Emergency Medicine

Case

A woman in her third decade with no known medical history was dropped off at the waiting area of the ED for evaluation of depressed mental status. Upon arrival, the patient was unresponsive and cyanotic, with a pulse oximetry of 65% on room air. Bag-valve mask (BVM) ventilation rapidly improved oxygen saturation to 90%. The patient’s other vital signs were: heart rate, 141 beats/min; blood pressure (BP), 117/65 mm Hg; and temperature, afebrile.

Upon examination, the patient’s pupils were pinpoint and her ventilatory effort was shallow, leading the emergency physician (EP) to suspect the patient’s depressed mental status was due to an opioid overdose.

The patient was given 2 mg of intravenous (IV) naloxone, after which she became more alert and responsive, with improved respiratory effort. After receiving naloxone, the patient vomited copiously. Pulmonary examination revealed diffuse rales, most prominently at the right lung base, and a cough productive of thick sputum.

During the patient’s course in the ED, she became increasingly hypotensive with systolic BP readings around 70 mm Hg; tachycardia, fluctuating at around 120 beats/min; and persistent hypoxia of 90% saturation on a nonrebreather mask. A chest X-ray demonstrated pulmonary edema with a continuous diaphragm sign suggesting pneumomediastinum. A computed tomography (CT) scan of the chest confirmed pulmonary edema with extensive pneumomediastinum, and the patient was admitted to the intensive care unit (ICU).

What is naloxone and why is it used?

Naloxone is a nonselective, short-acting, pure opioid antagonist that works at the mu, kappa, and sigma receptors, with the highest affinity for the mu receptor. It is a competitive opioid receptor antagonist that has an elimination half-life of approximately 30 minutes. Though naloxone was originally developed to reverse the effects of anesthesia postoperatively,¹ today it is more commonly used to treat ventilatory depression in patients whose clinical findings are most likely due to an opioid overdose.

What is acute opioid withdrawal syndrome?

Opioid-dependent individuals who abstain from use for more than a few hours generally develop opioid withdrawal syndrome (OWS). The effects of OWS include mild-to-moderate tachycardia and hypertension, nausea, vomiting, piloerection, rhinorrhea, and agitated behavior. However, when opioid-dependent patients receive naloxone, OWS develops at a much faster rate (ie, seconds after naloxone administration) and is often more severe.

Findings of naloxone-precipitated OWS include pronounced vital sign abnormalities, seizures,pulmonary edema, and cardiac arrhythmias such as ventricular tachycardia.² These latter findings are primarily due to the sudden release of catecholamines.³ In addition, patients suffer the psychological pangs of withdrawal, including dysphoria and drug craving, which often leads to poor decision-making as they search for additional opioids to alleviate these troubling effects.

What determines response to naloxone and development of OWS?

The severity of precipitated OWS following naloxone administration is determined by both the degree of the patient’s opioid dependency and the dosage and rate at which naloxone is given. The depth of opioid dependence is determined to a large extent by the quantity of opioid regularly used and the frequency of exposure. For example, a patient who takes 30 mg of oxycodone daily will likely demonstrate mild OWS, while one who uses 300 mg daily will demonstrate more severe OWS—whether due to abstinence or naloxone.

In addition, longer exposure time of the patient’s brain to opioids increases the dependency level. Continuous use of extended-release opioids or methadone, which are both of long duration, essentially “bathe” the brain receptors in opioid around the clock, whereas short-acting opioids, such as fentanyl or heroin, cause peaks and troughs in brain concentrations throughout the day. These trough periods reduce dependency, but increase the abuse liability of the opioid. Patients who only use opioids on the weekend, for example, will have minimal or no OWS following naloxone administration, nor will the toddler with an exploratory ingestion of an opioid medication found in the home. It is therefore important to gauge the extent of a patient’s opioid use to improve the safe use of naloxone in the ED.

What is the optimal dosing of naloxone and proper patient management?

It is essential for clinicians to remember that the ultimate goal of naloxone administration in the ED is to reverse ventilatory depression—not to restore a patient to a normal mental status.⁴ In fact, full awakening, in addition to precipitating OWS, may lead to difficult interpersonal situations in the ED, since such patients often insist on leaving the ED before the effects of naloxone wear off. This situation places the EP in the undesirable position of discharging a patient who may predictably relapse—though unlikely to die—after release.⁵

Management in the Hospital Setting. Given the advanced medical care environment in a hospital, the approach to opioid overdose patients can be metered. This means providing temporary noninvasive mechanical ventilatory support through BVM or laryngeal mask airways, which allow both oxygenation and ventilation (reducing the patient’s partial pressure of carbon dioxide), prior to giving naloxone.⁶ Studies on animal models have shown that lowering the partial pressure of carbon dioxide reduces the catecholamine response to naloxone.⁷

Although recent literature and textbook recommendations regarding naloxone dosages vary,¹ the safest initial dose of naloxone in the hospital setting is 0.04 mg (40 mcg) IV, or 0.08 mg (80 mcg) intramuscularly (IM).⁸ Whether given by IV or IM route, frequent reassessment of the adequacy of spontaneous ventilatory effort and oxygenation are required.

