their analysis, the authors found that many recommendations were based on lower quality evidence or relied on nonpatent-centered intermediate outcomes. Several groups, meanwhile, have evaluated the quality of evidence supporting CPG recommendations, finding them to be highly variable as well.^19–21 These findings likely reflect inherent difficulties in the process, by which guideline development groups distill a broad evidence base into useful clinical recommendations, a reality that may have influenced the Choosing Wisely^® list development groups seeking to make similar recommendations on low-value services.

These data should be taken in context due to several limitations. First, our sample of referenced CPGs includes only a small sample of all CPGs cited; thus, it may not be representative of all referenced guidelines. Second, the AGREE II assessment is inherently subjective, despite the availability of training materials. Third, data collection ended in April, 2014. Although this represents a majority of published lists to date, it is possible that more recent Choosing Wisely^®lists include a stronger focus on evidence quality. Finally, references cited by Choosing Wisely^®may not be representative of the entirety of the dataset that was considered when formulating the recommendations.

Despite these limitations, our findings suggest that Choosing Wisely^®recommendations vary in terms of evidence strength. Although our results reveal that the majority of recommendations cite guidelines or high-quality original research, evidence gaps remain, with a small number citing low-quality evidence or low-quality CPGs as their highest form of support. Given the barriers to the successful de-implementation of low-value services, such campaigns as Choosing Wisely^®face an uphill battle in their attempt to prompt behavior changes among providers and consumers.^6-9 As a result, it is incumbent on funding agencies and medical journals to promote studies evaluating the harms and overall value of the care we deliver.

Although a majority of Choosing Wisely^® recommendations cite high-quality evidence, some reference low-quality evidence or low-quality CPGs as their highest form of support. To overcome clinical inertia and other barriers to the successful de-implementation of low-value services, a clear rationale for the impetus to eradicate entrenched practices is critical.^2,22 Choosing Wisely^® has provided visionary leadership and a powerful platform to question low-value care. To expand the campaign’s efforts, the medical field must be able to generate the high-quality evidence necessary to support these efforts; further, list development groups must consider the availability of strong evidence when targeting services for de-implementation.

This work was supported, in part, by a grant from the Agency for Healthcare Research and Quality (No. K08HS020672, Dr. Cooke).

Disclosures

The authors have nothing to disclose.

As healthcare costs rise, physicians and other stakeholders are now seeking innovative and effective ways to reduce the provision of low-value services.^1,2 The Choosing Wisely^® campaign aims to further this goal by promoting lists of specific procedures, tests, and treatments that providers should avoid in selected clinical settings.³ On February 21, 2013, the Society of Hospital Medicine (SHM) released 2 Choosing Wisely^® lists consisting of adult and pediatric services that are seen as costly to consumers and to the healthcare system, but which are often nonbeneficial or even harmful.^4,5 A total of 80 physician and nurse specialty societies have joined in submitting additional lists.

Despite the growing enthusiasm for this effort, questions remain regarding the Choosing Wisely^® campaign’s ability to initiate the meaningful de-adoption of low-value services. Specifically, prior efforts to reduce the use of services deemed to be of questionable benefit have met several challenges.^2,6 Early analyses of the Choosing Wisely^® recommendations reveal similar roadblocks and variable uptakes of several recommendations.^7-10 While the reasons for difficulties in achieving de-adoption are broad, one important factor in whether clinicians are willing to follow guideline recommendations from such initiatives as Choosing Wisely^®is the extent to which they believe in the underlying evidence.¹¹ The current work seeks to formally evaluate the evidence supporting the Choosing Wisely^® recommendations, and to compare the quality of evidence supporting SHM lists to other published Choosing Wisely^® lists.

Data Sources

Using the online listing of published Choosing Wisely^® recommendations, a dataset was generated incorporating all 320 recommendations comprising the 58 lists published through August, 2014; these include both the adult and pediatric hospital medicine lists released by the SHM.^4,5,12 Although data collection ended at this point, this represents a majority of all 81 lists and 535 recommendations published through December, 2017. The reviewers (A.J.A., A.G., M.W., T.S.V., M.S., and C.R.C) extracted information about the references cited for each recommendation.

Data Analysis

The reviewers obtained each reference cited by a Choosing Wisely^® recommendation and categorized it by evidence strength along the following hierarchy: clinical practice guideline (CPG), primary research, review article, expert opinion, book, or others/unknown. CPGs were used as the highest level of evidence based on standard expectations for methodological rigor.¹³ Primary research was further rated as follows: systematic reviews and meta-analyses, randomized controlled trials (RCTs), observational studies, and case series. Each recommendation was graded using only the strongest piece of evidence cited.

Guideline Appraisal

We further sought to evaluate the strength of referenced CPGs. To accomplish this, a 10% random sample of the Choosing Wisely^® recommendations citing CPGs was selected, and the referenced CPGs were obtained. Separately, CPGs referenced by the SHM-published adult and pediatric lists were also obtained. For both groups, one CPG was randomly selected when a recommendation cited more than one CPG. These guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, a widely used instrument designed to assess CPG quality.^14,15 AGREE II consists of 25 questions categorized into 6 domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Guidelines are also assigned an overall score. Two trained reviewers (A.J.A. and A.G.) assessed each of the sampled CPGs using a standardized form. Scores were then standardized using the method recommended by the instrument and reported as a percentage of available points. Although a standard interpretation of scores is not provided by the instrument, prior applications deemed scores below 50% as deficient^16,17. When a recommendation item cited multiple CPGs, one was randomly selected. We also abstracted data on the year of publication, the evidence grade assigned to specific items recommended by Choosing Wisely^®, and whether the CPG addressed the referring recommendation. All data management and analysis were conducted using Stata (V14.2, StataCorp, College Station, Texas).

A total of 320 recommendations were considered in our analysis, including 10 published across the 2 hospital medicine lists. When limited to the highest quality citation for each of the recommendations, 225 (70.3%) cited CPGs, whereas 71 (22.2%) cited primary research articles (Table 1). Specifically, 29 (9.1%) cited systematic reviews and meta-analyses, 28 (8.8%) cited observational studies, and 13 (4.1%) cited RCTs. One recommendation (0.3%) cited a case series as its highest level of evidence, 7 (2.2%) cited review articles, 7 (2.2%) cited editorials or opinion pieces, and 10 (3.1%) cited other types of documents, such as websites or books. Among hospital medicine recommendations, 9 (90%) referenced CPGs and 1 (10%) cited an observational study.

For the AGREE II assessment, we included 23 CPGs from the 225 referenced across all recommendations, after which we separately selected 6 CPGs from the hospital medicine recommendations. There was no overlap. Notably, 4 hospital medicine recommendations referenced a common CPG. Among the random sample of referenced CPGs, the median overall score obtained by using AGREE II was 54.2% (IQR 33.3%-70.8%, Table 2). This was similar to the median overall among hospital medicine guidelines (58.2%, IQR 50.0%-83.3%). Both hospital medicine and other sampled guidelines tended to score poorly in stakeholder involvement (48.6%, IQR 44.1%-61.1% and 47.2%, IQR 38.9%-61.1%, respectively). There were no significant differences between hospital medicine-referenced CPGs and the larger sample of CPGs in any AGREE II subdomains. The median age from the CPG publication to the list publication was 7 years (IQR 4–7) for hospital medicine recommendations and 3 years (IQR 2–6) for the nonhospital medicine recommendations. Substantial agreement was found between raters on the overall guideline assessment (ICC 0.80, 95% CI 0.58-0.91; Supplementary Table 1).