While the rate of opioid reversal is slower when giving lower doses of naloxone, this approach reduces the severity of precipitated OWS. In fact, in most patients who receive low-dose naloxone administration will not awaken but will develop life-sustaining spontaneous ventilation.⁸

By monitoring of the patient’s ventilatory rate and depth, along with capnometry and pulse oximetry (without providing exogenous oxygen), the EP can identify the need for additional naloxone. Since the half-life of naloxone is shorter than that of many opioids, proper ventilatory monitoring is essential to assess for the waning of naloxone’s effects and return of respiratory depression.

Treatment in the Nonhospital Setting. Emergency medical service (EMS) workers typically, and often by situational necessity, approach opioid overdose patients more aggressively than do EPs in the ED. Although some EMS systems utilize the IV route, most EMS workers, like laypersons, administer an initial naloxone dose of 0.4 mg IM or 2 or 4 mg intranasally (IN). Due to the slower rate of absorption and lower bioavailability (with IN administration), both IM and IN naloxone equate to roughly 0.08 mg IV.

For patients in whom there is no risk for opioid dependence, the initial dose of naloxone is relatively inconsequential, and higher doses can be safely administered. However, for most patients, including those in the ED setting, in whom one cannot be certain of their depth of dependence, the safest approach is to “start low and go slow” with naloxone administration, while providing supportive care.

Case Conclusion

The patient was not opioid-naïve, explaining the catecholamine surge and related cardiovascular dysfunction and pulmonary edema. The pneumomediastinum and pulmonary aspiration were due to the violent retching and vomiting. After being admitted to the ICU, the patient was started on vancomycin and piperacillin/tazobactam for empiric coverage for mediastinal emphysema. She was kept NPO, assessed by cardiothoracic surgery, and treated with gentle fluid hydration.

A repeat CT showed a stable pneumomediastinum. Her hypoxia, tachycardia, and hypotension gradually improved over about 6 hours. The following day, the patient’s mental status normalized, and she discharged herself from the hospital against medical advice.

Case

A woman in her third decade with no known medical history was dropped off at the waiting area of the ED for evaluation of depressed mental status. Upon arrival, the patient was unresponsive and cyanotic, with a pulse oximetry of 65% on room air. Bag-valve mask (BVM) ventilation rapidly improved oxygen saturation to 90%. The patient’s other vital signs were: heart rate, 141 beats/min; blood pressure (BP), 117/65 mm Hg; and temperature, afebrile.

Upon examination, the patient’s pupils were pinpoint and her ventilatory effort was shallow, leading the emergency physician (EP) to suspect the patient’s depressed mental status was due to an opioid overdose.

The patient was given 2 mg of intravenous (IV) naloxone, after which she became more alert and responsive, with improved respiratory effort. After receiving naloxone, the patient vomited copiously. Pulmonary examination revealed diffuse rales, most prominently at the right lung base, and a cough productive of thick sputum.

During the patient’s course in the ED, she became increasingly hypotensive with systolic BP readings around 70 mm Hg; tachycardia, fluctuating at around 120 beats/min; and persistent hypoxia of 90% saturation on a nonrebreather mask. A chest X-ray demonstrated pulmonary edema with a continuous diaphragm sign suggesting pneumomediastinum. A computed tomography (CT) scan of the chest confirmed pulmonary edema with extensive pneumomediastinum, and the patient was admitted to the intensive care unit (ICU).

What is naloxone and why is it used?

Naloxone is a nonselective, short-acting, pure opioid antagonist that works at the mu, kappa, and sigma receptors, with the highest affinity for the mu receptor. It is a competitive opioid receptor antagonist that has an elimination half-life of approximately 30 minutes. Though naloxone was originally developed to reverse the effects of anesthesia postoperatively,¹ today it is more commonly used to treat ventilatory depression in patients whose clinical findings are most likely due to an opioid overdose.

What is acute opioid withdrawal syndrome?