Given the rising costs and the potential for iatrogenic harm, curbing ineffective practices has become an urgent concern. To achieve this, the Choosing Wisely^® campaign has taken an important step by targeting certain low-value practices for de-adoption. However, the evidence supporting recommendations is variable. Specifically, 25 recommendations cited case series, review articles, or lower quality evidence as their highest level of support; moreover, among recommendations citing CPGs, quality, timeliness, and support for the recommendation item were variable. Although the hospital medicine lists tended to cite higher-quality evidence in the form of CPGs, these CPGs were often less recent than the guidelines referenced by other lists.

Our findings parallel those of other works that evaluate evidence among Choosing Wisely^® recommendations and, more broadly, among CPGs.^18–21 Lin and Yancey evaluated the quality of primary care-focused Choosing Wisely^® recommendations using the Strength of Recommendation Taxonomy, a ranking system that evaluates evidence quality, consistency, and patient-centeredness.¹⁸ In their analysis, the authors found that many recommendations were based on lower quality evidence or relied on nonpatent-centered intermediate outcomes. Several groups, meanwhile, have evaluated the quality of evidence supporting CPG recommendations, finding them to be highly variable as well.^19–21 These findings likely reflect inherent difficulties in the process, by which guideline development groups distill a broad evidence base into useful clinical recommendations, a reality that may have influenced the Choosing Wisely^® list development groups seeking to make similar recommendations on low-value services.

These data should be taken in context due to several limitations. First, our sample of referenced CPGs includes only a small sample of all CPGs cited; thus, it may not be representative of all referenced guidelines. Second, the AGREE II assessment is inherently subjective, despite the availability of training materials. Third, data collection ended in April, 2014. Although this represents a majority of published lists to date, it is possible that more recent Choosing Wisely^®lists include a stronger focus on evidence quality. Finally, references cited by Choosing Wisely^®may not be representative of the entirety of the dataset that was considered when formulating the recommendations.

Despite these limitations, our findings suggest that Choosing Wisely^®recommendations vary in terms of evidence strength. Although our results reveal that the majority of recommendations cite guidelines or high-quality original research, evidence gaps remain, with a small number citing low-quality evidence or low-quality CPGs as their highest form of support. Given the barriers to the successful de-implementation of low-value services, such campaigns as Choosing Wisely^®face an uphill battle in their attempt to prompt behavior changes among providers and consumers.^6-9 As a result, it is incumbent on funding agencies and medical journals to promote studies evaluating the harms and overall value of the care we deliver.

Although a majority of Choosing Wisely^® recommendations cite high-quality evidence, some reference low-quality evidence or low-quality CPGs as their highest form of support. To overcome clinical inertia and other barriers to the successful de-implementation of low-value services, a clear rationale for the impetus to eradicate entrenched practices is critical.^2,22 Choosing Wisely^® has provided visionary leadership and a powerful platform to question low-value care. To expand the campaign’s efforts, the medical field must be able to generate the high-quality evidence necessary to support these efforts; further, list development groups must consider the availability of strong evidence when targeting services for de-implementation.

This work was supported, in part, by a grant from the Agency for Healthcare Research and Quality (No. K08HS020672, Dr. Cooke).

Disclosures

The authors have nothing to disclose.

Central line–associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) are morbid and expensive healthcare-associated infections (HAIs).^1-8 While these HAIs are prevalent in intensive care units (ICUs) and general wards, most of the research, prevention efforts, and financial penalties have been focused in the ICU.^9,10 For hospitalists, who are taking a larger role in caring for the critically ill,^11,12 it is optimal to understand best preventive practices.

There has been a national puTash to standardize procedures and products to prevent CLABSI and CAUTI.^2,13-16 CLABSI has transitioned from a common ICU complication to a “never event.” Success has been reflected in the prevention of 25,000 CLABSIs over the last decade, translating to a 58% reduction in infections, with 6000 deaths prevented and $414 million saved.² CLABSI prevention principles have been applied to CAUTI prevention (ie, aseptic insertion, maintenance care, prompting removal) but with slower adoption¹⁷ and fewer dramatic CAUTI reductions,¹⁸ due in part to weaker recognition¹⁹ of CAUTI as a serious clinical event, despite its morbidity²⁰ and cost.²¹

Despite recent improvements in preventing HAIs, there is a marked variability in how hospitals perform in preventing these infections.²² To inform infection prevention strategies for a large-scale implementation project funded by the Agency for Healthcare Research and Quality and focused on ICUs with persistently elevated CLABSI and/or CAUTI rates,²³ we performed a systematic search of interventions to prevent CLABSI and CAUTI in the ICU setting. This evidence was synthesized to help units select and prioritize interventions to prevent these HAIs.

Literature Search Strategy

We performed a systematic search to identify CLABSI and CAUTI prevention studies and synthesized findings using a narrative review process. Using criteria developed and refined from seminal articles on the topic,^10,14,24-34 we searched the PubMed and Cochrane databases from their inception to October of 2015 using Medical Subject Headings (MeSHs) for “central venous catheters,” “CLABSI,” “central line associated bloodstream infection,” “catheter related bloodstream infection,” “intravascular devices,” “urinary catheterization,” “urinary catheters,” “urinary tract infections,” “CAUTI,” and “catheter associated urinary tract infections” and filtered for articles containing the MeSHs “intensive care unit” and “ICU.” Supplemental Figure 1 details the search, yielding 102 studies for CLABSI and 28 studies for CAUTI, including 7 studies with CLABSI and CAUTI interventions.

Eligibility Criteria Review

Study Design

We included randomized and nonrandomized studies that implemented at least 1 intervention to prevent CLABSI or CAUTI in an adult ICU setting and reported the preintervention or control group data to compare with the postintervention data. We excluded general ward, outpatient/ambulatory, and neonatal/pediatric settings. Interventions to prevent CLABSI or CAUTI were included. We excluded interventions focused on diagnosis or treatment or those that lacked adequate description of the intervention for replication. Studies with interventions that are no longer standard of care in the United States (US) were excluded, as were studies not available in English.

Outcomes

Primary Outcomes for Central Vascular Catheter Infection

• CLABSI: A lab-confirmed bloodstream infection in a patient who has had a central line for at least 48 hours on the date of the development of the bloodstream infection and without another known source of infection. We included studies that reported CLABSIs per 1000 central line days or those that provided data to permit calculation of this ratio. This measure is similar to current National Healthcare Safety Network (NHSN) surveillance definitions.²²
• Catheter-related bloodstream infection (CRBSI): A lab-confirmed bloodstream infection attributed to an intravascular catheter by a quantitative culture of the catheter tip or by differences in growth between catheter and peripheral venipuncture blood culture specimens.³⁵ This microbiologic definition of a central line bloodstream infection was often used prior to NHSN reporting, with rates provided as the number of CRBSIs per 1000 central line days.

Primary Outcome for Urinary Catheter Infection

• CAUTI: Urinary tract infection occurring in patients during or after the recent use of an indwelling urinary catheter. We included studies that reported CAUTIs per 1000 urinary catheter days or those that provided data to permit calculation of this ratio (similar to the current NHSN surveillance definitions).²² We excluded studies where CAUTI was defined as bacteriuria alone, without symptoms.