Opioid-dependent individuals who abstain from use for more than a few hours generally develop opioid withdrawal syndrome (OWS). The effects of OWS include mild-to-moderate tachycardia and hypertension, nausea, vomiting, piloerection, rhinorrhea, and agitated behavior. However, when opioid-dependent patients receive naloxone, OWS develops at a much faster rate (ie, seconds after naloxone administration) and is often more severe.

Findings of naloxone-precipitated OWS include pronounced vital sign abnormalities, seizures,pulmonary edema, and cardiac arrhythmias such as ventricular tachycardia.² These latter findings are primarily due to the sudden release of catecholamines.³ In addition, patients suffer the psychological pangs of withdrawal, including dysphoria and drug craving, which often leads to poor decision-making as they search for additional opioids to alleviate these troubling effects.

What determines response to naloxone and development of OWS?

The severity of precipitated OWS following naloxone administration is determined by both the degree of the patient’s opioid dependency and the dosage and rate at which naloxone is given. The depth of opioid dependence is determined to a large extent by the quantity of opioid regularly used and the frequency of exposure. For example, a patient who takes 30 mg of oxycodone daily will likely demonstrate mild OWS, while one who uses 300 mg daily will demonstrate more severe OWS—whether due to abstinence or naloxone.

In addition, longer exposure time of the patient’s brain to opioids increases the dependency level. Continuous use of extended-release opioids or methadone, which are both of long duration, essentially “bathe” the brain receptors in opioid around the clock, whereas short-acting opioids, such as fentanyl or heroin, cause peaks and troughs in brain concentrations throughout the day. These trough periods reduce dependency, but increase the abuse liability of the opioid. Patients who only use opioids on the weekend, for example, will have minimal or no OWS following naloxone administration, nor will the toddler with an exploratory ingestion of an opioid medication found in the home. It is therefore important to gauge the extent of a patient’s opioid use to improve the safe use of naloxone in the ED.

What is the optimal dosing of naloxone and proper patient management?

It is essential for clinicians to remember that the ultimate goal of naloxone administration in the ED is to reverse ventilatory depression—not to restore a patient to a normal mental status.⁴ In fact, full awakening, in addition to precipitating OWS, may lead to difficult interpersonal situations in the ED, since such patients often insist on leaving the ED before the effects of naloxone wear off. This situation places the EP in the undesirable position of discharging a patient who may predictably relapse—though unlikely to die—after release.⁵

Management in the Hospital Setting. Given the advanced medical care environment in a hospital, the approach to opioid overdose patients can be metered. This means providing temporary noninvasive mechanical ventilatory support through BVM or laryngeal mask airways, which allow both oxygenation and ventilation (reducing the patient’s partial pressure of carbon dioxide), prior to giving naloxone.⁶ Studies on animal models have shown that lowering the partial pressure of carbon dioxide reduces the catecholamine response to naloxone.⁷

Although recent literature and textbook recommendations regarding naloxone dosages vary,¹ the safest initial dose of naloxone in the hospital setting is 0.04 mg (40 mcg) IV, or 0.08 mg (80 mcg) intramuscularly (IM).⁸ Whether given by IV or IM route, frequent reassessment of the adequacy of spontaneous ventilatory effort and oxygenation are required.

While the rate of opioid reversal is slower when giving lower doses of naloxone, this approach reduces the severity of precipitated OWS. In fact, in most patients who receive low-dose naloxone administration will not awaken but will develop life-sustaining spontaneous ventilation.⁸

By monitoring of the patient’s ventilatory rate and depth, along with capnometry and pulse oximetry (without providing exogenous oxygen), the EP can identify the need for additional naloxone. Since the half-life of naloxone is shorter than that of many opioids, proper ventilatory monitoring is essential to assess for the waning of naloxone’s effects and return of respiratory depression.

Treatment in the Nonhospital Setting. Emergency medical service (EMS) workers typically, and often by situational necessity, approach opioid overdose patients more aggressively than do EPs in the ED. Although some EMS systems utilize the IV route, most EMS workers, like laypersons, administer an initial naloxone dose of 0.4 mg IM or 2 or 4 mg intranasally (IN). Due to the slower rate of absorption and lower bioavailability (with IN administration), both IM and IN naloxone equate to roughly 0.08 mg IV.

For patients in whom there is no risk for opioid dependence, the initial dose of naloxone is relatively inconsequential, and higher doses can be safely administered. However, for most patients, including those in the ED setting, in whom one cannot be certain of their depth of dependence, the safest approach is to “start low and go slow” with naloxone administration, while providing supportive care.

Case Conclusion

The patient was not opioid-naïve, explaining the catecholamine surge and related cardiovascular dysfunction and pulmonary edema. The pneumomediastinum and pulmonary aspiration were due to the violent retching and vomiting. After being admitted to the ICU, the patient was started on vancomycin and piperacillin/tazobactam for empiric coverage for mediastinal emphysema. She was kept NPO, assessed by cardiothoracic surgery, and treated with gentle fluid hydration.