Secondary Outcomes

• Central line utilization ratio: The device utilization ratio (DUR) measure of central line use is calculated as central line days divided by patient days.
• Urinary catheter utilization ratio: The DUR measure of urinary catheter use is calculated as indwelling urinary catheter days divided by patient days, as used in NHSN surveillance, excluding other catheter types.²² We excluded other measures of urinary catheter use because of a large variation in definitions, which limits the ability to compare measures across studies.

Data Synthesis and Analysis

Information on the ICU and intervention type, intervention components, outcomes, and whether interventions were in use prior to the study was abstracted by CAUTI and CLABSI experts (JM and PKP) and confirmed by a second author.

We compared interventions found in the literature to components of the previously published urinary catheter “life cycle,” a conceptual model used to organize and prioritize interventions for a reduction in CAUTI (Figure 1).³⁶

Conceptual Model for Disrupting the Life Cycle of a Catheter

Our data analysis demonstrated that components of the urinary catheter life cycle (Figure 1) were useful and could be applied to vascular catheters, but changes were needed to make the model more valuable to hospitalists implementing CLABSI and CAUTI prevention interventions. We found that the previously named stage 1 (catheter placement) is better described in 2 stages: stage 0, avoid catheter if possible, and stage 1, ensure aseptic placement. Additionally, we tailored the model to include actionable language, describing ways to disrupt the life cycle. Finally, we added a component to represent interventions to improve implementation and sustainability, such as auditing compliance and timely feedback to clinicians. Thus, we introduce a new conceptual model, “Disrupting the Life Cycle of a Catheter” (Figure 2)

Central Vascular Catheter Interventional Study Results

Characteristics of Included Central Vascular Catheter Infection Studies

Of the 102 central vascular catheter (CVC) studies that met the inclusion criteria (reporting outcomes for 105 intervention cohorts), 59 studies^{10,14,16,24-27,38-89} reporting outcomes for 61 intervention cohorts were performed in the US. Study designs included 14 randomized controlled trials (RCTs)^{48,64,68,74,79,90-98} and 88 before–after studies (Appendix Table 1). ^{10,14,16,24-27,33,38-47,49-63,69-73,75-78,80-89,99-131} Many RCTs evaluated antimicrobial products (CVCs, hubs, bathing) as interventions,^{48,68,74,90-95,97,98} but a few RCTs studied interventions^64,79,93 impacting catheter care or use (Appendix Table 1). Fifty-one studies took place in tertiary care hospitals and 55 in academic hospitals. Thirty-one studies were multicenter; the largest included 792 hospitals and 1071 ICUs.²⁴ ICU bed size ranged from 5 to 59.

CVC Study Outcomes

Sixty-three studies reported CLABSI outcomes, and 39 reported CRBSI outcomes (Table 2). Many studies had preintervention or control rates above the 2013 NHSN 75th percentiles,²² which varied by ICU type. Preintervention or control infection rates per 1000 catheter days varied widely (means: CLABSI 7.5, CRBSI 6.3); US studies reported ranges of 1.1 to 12.1 CLABSI and 1.2 to 11.0 CRBSI per 1000 catheter days; non-US studies reported ranges of 1.4 to 45.9 CLABSI and 1.6 to 22.7 CRBSI per 1000 catheter days. Postintervention rates varied widely, with overall means of 2.8 CLABSI and 2.5 CRBSI per 1000 catheter days, including US study ranges of 0 to 8.9 CLABSI and 0 to 5.4 CRBSI, and non-US study ranges of 0 to 17.1 CLABSI and 0 to 15.9 CRBSI.

CVC Interventions

CVC study interventions are summarized in Table 1, categorized by catheter life cycle component (Figure 2). Thirty-two included studies used a single intervention to prevent CVC infection. Interventions to avoid placement when possible were infrequent. Insertion-stage interventions were common and included avoiding the femoral site during placement, ensuring maximal sterile barriers, and chlorhexidine skin preparation. Standardizing basic products for central line insertion was often done by providing ICUs with a CLABSI insertion kit or stocked cart. In some studies, this was implemented prior to the intervention, and in others, the kit or cart itself was the intervention. Maintenance-stage interventions included scrubbing the hub prior to use, replacing wet or soiled dressings, accessing the catheter with sterile devices, and performing aseptic dressing changes. A recent systematic review and meta-analysis of CVC infection prevention studies indicated that implementing care bundles and/or checklists appears to yield stronger risk reductions than interventions without these components.¹³² The most common catheter removal interventions were daily audits of line removal and CLABSI rounds focused on ongoing catheter necessity.

Common implementation and sustainability interventions included outcome surveillance, such as feedback on CLABSI, and socio-adaptive interventions to prompt improvements in patient safety culture. Process and outcome surveillance as interventions were implemented in about one-quarter of the studies reviewed (AppendixTable 1).

CAUTI Interventional Study Results

Characteristics of Included CAUTI Studies

Of the 28 CAUTI studies that met the inclusion criteria (reporting outcomes for 30 intervention cohorts), 14 studies (reporting outcomes for 16 intervention cohorts) were performed in the US.^{28,34,53,66,68,133-141} Study designs included 2 RCTs (focused on urinary catheter avoidance or removal¹⁴² and chlorhexidine bathing⁶⁸) and 26 nonrandomized, before–after studies^{28,30,33,34,53,66,109,114-116,133-141,143-149} (Appendix Table 1). The number of hospitals per study varied from 1 to 53, with the majority being single-hospital interventions.

CAUTI Study Outcomes

All 28 studies reported CAUTIs per 1000 catheter days for both intervention and comparison groups (Table 2). Preintervention or control CAUTI rates varied widely, with an overall mean of 12.5 CAUTIs per 1000 catheter days; US studies reported a range from 1.4 to 15.8 CAUTIs per 1000 catheter days; non-US studies reported a range from 0.8 to 90.1 CAUTIs per 1000 catheter days. Many studies had preintervention or control rates above the 2013 NHSN 75th percentiles.²² Postintervention CAUTI rates varied widely, with an overall mean of 7.0 CAUTIs per 1000 catheter days, including a US study range from 0 to 11.2 and a non-US study range from 1.9 to 65.7.

Overall (Table 2), 27 of the 30 intervention cohorts described in the 28 studies reported fewer CAUTIs, including all ICU types. Lower postintervention CAUTI rates were reported in 25 studies, with a mean 49.4% reduction, including 11 statistically significant reductions; many studies did not report the level of statistical significance or described inadequate power to detect a significant change (Table 2).

Urinary catheter utilization rates were reported for 11 studies (Table 2). A decreased urinary catheter utilization rate was reported in 7 studies (4 with statistically signficiant reductions), with a mean 16% reduction (Table 2). Other outcomes included cost savings, the potential for unintended negative outcomes, and clinician compliance with intervention components. Positive cost savings were reported in 5 studies.^{30,34,133,141,149}

CAUTI Interventions

Of the 28 included CAUTI prevention studies, only 5 studied single interventions. Interventions were categorized in Table 1 by “life cycle” stages or as interventions to improve implementation and sustainability (Figure 2). Interventions to restrict indwelling urinary catheter use were common, including creating lists of approved indications selected by unit or hospital policy and requiring catheter orders with approved indications. Eight studies published approved indication lists.^{28,34,133-135,138,142,146} Although several studies describe the encouragement and use of bladder scanners and urinary catheter alternatives, none described purchasing these catheter alternatives.

Interventions to avoid indwelling urinary catheters included education about external catheters,^{28,34,109,133,140,144-146} urinary retention protocols,^{34,144,135,141} and bladder scanner simulation training.¹³³ Interventions to improve aseptic insertion^{28,34,66,109,116,139-141-143-146,150} and maintenance care^{28,34,66,109,116,133,135,136,139-141,143-146,150} of urinary catheters were common. Four studies used a standardized urinary catheter kit or cart,^{28,34,139,142} and 2 studies used a commercial urinary catheter securement device.^34,140 A CAUTI bundle checklist in daily patient care rounds was tested in 3 studies (Table 1).^66,136,150 Reminder and stop order strategies, with the potential to reduce CAUTI rates by >50%,¹⁵¹ were included in 15 studies, with inteventions such as nurse-empowered stop orders. Several implementation and sustainability interventions were described, including socio-adaptive strategies such as holding multidisciplinary meetings to obtain unit or clinician feedback to inform design and improve buy-in and providing frequent feedback to ICU clinicians, including audits of catheter use appropriateness and catheter-associated infections.

This extensive literature review yielded a large body of literature demonstrating success in preventing CLABSI and CAUTI in all types of adult ICUs, including in general medical and surgical ICUs and in specialized units with historically higher rates, such as trauma, burn, and neurosurgical. Reported reductions in catheter infections were impressive (>65% for CLABSI or CRBSI and nearly 50% for CAUTI), though several studies had limited power to detect statistical significance. DURs were reported more rarely (particularly for vascular catheters) and often without power to detect statistical significance. Nevertheless, 7 studies reported reduced urinary catheter use (16% mean reduction), which would be anticipated to be clinically significant.

The conceptual model introduced for “Disrupting the Life Cycle of a Catheter” (Figure 2) can be a helpful tool for hospitalists and intensivists to assess and prioritize potential strategies for reducing catheter-associated infections. This study’s results indicate that CLABSI prevention studies often used interventions that optimize best practices during aseptic insertion and maintenance, but few studies emphasized reducing inappropriate central line use. Conversely, CAUTI prevention often targeted avoiding placement and prompting the removal of urinary catheters, with fewer studies evaluating innovative products or technical skill advancement for aseptic insertion or maintenance, though educational interventions to standardize aseptic catheter use were common. Recently, recommendations for reducing the inappropriate use of urinary catheters and intravenous catheters, including scenarios common in ICUs, were developed by using the rigorous RAND/UCLA Appropriateness Method^152,153; these resources may be helpful to hospitalists designing and implementing interventions to reduce catheter use.

In reviewing the US studies of 5 units demonstrating the greatest success in preventing CLABSI^{56,62,65,78,83} and CAUTI,^28,34,66,134 several shared features emerged. Interventions that addressed multiple steps within the life cycle of a catheter (avoidance, insertion, maintenance, and removal) were common. Previous work has shown that assuring compliance in infection prevention efforts is a key to success,¹⁵⁴ and in both CLABSI and CAUTI studies, auditing was included in these successful interventions. Specifically for CLABSI, the checklist, a central quality improvement tool, was frequently associated with success. Unique to CAUTI, engaging a multidisciplinary team including nurse leadership seemed critical to optimize implementation and sustainability efforts. In addition, a focus on stage 3 (removal), including protocols to remove by default, was associated with success in CAUTI studies.

Our review was limited by a frequent lack of reporting of statistical significance or by inadequate power to detect a significant change and great variety. The ability to compare the impact of specific interventions is limited because studies varied greatly with respect to the type of intervention, duration of data collection, and outcomes assessed. We also anticipate that successful interventions are more likely to be published than are trials without success. Strengths include the use of a rigorous search process and the inclusion and review of several types of interventions implemented in ICUs.

In conclusion, despite high catheter use in ICUs, the literature includes many successful interventions for the prevention of vascular and urinary catheter infections in multiple ICU types. This review indicates that targeting multiple steps within the life cycle of a catheter, particularly when combined with interventions to optimize implementation and sustainability, can improve success in reducing CLABSI and CAUTI in the ICU.

Acknowledgments

The authors thank all members of the National Project Team for the AHRQ Safety Program for Intensive Care Units: Preventing CLABSI and CAUTI.

Disclosure

Agency for Healthcare Research and Quality (AHRQ) contract #HHSP233201500016I/HHSP23337002T provided funding for this study. J.M.’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, VA Ann Arbor Patient Safety Center of Inquiry, the Health Research and Educational Trust, American Hospital Association and the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the US Department of Veterans Affairs. All authors report no conflicts of interest relevant to this article.

Central line–associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) are morbid and expensive healthcare-associated infections (HAIs).^1-8 While these HAIs are prevalent in intensive care units (ICUs) and general wards, most of the research, prevention efforts, and financial penalties have been focused in the ICU.^9,10 For hospitalists, who are taking a larger role in caring for the critically ill,^11,12 it is optimal to understand best preventive practices.

There has been a national puTash to standardize procedures and products to prevent CLABSI and CAUTI.^2,13-16 CLABSI has transitioned from a common ICU complication to a “never event.” Success has been reflected in the prevention of 25,000 CLABSIs over the last decade, translating to a 58% reduction in infections, with 6000 deaths prevented and $414 million saved.² CLABSI prevention principles have been applied to CAUTI prevention (ie, aseptic insertion, maintenance care, prompting removal) but with slower adoption¹⁷ and fewer dramatic CAUTI reductions,¹⁸ due in part to weaker recognition¹⁹ of CAUTI as a serious clinical event, despite its morbidity²⁰ and cost.²¹

Despite recent improvements in preventing HAIs, there is a marked variability in how hospitals perform in preventing these infections.²² To inform infection prevention strategies for a large-scale implementation project funded by the Agency for Healthcare Research and Quality and focused on ICUs with persistently elevated CLABSI and/or CAUTI rates,²³ we performed a systematic search of interventions to prevent CLABSI and CAUTI in the ICU setting. This evidence was synthesized to help units select and prioritize interventions to prevent these HAIs.

Literature Search Strategy

We performed a systematic search to identify CLABSI and CAUTI prevention studies and synthesized findings using a narrative review process. Using criteria developed and refined from seminal articles on the topic,^10,14,24-34 we searched the PubMed and Cochrane databases from their inception to October of 2015 using Medical Subject Headings (MeSHs) for “central venous catheters,” “CLABSI,” “central line associated bloodstream infection,” “catheter related bloodstream infection,” “intravascular devices,” “urinary catheterization,” “urinary catheters,” “urinary tract infections,” “CAUTI,” and “catheter associated urinary tract infections” and filtered for articles containing the MeSHs “intensive care unit” and “ICU.” Supplemental Figure 1 details the search, yielding 102 studies for CLABSI and 28 studies for CAUTI, including 7 studies with CLABSI and CAUTI interventions.

Eligibility Criteria Review

Study Design

We included randomized and nonrandomized studies that implemented at least 1 intervention to prevent CLABSI or CAUTI in an adult ICU setting and reported the preintervention or control group data to compare with the postintervention data. We excluded general ward, outpatient/ambulatory, and neonatal/pediatric settings. Interventions to prevent CLABSI or CAUTI were included. We excluded interventions focused on diagnosis or treatment or those that lacked adequate description of the intervention for replication. Studies with interventions that are no longer standard of care in the United States (US) were excluded, as were studies not available in English.