A repeat CT showed a stable pneumomediastinum. Her hypoxia, tachycardia, and hypotension gradually improved over about 6 hours. The following day, the patient’s mental status normalized, and she discharged herself from the hospital against medical advice.

Case

A woman in her third decade with no known medical history was dropped off at the waiting area of the ED for evaluation of depressed mental status. Upon arrival, the patient was unresponsive and cyanotic, with a pulse oximetry of 65% on room air. Bag-valve mask (BVM) ventilation rapidly improved oxygen saturation to 90%. The patient’s other vital signs were: heart rate, 141 beats/min; blood pressure (BP), 117/65 mm Hg; and temperature, afebrile.

Upon examination, the patient’s pupils were pinpoint and her ventilatory effort was shallow, leading the emergency physician (EP) to suspect the patient’s depressed mental status was due to an opioid overdose.

The patient was given 2 mg of intravenous (IV) naloxone, after which she became more alert and responsive, with improved respiratory effort. After receiving naloxone, the patient vomited copiously. Pulmonary examination revealed diffuse rales, most prominently at the right lung base, and a cough productive of thick sputum.

During the patient’s course in the ED, she became increasingly hypotensive with systolic BP readings around 70 mm Hg; tachycardia, fluctuating at around 120 beats/min; and persistent hypoxia of 90% saturation on a nonrebreather mask. A chest X-ray demonstrated pulmonary edema with a continuous diaphragm sign suggesting pneumomediastinum. A computed tomography (CT) scan of the chest confirmed pulmonary edema with extensive pneumomediastinum, and the patient was admitted to the intensive care unit (ICU).

What is naloxone and why is it used?

Naloxone is a nonselective, short-acting, pure opioid antagonist that works at the mu, kappa, and sigma receptors, with the highest affinity for the mu receptor. It is a competitive opioid receptor antagonist that has an elimination half-life of approximately 30 minutes. Though naloxone was originally developed to reverse the effects of anesthesia postoperatively,¹ today it is more commonly used to treat ventilatory depression in patients whose clinical findings are most likely due to an opioid overdose.

What is acute opioid withdrawal syndrome?

Opioid-dependent individuals who abstain from use for more than a few hours generally develop opioid withdrawal syndrome (OWS). The effects of OWS include mild-to-moderate tachycardia and hypertension, nausea, vomiting, piloerection, rhinorrhea, and agitated behavior. However, when opioid-dependent patients receive naloxone, OWS develops at a much faster rate (ie, seconds after naloxone administration) and is often more severe.

Findings of naloxone-precipitated OWS include pronounced vital sign abnormalities, seizures,pulmonary edema, and cardiac arrhythmias such as ventricular tachycardia.² These latter findings are primarily due to the sudden release of catecholamines.³ In addition, patients suffer the psychological pangs of withdrawal, including dysphoria and drug craving, which often leads to poor decision-making as they search for additional opioids to alleviate these troubling effects.

What determines response to naloxone and development of OWS?

The severity of precipitated OWS following naloxone administration is determined by both the degree of the patient’s opioid dependency and the dosage and rate at which naloxone is given. The depth of opioid dependence is determined to a large extent by the quantity of opioid regularly used and the frequency of exposure. For example, a patient who takes 30 mg of oxycodone daily will likely demonstrate mild OWS, while one who uses 300 mg daily will demonstrate more severe OWS—whether due to abstinence or naloxone.

In addition, longer exposure time of the patient’s brain to opioids increases the dependency level. Continuous use of extended-release opioids or methadone, which are both of long duration, essentially “bathe” the brain receptors in opioid around the clock, whereas short-acting opioids, such as fentanyl or heroin, cause peaks and troughs in brain concentrations throughout the day. These trough periods reduce dependency, but increase the abuse liability of the opioid. Patients who only use opioids on the weekend, for example, will have minimal or no OWS following naloxone administration, nor will the toddler with an exploratory ingestion of an opioid medication found in the home. It is therefore important to gauge the extent of a patient’s opioid use to improve the safe use of naloxone in the ED.

What is the optimal dosing of naloxone and proper patient management?