Outcomes

Primary Outcomes for Central Vascular Catheter Infection

• CLABSI: A lab-confirmed bloodstream infection in a patient who has had a central line for at least 48 hours on the date of the development of the bloodstream infection and without another known source of infection. We included studies that reported CLABSIs per 1000 central line days or those that provided data to permit calculation of this ratio. This measure is similar to current National Healthcare Safety Network (NHSN) surveillance definitions.²²
• Catheter-related bloodstream infection (CRBSI): A lab-confirmed bloodstream infection attributed to an intravascular catheter by a quantitative culture of the catheter tip or by differences in growth between catheter and peripheral venipuncture blood culture specimens.³⁵ This microbiologic definition of a central line bloodstream infection was often used prior to NHSN reporting, with rates provided as the number of CRBSIs per 1000 central line days.

Primary Outcome for Urinary Catheter Infection

• CAUTI: Urinary tract infection occurring in patients during or after the recent use of an indwelling urinary catheter. We included studies that reported CAUTIs per 1000 urinary catheter days or those that provided data to permit calculation of this ratio (similar to the current NHSN surveillance definitions).²² We excluded studies where CAUTI was defined as bacteriuria alone, without symptoms.

Secondary Outcomes

• Central line utilization ratio: The device utilization ratio (DUR) measure of central line use is calculated as central line days divided by patient days.
• Urinary catheter utilization ratio: The DUR measure of urinary catheter use is calculated as indwelling urinary catheter days divided by patient days, as used in NHSN surveillance, excluding other catheter types.²² We excluded other measures of urinary catheter use because of a large variation in definitions, which limits the ability to compare measures across studies.

Data Synthesis and Analysis

Information on the ICU and intervention type, intervention components, outcomes, and whether interventions were in use prior to the study was abstracted by CAUTI and CLABSI experts (JM and PKP) and confirmed by a second author.

We compared interventions found in the literature to components of the previously published urinary catheter “life cycle,” a conceptual model used to organize and prioritize interventions for a reduction in CAUTI (Figure 1).³⁶

Conceptual Model for Disrupting the Life Cycle of a Catheter

Our data analysis demonstrated that components of the urinary catheter life cycle (Figure 1) were useful and could be applied to vascular catheters, but changes were needed to make the model more valuable to hospitalists implementing CLABSI and CAUTI prevention interventions. We found that the previously named stage 1 (catheter placement) is better described in 2 stages: stage 0, avoid catheter if possible, and stage 1, ensure aseptic placement. Additionally, we tailored the model to include actionable language, describing ways to disrupt the life cycle. Finally, we added a component to represent interventions to improve implementation and sustainability, such as auditing compliance and timely feedback to clinicians. Thus, we introduce a new conceptual model, “Disrupting the Life Cycle of a Catheter” (Figure 2)

Central Vascular Catheter Interventional Study Results

Characteristics of Included Central Vascular Catheter Infection Studies

Of the 102 central vascular catheter (CVC) studies that met the inclusion criteria (reporting outcomes for 105 intervention cohorts), 59 studies^{10,14,16,24-27,38-89} reporting outcomes for 61 intervention cohorts were performed in the US. Study designs included 14 randomized controlled trials (RCTs)^{48,64,68,74,79,90-98} and 88 before–after studies (Appendix Table 1). ^{10,14,16,24-27,33,38-47,49-63,69-73,75-78,80-89,99-131} Many RCTs evaluated antimicrobial products (CVCs, hubs, bathing) as interventions,^{48,68,74,90-95,97,98} but a few RCTs studied interventions^64,79,93 impacting catheter care or use (Appendix Table 1). Fifty-one studies took place in tertiary care hospitals and 55 in academic hospitals. Thirty-one studies were multicenter; the largest included 792 hospitals and 1071 ICUs.²⁴ ICU bed size ranged from 5 to 59.

CVC Study Outcomes

Sixty-three studies reported CLABSI outcomes, and 39 reported CRBSI outcomes (Table 2). Many studies had preintervention or control rates above the 2013 NHSN 75th percentiles,²² which varied by ICU type. Preintervention or control infection rates per 1000 catheter days varied widely (means: CLABSI 7.5, CRBSI 6.3); US studies reported ranges of 1.1 to 12.1 CLABSI and 1.2 to 11.0 CRBSI per 1000 catheter days; non-US studies reported ranges of 1.4 to 45.9 CLABSI and 1.6 to 22.7 CRBSI per 1000 catheter days. Postintervention rates varied widely, with overall means of 2.8 CLABSI and 2.5 CRBSI per 1000 catheter days, including US study ranges of 0 to 8.9 CLABSI and 0 to 5.4 CRBSI, and non-US study ranges of 0 to 17.1 CLABSI and 0 to 15.9 CRBSI.

CVC Interventions

CVC study interventions are summarized in Table 1, categorized by catheter life cycle component (Figure 2). Thirty-two included studies used a single intervention to prevent CVC infection. Interventions to avoid placement when possible were infrequent. Insertion-stage interventions were common and included avoiding the femoral site during placement, ensuring maximal sterile barriers, and chlorhexidine skin preparation. Standardizing basic products for central line insertion was often done by providing ICUs with a CLABSI insertion kit or stocked cart. In some studies, this was implemented prior to the intervention, and in others, the kit or cart itself was the intervention. Maintenance-stage interventions included scrubbing the hub prior to use, replacing wet or soiled dressings, accessing the catheter with sterile devices, and performing aseptic dressing changes. A recent systematic review and meta-analysis of CVC infection prevention studies indicated that implementing care bundles and/or checklists appears to yield stronger risk reductions than interventions without these components.¹³² The most common catheter removal interventions were daily audits of line removal and CLABSI rounds focused on ongoing catheter necessity.

Common implementation and sustainability interventions included outcome surveillance, such as feedback on CLABSI, and socio-adaptive interventions to prompt improvements in patient safety culture. Process and outcome surveillance as interventions were implemented in about one-quarter of the studies reviewed (AppendixTable 1).

CAUTI Interventional Study Results

Characteristics of Included CAUTI Studies

Of the 28 CAUTI studies that met the inclusion criteria (reporting outcomes for 30 intervention cohorts), 14 studies (reporting outcomes for 16 intervention cohorts) were performed in the US.^{28,34,53,66,68,133-141} Study designs included 2 RCTs (focused on urinary catheter avoidance or removal¹⁴² and chlorhexidine bathing⁶⁸) and 26 nonrandomized, before–after studies^{28,30,33,34,53,66,109,114-116,133-141,143-149} (Appendix Table 1). The number of hospitals per study varied from 1 to 53, with the majority being single-hospital interventions.

CAUTI Study Outcomes

All 28 studies reported CAUTIs per 1000 catheter days for both intervention and comparison groups (Table 2). Preintervention or control CAUTI rates varied widely, with an overall mean of 12.5 CAUTIs per 1000 catheter days; US studies reported a range from 1.4 to 15.8 CAUTIs per 1000 catheter days; non-US studies reported a range from 0.8 to 90.1 CAUTIs per 1000 catheter days. Many studies had preintervention or control rates above the 2013 NHSN 75th percentiles.²² Postintervention CAUTI rates varied widely, with an overall mean of 7.0 CAUTIs per 1000 catheter days, including a US study range from 0 to 11.2 and a non-US study range from 1.9 to 65.7.