It is essential for clinicians to remember that the ultimate goal of naloxone administration in the ED is to reverse ventilatory depression—not to restore a patient to a normal mental status.⁴ In fact, full awakening, in addition to precipitating OWS, may lead to difficult interpersonal situations in the ED, since such patients often insist on leaving the ED before the effects of naloxone wear off. This situation places the EP in the undesirable position of discharging a patient who may predictably relapse—though unlikely to die—after release.⁵

Management in the Hospital Setting. Given the advanced medical care environment in a hospital, the approach to opioid overdose patients can be metered. This means providing temporary noninvasive mechanical ventilatory support through BVM or laryngeal mask airways, which allow both oxygenation and ventilation (reducing the patient’s partial pressure of carbon dioxide), prior to giving naloxone.⁶ Studies on animal models have shown that lowering the partial pressure of carbon dioxide reduces the catecholamine response to naloxone.⁷

Although recent literature and textbook recommendations regarding naloxone dosages vary,¹ the safest initial dose of naloxone in the hospital setting is 0.04 mg (40 mcg) IV, or 0.08 mg (80 mcg) intramuscularly (IM).⁸ Whether given by IV or IM route, frequent reassessment of the adequacy of spontaneous ventilatory effort and oxygenation are required.

While the rate of opioid reversal is slower when giving lower doses of naloxone, this approach reduces the severity of precipitated OWS. In fact, in most patients who receive low-dose naloxone administration will not awaken but will develop life-sustaining spontaneous ventilation.⁸

By monitoring of the patient’s ventilatory rate and depth, along with capnometry and pulse oximetry (without providing exogenous oxygen), the EP can identify the need for additional naloxone. Since the half-life of naloxone is shorter than that of many opioids, proper ventilatory monitoring is essential to assess for the waning of naloxone’s effects and return of respiratory depression.

Treatment in the Nonhospital Setting. Emergency medical service (EMS) workers typically, and often by situational necessity, approach opioid overdose patients more aggressively than do EPs in the ED. Although some EMS systems utilize the IV route, most EMS workers, like laypersons, administer an initial naloxone dose of 0.4 mg IM or 2 or 4 mg intranasally (IN). Due to the slower rate of absorption and lower bioavailability (with IN administration), both IM and IN naloxone equate to roughly 0.08 mg IV.

For patients in whom there is no risk for opioid dependence, the initial dose of naloxone is relatively inconsequential, and higher doses can be safely administered. However, for most patients, including those in the ED setting, in whom one cannot be certain of their depth of dependence, the safest approach is to “start low and go slow” with naloxone administration, while providing supportive care.

Case Conclusion

The patient was not opioid-naïve, explaining the catecholamine surge and related cardiovascular dysfunction and pulmonary edema. The pneumomediastinum and pulmonary aspiration were due to the violent retching and vomiting. After being admitted to the ICU, the patient was started on vancomycin and piperacillin/tazobactam for empiric coverage for mediastinal emphysema. She was kept NPO, assessed by cardiothoracic surgery, and treated with gentle fluid hydration.

A repeat CT showed a stable pneumomediastinum. Her hypoxia, tachycardia, and hypotension gradually improved over about 6 hours. The following day, the patient’s mental status normalized, and she discharged herself from the hospital against medical advice.

ANSWER

The radiograph shows an adequately positioned endotracheal tube. It also shows bilateral infiltrates, greater in the right than in the left lung.

A pigtail catheter is present, up high near the apex; despite this, a pneumothorax of moderate size remains on the right. The likely explanation is that the catheter is either not properly positioned or is kinked. 

Prompt surgical consultation for new chest tube placement was obtained.

ANSWER

The radiograph shows an adequately positioned endotracheal tube. It also shows bilateral infiltrates, greater in the right than in the left lung.

A pigtail catheter is present, up high near the apex; despite this, a pneumothorax of moderate size remains on the right. The likely explanation is that the catheter is either not properly positioned or is kinked. 

Prompt surgical consultation for new chest tube placement was obtained.

ANSWER

The radiograph shows an adequately positioned endotracheal tube. It also shows bilateral infiltrates, greater in the right than in the left lung.

A pigtail catheter is present, up high near the apex; despite this, a pneumothorax of moderate size remains on the right. The likely explanation is that the catheter is either not properly positioned or is kinked. 

Prompt surgical consultation for new chest tube placement was obtained.

Hyperkalemia is common in patients with cardiovascular disease. Its consequences can be severe and life-threatening, and its management and prevention require a multidisciplinary approach that entails reducing intake of high-potassium foods, adjusting medications that cause hyperkalemia, and adding medications that reduce the plasma potassium concentration. With this approach, patients at high risk can receive the cardiorenal benefits of drugs that block the renin-angiotensin-aldosterone system without developing hyperkalemia.