Overall (Table 2), 27 of the 30 intervention cohorts described in the 28 studies reported fewer CAUTIs, including all ICU types. Lower postintervention CAUTI rates were reported in 25 studies, with a mean 49.4% reduction, including 11 statistically significant reductions; many studies did not report the level of statistical significance or described inadequate power to detect a significant change (Table 2).

Urinary catheter utilization rates were reported for 11 studies (Table 2). A decreased urinary catheter utilization rate was reported in 7 studies (4 with statistically signficiant reductions), with a mean 16% reduction (Table 2). Other outcomes included cost savings, the potential for unintended negative outcomes, and clinician compliance with intervention components. Positive cost savings were reported in 5 studies.^{30,34,133,141,149}

CAUTI Interventions

Of the 28 included CAUTI prevention studies, only 5 studied single interventions. Interventions were categorized in Table 1 by “life cycle” stages or as interventions to improve implementation and sustainability (Figure 2). Interventions to restrict indwelling urinary catheter use were common, including creating lists of approved indications selected by unit or hospital policy and requiring catheter orders with approved indications. Eight studies published approved indication lists.^{28,34,133-135,138,142,146} Although several studies describe the encouragement and use of bladder scanners and urinary catheter alternatives, none described purchasing these catheter alternatives.

Interventions to avoid indwelling urinary catheters included education about external catheters,^{28,34,109,133,140,144-146} urinary retention protocols,^{34,144,135,141} and bladder scanner simulation training.¹³³ Interventions to improve aseptic insertion^{28,34,66,109,116,139-141-143-146,150} and maintenance care^{28,34,66,109,116,133,135,136,139-141,143-146,150} of urinary catheters were common. Four studies used a standardized urinary catheter kit or cart,^{28,34,139,142} and 2 studies used a commercial urinary catheter securement device.^34,140 A CAUTI bundle checklist in daily patient care rounds was tested in 3 studies (Table 1).^66,136,150 Reminder and stop order strategies, with the potential to reduce CAUTI rates by >50%,¹⁵¹ were included in 15 studies, with inteventions such as nurse-empowered stop orders. Several implementation and sustainability interventions were described, including socio-adaptive strategies such as holding multidisciplinary meetings to obtain unit or clinician feedback to inform design and improve buy-in and providing frequent feedback to ICU clinicians, including audits of catheter use appropriateness and catheter-associated infections.

This extensive literature review yielded a large body of literature demonstrating success in preventing CLABSI and CAUTI in all types of adult ICUs, including in general medical and surgical ICUs and in specialized units with historically higher rates, such as trauma, burn, and neurosurgical. Reported reductions in catheter infections were impressive (>65% for CLABSI or CRBSI and nearly 50% for CAUTI), though several studies had limited power to detect statistical significance. DURs were reported more rarely (particularly for vascular catheters) and often without power to detect statistical significance. Nevertheless, 7 studies reported reduced urinary catheter use (16% mean reduction), which would be anticipated to be clinically significant.

The conceptual model introduced for “Disrupting the Life Cycle of a Catheter” (Figure 2) can be a helpful tool for hospitalists and intensivists to assess and prioritize potential strategies for reducing catheter-associated infections. This study’s results indicate that CLABSI prevention studies often used interventions that optimize best practices during aseptic insertion and maintenance, but few studies emphasized reducing inappropriate central line use. Conversely, CAUTI prevention often targeted avoiding placement and prompting the removal of urinary catheters, with fewer studies evaluating innovative products or technical skill advancement for aseptic insertion or maintenance, though educational interventions to standardize aseptic catheter use were common. Recently, recommendations for reducing the inappropriate use of urinary catheters and intravenous catheters, including scenarios common in ICUs, were developed by using the rigorous RAND/UCLA Appropriateness Method^152,153; these resources may be helpful to hospitalists designing and implementing interventions to reduce catheter use.

In reviewing the US studies of 5 units demonstrating the greatest success in preventing CLABSI^{56,62,65,78,83} and CAUTI,^28,34,66,134 several shared features emerged. Interventions that addressed multiple steps within the life cycle of a catheter (avoidance, insertion, maintenance, and removal) were common. Previous work has shown that assuring compliance in infection prevention efforts is a key to success,¹⁵⁴ and in both CLABSI and CAUTI studies, auditing was included in these successful interventions. Specifically for CLABSI, the checklist, a central quality improvement tool, was frequently associated with success. Unique to CAUTI, engaging a multidisciplinary team including nurse leadership seemed critical to optimize implementation and sustainability efforts. In addition, a focus on stage 3 (removal), including protocols to remove by default, was associated with success in CAUTI studies.

Our review was limited by a frequent lack of reporting of statistical significance or by inadequate power to detect a significant change and great variety. The ability to compare the impact of specific interventions is limited because studies varied greatly with respect to the type of intervention, duration of data collection, and outcomes assessed. We also anticipate that successful interventions are more likely to be published than are trials without success. Strengths include the use of a rigorous search process and the inclusion and review of several types of interventions implemented in ICUs.

In conclusion, despite high catheter use in ICUs, the literature includes many successful interventions for the prevention of vascular and urinary catheter infections in multiple ICU types. This review indicates that targeting multiple steps within the life cycle of a catheter, particularly when combined with interventions to optimize implementation and sustainability, can improve success in reducing CLABSI and CAUTI in the ICU.

Acknowledgments

The authors thank all members of the National Project Team for the AHRQ Safety Program for Intensive Care Units: Preventing CLABSI and CAUTI.

Disclosure

Agency for Healthcare Research and Quality (AHRQ) contract #HHSP233201500016I/HHSP23337002T provided funding for this study. J.M.’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, VA Ann Arbor Patient Safety Center of Inquiry, the Health Research and Educational Trust, American Hospital Association and the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the US Department of Veterans Affairs. All authors report no conflicts of interest relevant to this article.

Central line–associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) are morbid and expensive healthcare-associated infections (HAIs).^1-8 While these HAIs are prevalent in intensive care units (ICUs) and general wards, most of the research, prevention efforts, and financial penalties have been focused in the ICU.^9,10 For hospitalists, who are taking a larger role in caring for the critically ill,^11,12 it is optimal to understand best preventive practices.

There has been a national puTash to standardize procedures and products to prevent CLABSI and CAUTI.^2,13-16 CLABSI has transitioned from a common ICU complication to a “never event.” Success has been reflected in the prevention of 25,000 CLABSIs over the last decade, translating to a 58% reduction in infections, with 6000 deaths prevented and $414 million saved.² CLABSI prevention principles have been applied to CAUTI prevention (ie, aseptic insertion, maintenance care, prompting removal) but with slower adoption¹⁷ and fewer dramatic CAUTI reductions,¹⁸ due in part to weaker recognition¹⁹ of CAUTI as a serious clinical event, despite its morbidity²⁰ and cost.²¹

Despite recent improvements in preventing HAIs, there is a marked variability in how hospitals perform in preventing these infections.²² To inform infection prevention strategies for a large-scale implementation project funded by the Agency for Healthcare Research and Quality and focused on ICUs with persistently elevated CLABSI and/or CAUTI rates,²³ we performed a systematic search of interventions to prevent CLABSI and CAUTI in the ICU setting. This evidence was synthesized to help units select and prioritize interventions to prevent these HAIs.