98% OF POTASSIUM IS INSIDE CELLS

The body of a typical 70-kg man contains about 3,500 mmol of potassium, 98% of which is in the intracellular space; the remaining 2% is in the extracellular space. This large intracellular-to-extracellular gradient determines the cell voltage and explains why disorders in plasma potassium give rise to manifestations in excitable tissues such as the heart and nervous system.

The most important determinants of potassium distribution between the intracellular and extracellular space are insulin and beta-adrenergic receptor stimulation.

Maintenance of total-body potassium content is primarily the job of the kidneys, with a small contribution by the gastrointestinal tract.^1,2 Hyperkalemia is most commonly encountered in patients with decreased kidney function.

The normal kidney can secrete a large amount of potassium, making hyperkalemia uncommon in the absence of kidney disease. This large capacity may have evolved to handle the diet of Paleolithic humans, which contained 4 times as much potassium as contemporary diets.^3,4 With the onset of agriculture, dietary intake of potassium has progressively declined while sodium intake has risen. A popular theory suggests this mismatch between the modern diet and the nutritional requirements encoded in the human genome during evolution may contribute to chronic diseases such as hypertension, stroke, kidney stones, and bone disease.⁵

MANY POTENTIAL CAUSES OF HYPERKALEMIA

Causes of hyperkalemia are outlined in Table 1. Shifting of potassium from the cells to the extracellular space is a cause of transient hyperkalemia, while chronic hyperkalemia indicates an impairment in renal potassium secretion. The following discussion is a guide to the approach to the hyperkalemic patient.

Is the patient’s hyperkalemia really pseudohyperkalemia?

Pseudohyperkalemia, an artifact of measurement, occurs due to mechanical release of potassium from cells during phlebotomy or specimen processing.⁶ This diagnosis is made when the serum potassium concentration exceeds the plasma potassium concentration by more than 0.5 mmol/L, and should be considered when hyperkalemia occurs in the absence of a clinical risk factor. Fist-clenching, application of a tight-fitting tourniquet, or use of small-bore needles during phlebotomy can all cause pseudohyperkalemia.

Mechanism of pseudohyperkalemia. Since serum is the liquid part of blood remaining after coagulation, release of potassium from cells injured during the process of coagulation raises the potassium level in the serum. Plasma is the cell-free part of blood that has been treated with anticoagulants; it has no cells that can be injured and release potassium. Thus, the serum potassium level will be higher than that in the plasma.

Reverse pseudohyperkalemia, in contrast, occurs when the plasma potassium level is falsely elevated but the serum value is normal. This situation has been described in hematologic disorders characterized by pronounced leukocytosis in which malignant cells are prone to lysis with minimal mechanical stress due to increased fragility or altered sodium-potassium ATPase pump activity.⁷ This phenomenon is unusual but occurs because the cells are so fragile.

A spurious increase in plasma potassium concentration along with a low plasma calcium concentration raises the possibility of calcium chelation and release of potassium in a sample tube contaminated with the anticoagulant ethylenediaminetetraacetic acid.

Is there increased potassium intake?

Increased potassium intake is a potential cause of hyperkalemia in patients with decreased kidney function or adrenal disease.

Foods naturally rich in potassium include bananas (a medium-sized banana contains 451 mg or 12 mmol of potassium) and potatoes (844 mg or 22 mmol in a large baked potato with skin). Other potassium-rich foods are melons, citrus juice, and avocados. Less-obvious food sources include raw coconut juice (potassium concentration 44.3 mmol/L) and noni juice (56 mmol/L).

Salt substitutes, recommended to hypertensive patients with chronic kidney disease, can be a hidden source of dietary potassium.

Clay ingestion is a potential cause of dyskalemia. White clay consumption causes hypokalemia due to potassium binding in the gastrointestinal tract. Red clay or river bed clay, on the other hand, is enriched in potassium (100 mmol of potassium in 100 g of clay) and can cause life-threatening hyperkalemia in patients with chronic kidney disease.⁸

Eating burnt match heads. Some individuals chew and ingest burnt match heads, a condition called cautopyreiophagia. In one reported case,⁹ this activity contributed an additional 80 mmol of daily potassium intake in a dialysis patient, resulting in a plasma potassium concentration of 8 mmol/L.

Acute hyperkalemia can be the result of redistribution of cellular potassium. Shifting of as little as 2% of the body’s potassium from the intracellular to the extracellular space can double the plasma potassium concentration.

Tissue injury. Hyperkalemia frequently occurs in diseases that cause tissue injury such as rhabdomyolysis, trauma, massive hemolysis, and tumor lysis.

Insulin deficiency. Insulin and catecholamines are major regulators of potassium distribution within the body. After a meal, release of insulin not only regulates the plasma glucose concentration, it also causes potassium to move into cells until the kidneys have had sufficient time to excrete the dietary potassium load and reestablish total-body potassium content.

Exercise, beta-blockers. During exercise, potassium is released from skeletal muscle cells and accumulates in the interstitial compartment, where it exerts a vasodilatory effect. The simultaneous increase in circulating catecholamines regulates this release by promoting cell potassium uptake through beta-adrenergic receptor stimulation.

Metabolic acidosis can facilitate exit (ie, shift) of potassium from cells, but this effect depends on the type of acidosis. Hyperchloremic normal anion gap acidosis (mineral acidosis) most commonly causes this effect due to the relative impermeability of the cell membrane to the chloride anion. As hydrogen ions move into the cell due to accumulation of ammonium chloride or hydrogen chloride, electrical neutrality is maintained by potassium exit.

In contrast, organic acidosis (due to lactic, beta-hydroxybutyric, or methylmalonic acid) tends not to cause a potassium shift, since most organic anions readily cross the cell membrane along with hydrogen. Lactic acidosis is often associated with potassium shift, but this effect is due to loss of cell integrity as a result of cell ischemia. The hyperkalemia typically present on admission in patients with diabetic ketoacidosis is the result of insulin deficiency and hypertonicity and not the underlying organic acidosis.¹⁰

Hypertonic states can cause hyperkalemia due to cell shift. For example, hyperglycemia, as in diabetic ketoacidosis, pulls water from the intracellular into the extracellular compartment, thereby concentrating intracellular potassium and creating a more favorable gradient for potassium efflux through membrane channels. This same effect can occur in neurosurgical patients given large amounts of hypertonic mannitol. Repetitive doses of immunoglobulin can lead to extracellular accumulation of sorbitol, maltose, or sucrose, since these sugars are added to the preparations to prevent immunoglobulin aggregation.¹¹

Is a disturbance in renal potassium excretion present?

Sustained hyperkalemia is more commonly associated with decreases in renal potassium excretion than with a cellular shift. In most instances the clinician can distinguish between cell shift and impaired renal excretion based on the available clinical data.

The transtubular potassium gradient has been used to determine whether there is a disturbance in renal potassium excretion and to assess renal potassium handling.¹²

This calculation is based on the assumption that only water is reabsorbed past the cortical collecting duct, and not solutes. It has fallen out of favor since we have found this assumption to be incorrect; a large amount of urea is reabsorbed daily in the downstream medullary collecting duct as a result of intrarenal recycling of urea.

The one situation in which the transtubular potassium gradient may be of use is determining whether hyperkalemia is a result of low aldosterone levels as opposed to aldosterone resistance. One can compare the transtubular potassium gradient before and after a physiologic dose (0.05 mg) of 9-alpha fludrocortisone. An increase of more than 6 over a 4-hour period favors aldosterone deficiency, whereas smaller changes would indicate aldosterone resistance.

24-hour potassium excretion, spot urine potassium-creatinine ratio.  A better way to assess renal potassium handling is to measure the amount of potassium in a 24-hour urine collection or determine a spot urine potassium-creatinine ratio. A 24-hour urinary potassium excretion of less than 15 mmol or a potassium-creatinine ratio less than 1 suggests an extrarenal cause of hypokalemia. A ratio greater than 20 would be an appropriate renal response to hyperkalemia.

One or more of 3 abnormalities should be considered in the hyperkalemic patient with impaired renal excretion of potassium:

• Decreased distal delivery of sodium
• Mineralocorticoid deficiency
• Abnormal cortical collecting tubule function.¹³

Under normal circumstances, potassium is freely filtered across the glomerulus and then mostly reabsorbed in the proximal tubule and thick ascending limb. Potassium secretion begins in the distal convoluted tubule and increases in magnitude into the collecting duct. Tubular secretion is the component of potassium handling that varies and is regulated according to physiologic needs.

In acute kidney injury, the rapid decline in glomerular filtration rate and reduction in functioning nephron mass lead to decreased distal potassium secretion.

Hyperkalemia is a frequent problem when oliguria is present, since the reduction in distal delivery of sodium and water further impairs potassium secretion. Patients with oliguric acute kidney injury are more likely to have a more severe underlying disease state, and therefore tissue breakdown and catabolism further increase the risk of hyperkalemia.

In contrast, in nonoliguric patients, the renal injury tends to be less severe, and enough sodium and water are usually delivered distally to prevent hyperkalemia.