Literature Search Strategy

We performed a systematic search to identify CLABSI and CAUTI prevention studies and synthesized findings using a narrative review process. Using criteria developed and refined from seminal articles on the topic,^10,14,24-34 we searched the PubMed and Cochrane databases from their inception to October of 2015 using Medical Subject Headings (MeSHs) for “central venous catheters,” “CLABSI,” “central line associated bloodstream infection,” “catheter related bloodstream infection,” “intravascular devices,” “urinary catheterization,” “urinary catheters,” “urinary tract infections,” “CAUTI,” and “catheter associated urinary tract infections” and filtered for articles containing the MeSHs “intensive care unit” and “ICU.” Supplemental Figure 1 details the search, yielding 102 studies for CLABSI and 28 studies for CAUTI, including 7 studies with CLABSI and CAUTI interventions.

Eligibility Criteria Review

Study Design

We included randomized and nonrandomized studies that implemented at least 1 intervention to prevent CLABSI or CAUTI in an adult ICU setting and reported the preintervention or control group data to compare with the postintervention data. We excluded general ward, outpatient/ambulatory, and neonatal/pediatric settings. Interventions to prevent CLABSI or CAUTI were included. We excluded interventions focused on diagnosis or treatment or those that lacked adequate description of the intervention for replication. Studies with interventions that are no longer standard of care in the United States (US) were excluded, as were studies not available in English.

Outcomes

Primary Outcomes for Central Vascular Catheter Infection

• CLABSI: A lab-confirmed bloodstream infection in a patient who has had a central line for at least 48 hours on the date of the development of the bloodstream infection and without another known source of infection. We included studies that reported CLABSIs per 1000 central line days or those that provided data to permit calculation of this ratio. This measure is similar to current National Healthcare Safety Network (NHSN) surveillance definitions.²²
• Catheter-related bloodstream infection (CRBSI): A lab-confirmed bloodstream infection attributed to an intravascular catheter by a quantitative culture of the catheter tip or by differences in growth between catheter and peripheral venipuncture blood culture specimens.³⁵ This microbiologic definition of a central line bloodstream infection was often used prior to NHSN reporting, with rates provided as the number of CRBSIs per 1000 central line days.

Primary Outcome for Urinary Catheter Infection

• CAUTI: Urinary tract infection occurring in patients during or after the recent use of an indwelling urinary catheter. We included studies that reported CAUTIs per 1000 urinary catheter days or those that provided data to permit calculation of this ratio (similar to the current NHSN surveillance definitions).²² We excluded studies where CAUTI was defined as bacteriuria alone, without symptoms.

Secondary Outcomes

• Central line utilization ratio: The device utilization ratio (DUR) measure of central line use is calculated as central line days divided by patient days.
• Urinary catheter utilization ratio: The DUR measure of urinary catheter use is calculated as indwelling urinary catheter days divided by patient days, as used in NHSN surveillance, excluding other catheter types.²² We excluded other measures of urinary catheter use because of a large variation in definitions, which limits the ability to compare measures across studies.

Data Synthesis and Analysis

Information on the ICU and intervention type, intervention components, outcomes, and whether interventions were in use prior to the study was abstracted by CAUTI and CLABSI experts (JM and PKP) and confirmed by a second author.

We compared interventions found in the literature to components of the previously published urinary catheter “life cycle,” a conceptual model used to organize and prioritize interventions for a reduction in CAUTI (Figure 1).³⁶

Conceptual Model for Disrupting the Life Cycle of a Catheter

Our data analysis demonstrated that components of the urinary catheter life cycle (Figure 1) were useful and could be applied to vascular catheters, but changes were needed to make the model more valuable to hospitalists implementing CLABSI and CAUTI prevention interventions. We found that the previously named stage 1 (catheter placement) is better described in 2 stages: stage 0, avoid catheter if possible, and stage 1, ensure aseptic placement. Additionally, we tailored the model to include actionable language, describing ways to disrupt the life cycle. Finally, we added a component to represent interventions to improve implementation and sustainability, such as auditing compliance and timely feedback to clinicians. Thus, we introduce a new conceptual model, “Disrupting the Life Cycle of a Catheter” (Figure 2)

Central Vascular Catheter Interventional Study Results

Characteristics of Included Central Vascular Catheter Infection Studies

Of the 102 central vascular catheter (CVC) studies that met the inclusion criteria (reporting outcomes for 105 intervention cohorts), 59 studies^{10,14,16,24-27,38-89} reporting outcomes for 61 intervention cohorts were performed in the US. Study designs included 14 randomized controlled trials (RCTs)^{48,64,68,74,79,90-98} and 88 before–after studies (Appendix Table 1). ^{10,14,16,24-27,33,38-47,49-63,69-73,75-78,80-89,99-131} Many RCTs evaluated antimicrobial products (CVCs, hubs, bathing) as interventions,^{48,68,74,90-95,97,98} but a few RCTs studied interventions^64,79,93 impacting catheter care or use (Appendix Table 1). Fifty-one studies took place in tertiary care hospitals and 55 in academic hospitals. Thirty-one studies were multicenter; the largest included 792 hospitals and 1071 ICUs.²⁴ ICU bed size ranged from 5 to 59.

CVC Study Outcomes

Sixty-three studies reported CLABSI outcomes, and 39 reported CRBSI outcomes (Table 2). Many studies had preintervention or control rates above the 2013 NHSN 75th percentiles,²² which varied by ICU type. Preintervention or control infection rates per 1000 catheter days varied widely (means: CLABSI 7.5, CRBSI 6.3); US studies reported ranges of 1.1 to 12.1 CLABSI and 1.2 to 11.0 CRBSI per 1000 catheter days; non-US studies reported ranges of 1.4 to 45.9 CLABSI and 1.6 to 22.7 CRBSI per 1000 catheter days. Postintervention rates varied widely, with overall means of 2.8 CLABSI and 2.5 CRBSI per 1000 catheter days, including US study ranges of 0 to 8.9 CLABSI and 0 to 5.4 CRBSI, and non-US study ranges of 0 to 17.1 CLABSI and 0 to 15.9 CRBSI.

CVC Interventions

CVC study interventions are summarized in Table 1, categorized by catheter life cycle component (Figure 2). Thirty-two included studies used a single intervention to prevent CVC infection. Interventions to avoid placement when possible were infrequent. Insertion-stage interventions were common and included avoiding the femoral site during placement, ensuring maximal sterile barriers, and chlorhexidine skin preparation. Standardizing basic products for central line insertion was often done by providing ICUs with a CLABSI insertion kit or stocked cart. In some studies, this was implemented prior to the intervention, and in others, the kit or cart itself was the intervention. Maintenance-stage interventions included scrubbing the hub prior to use, replacing wet or soiled dressings, accessing the catheter with sterile devices, and performing aseptic dressing changes. A recent systematic review and meta-analysis of CVC infection prevention studies indicated that implementing care bundles and/or checklists appears to yield stronger risk reductions than interventions without these components.¹³² The most common catheter removal interventions were daily audits of line removal and CLABSI rounds focused on ongoing catheter necessity.

Common implementation and sustainability interventions included outcome surveillance, such as feedback on CLABSI, and socio-adaptive interventions to prompt improvements in patient safety culture. Process and outcome surveillance as interventions were implemented in about one-quarter of the studies reviewed (AppendixTable 1).

CAUTI Interventional Study Results

Characteristics of Included CAUTI Studies

Of the 28 CAUTI studies that met the inclusion criteria (reporting outcomes for 30 intervention cohorts), 14 studies (reporting outcomes for 16 intervention cohorts) were performed in the US.^{28,34,53,66,68,133-141} Study designs included 2 RCTs (focused on urinary catheter avoidance or removal¹⁴² and chlorhexidine bathing⁶⁸) and 26 nonrandomized, before–after studies^{28,30,33,34,53,66,109,114-116,133-141,143-149} (Appendix Table 1). The number of hospitals per study varied from 1 to 53, with the majority being single-hospital interventions.

CAUTI Study Outcomes

All 28 studies reported CAUTIs per 1000 catheter days for both intervention and comparison groups (Table 2). Preintervention or control CAUTI rates varied widely, with an overall mean of 12.5 CAUTIs per 1000 catheter days; US studies reported a range from 1.4 to 15.8 CAUTIs per 1000 catheter days; non-US studies reported a range from 0.8 to 90.1 CAUTIs per 1000 catheter days. Many studies had preintervention or control rates above the 2013 NHSN 75th percentiles.²² Postintervention CAUTI rates varied widely, with an overall mean of 7.0 CAUTIs per 1000 catheter days, including a US study range from 0 to 11.2 and a non-US study range from 1.9 to 65.7.

Overall (Table 2), 27 of the 30 intervention cohorts described in the 28 studies reported fewer CAUTIs, including all ICU types. Lower postintervention CAUTI rates were reported in 25 studies, with a mean 49.4% reduction, including 11 statistically significant reductions; many studies did not report the level of statistical significance or described inadequate power to detect a significant change (Table 2).

Urinary catheter utilization rates were reported for 11 studies (Table 2). A decreased urinary catheter utilization rate was reported in 7 studies (4 with statistically signficiant reductions), with a mean 16% reduction (Table 2). Other outcomes included cost savings, the potential for unintended negative outcomes, and clinician compliance with intervention components. Positive cost savings were reported in 5 studies.^{30,34,133,141,149}

CAUTI Interventions

Of the 28 included CAUTI prevention studies, only 5 studied single interventions. Interventions were categorized in Table 1 by “life cycle” stages or as interventions to improve implementation and sustainability (Figure 2). Interventions to restrict indwelling urinary catheter use were common, including creating lists of approved indications selected by unit or hospital policy and requiring catheter orders with approved indications. Eight studies published approved indication lists.^{28,34,133-135,138,142,146} Although several studies describe the encouragement and use of bladder scanners and urinary catheter alternatives, none described purchasing these catheter alternatives.

Interventions to avoid indwelling urinary catheters included education about external catheters,^{28,34,109,133,140,144-146} urinary retention protocols,^{34,144,135,141} and bladder scanner simulation training.¹³³ Interventions to improve aseptic insertion^{28,34,66,109,116,139-141-143-146,150} and maintenance care^{28,34,66,109,116,133,135,136,139-141,143-146,150} of urinary catheters were common. Four studies used a standardized urinary catheter kit or cart,^{28,34,139,142} and 2 studies used a commercial urinary catheter securement device.^34,140 A CAUTI bundle checklist in daily patient care rounds was tested in 3 studies (Table 1).^66,136,150 Reminder and stop order strategies, with the potential to reduce CAUTI rates by >50%,¹⁵¹ were included in 15 studies, with inteventions such as nurse-empowered stop orders. Several implementation and sustainability interventions were described, including socio-adaptive strategies such as holding multidisciplinary meetings to obtain unit or clinician feedback to inform design and improve buy-in and providing frequent feedback to ICU clinicians, including audits of catheter use appropriateness and catheter-associated infections.

This extensive literature review yielded a large body of literature demonstrating success in preventing CLABSI and CAUTI in all types of adult ICUs, including in general medical and surgical ICUs and in specialized units with historically higher rates, such as trauma, burn, and neurosurgical. Reported reductions in catheter infections were impressive (>65% for CLABSI or CRBSI and nearly 50% for CAUTI), though several studies had limited power to detect statistical significance. DURs were reported more rarely (particularly for vascular catheters) and often without power to detect statistical significance. Nevertheless, 7 studies reported reduced urinary catheter use (16% mean reduction), which would be anticipated to be clinically significant.

The conceptual model introduced for “Disrupting the Life Cycle of a Catheter” (Figure 2) can be a helpful tool for hospitalists and intensivists to assess and prioritize potential strategies for reducing catheter-associated infections. This study’s results indicate that CLABSI prevention studies often used interventions that optimize best practices during aseptic insertion and maintenance, but few studies emphasized reducing inappropriate central line use. Conversely, CAUTI prevention often targeted avoiding placement and prompting the removal of urinary catheters, with fewer studies evaluating innovative products or technical skill advancement for aseptic insertion or maintenance, though educational interventions to standardize aseptic catheter use were common. Recently, recommendations for reducing the inappropriate use of urinary catheters and intravenous catheters, including scenarios common in ICUs, were developed by using the rigorous RAND/UCLA Appropriateness Method^152,153; these resources may be helpful to hospitalists designing and implementing interventions to reduce catheter use.

In reviewing the US studies of 5 units demonstrating the greatest success in preventing CLABSI^{56,62,65,78,83} and CAUTI,^28,34,66,134 several shared features emerged. Interventions that addressed multiple steps within the life cycle of a catheter (avoidance, insertion, maintenance, and removal) were common. Previous work has shown that assuring compliance in infection prevention efforts is a key to success,¹⁵⁴ and in both CLABSI and CAUTI studies, auditing was included in these successful interventions. Specifically for CLABSI, the checklist, a central quality improvement tool, was frequently associated with success. Unique to CAUTI, engaging a multidisciplinary team including nurse leadership seemed critical to optimize implementation and sustainability efforts. In addition, a focus on stage 3 (removal), including protocols to remove by default, was associated with success in CAUTI studies.

Our review was limited by a frequent lack of reporting of statistical significance or by inadequate power to detect a significant change and great variety. The ability to compare the impact of specific interventions is limited because studies varied greatly with respect to the type of intervention, duration of data collection, and outcomes assessed. We also anticipate that successful interventions are more likely to be published than are trials without success. Strengths include the use of a rigorous search process and the inclusion and review of several types of interventions implemented in ICUs.

In conclusion, despite high catheter use in ICUs, the literature includes many successful interventions for the prevention of vascular and urinary catheter infections in multiple ICU types. This review indicates that targeting multiple steps within the life cycle of a catheter, particularly when combined with interventions to optimize implementation and sustainability, can improve success in reducing CLABSI and CAUTI in the ICU.

Acknowledgments

The authors thank all members of the National Project Team for the AHRQ Safety Program for Intensive Care Units: Preventing CLABSI and CAUTI.

Disclosure

Agency for Healthcare Research and Quality (AHRQ) contract #HHSP233201500016I/HHSP23337002T provided funding for this study. J.M.’s other research is funded by AHRQ (2R01HS018334-04), the NIH-LRP program, the VA National Center for Patient Safety, VA Ann Arbor Patient Safety Center of Inquiry, the Health Research and Educational Trust, American Hospital Association and the Centers for Disease Control and Prevention. The findings and conclusions in this report are those of the authors and do not necessarily represent those of the sponsor, the Agency for Healthcare Research and Quality, or the US Department of Veterans Affairs. All authors report no conflicts of interest relevant to this article.