In chronic kidney disease, nephron dropout and reduction in collecting tubule mass also lead to a global decline in distal potassium secretion. However, this is countered by an increased capacity of the remaining individual nephrons for potassium secretion. High flow, increased distal sodium delivery, and increased activity and number of sodium-potassium ATPase pumps in the remaining nephrons account for this increased secretory capacity.¹⁴ As renal function declines over time, colonic potassium secretion progressively increases.¹⁵

These adaptive changes help to keep the plasma potassium concentration within the normal range until the glomerular filtration rate falls to less than 10 or 15 mL/min. Development of hyperkalemia with more modest reductions in the glomerular filtration rate suggest decreased mineralocorticoid activity or a specific lesion of the tubule.

Mineralocorticoid deficiency

Aldosterone deficiency can occur alone or in combination with decreased cortisol levels. Destruction of the adrenal glands is suggested when both hormones are reduced. Enzyme defects in cortisol metabolism can result in either isolated deficiency of aldosterone or adrenogenital syndromes associated with decreased mineralocorticoid activity.

Heparin administration leads to a reversible defect in adrenal synthesis of aldosterone. Drugs that block the stimulatory effect of angiotensin II on the zona glomerulosa cells of the adrenal gland will lower aldosterone.

Renin-angiotensin-aldosterone system blockers. Angiotensin-converting enzyme inhibitors block the formation of angiotensin II, whereas angiotensin II receptor blockers prevent angiotensin II from binding to its adrenal receptor. The direct renin inhibitor aliskiren lowers angiotensin II levels by blocking the enzymatic activity of renin and lowers the circulating levels of both angiotensin I and II.¹⁶

The syndrome of hyporeninemic hypoaldosteronism is a common cause of hyperkalemia in patients who have a glomerular filtration rate between 40 and 60 mL/min. Diabetic nephropathy and interstitial renal disease are the most common clinical entities associated with this syndrome.¹⁰ Other causes include analgesic nephropathy, urinary tract obstruction, sickle cell disease, systemic lupus erythematosus, and amyloidosis.

Nonsteroidal anti-inflammatory drugs can cause hyperkalemia by suppressing renin release and reducing delivery of sodium to the distal nephron.¹⁸

Calcineurin inhibitors impair potassium secretion by suppressing renin release and by direct tubular effects.¹⁹

Beta-blockers. Beta-1 and to a lesser extent beta-2 receptor blockade can also result in a hyporeninemic state.

Distal tubular defect

Hyperkalemia can result from interstitial renal diseases that specifically affect the distal nephron. In this setting, the glomerular filtration rate is only mildly reduced, and circulating aldosterone levels are normal.

Renal transplant, lupus erythematosus, amyloidosis, urinary obstruction, and sickle cell disease are conditions in which an impairment in renin release may coexist with a defect in tubular secretion.

Potassium-sparing diuretics impair the ability of the cortical collecting tubule to secrete potassium. Specifically, amiloride and triamterene inhibit sodium reabsorption mediated by the epithelial sodium channel located on the apical membrane of the principal cell. This effect abolishes the lumen’s negative potential and thereby removes a driving force for potassium secretion.

Trimethoprim and pentamidine cause similar effects.

Spironolactone and eplerenone compete with aldosterone at the level of the mineralocorticoid receptor and can result in hyperkalemia.

Drospirenone, a non-testosterone-derived progestin contained in certain oral contraceptives, possesses mineralocorticoid-blocking effects similar to those of spironolactone.

The plasma potassium level should be monitored when these drugs are prescribed in patients receiving potassium supplements, renin-angiotensin-aldosterone system blockers, or nonsteroidal anti-inflammatory drugs.²⁰

CLINICAL FEATURES OF HYPERKALEMIA

Neuromuscular manifestations of hyperkalemia include paresthesias and fasciculations in the arms and legs. Severe elevation in potassium can give rise to an ascending paralysis with eventual flaccid quadriplegia. Typically, the trunk, head, and respiratory muscles are spared, and respiratory failure is rare.

Cardiac signs

Hyperkalemia has depolarizing effects on the heart that are manifested by changes in the electrocardiogram (Figure 2). The progressive changes of hyperkalemia are classically listed as:

• Peaked T waves that are tall, narrow, and symmetrical and can occasionally be confused with the hyperacute T-wave change associated with an ST-segment elevation myocardial infarction.²¹ However, in the latter condition, the T waves tend to be more broad-based and asymmetric in shape.
• ST-segment depression
• Widening of the PR interval
• Widening of the QRS interval
• Loss of the P wave
• A sine-wave pattern—an ominous development and a harbinger of impending ventricular fibrillation and asystole.

The plasma potassium concentration often correlates poorly with cardiac manifestations. In a retrospective review, only 16 of 90 cases met strict criteria for electrocardiographic changes reflective of hyperkalemia (defined as new peaked and symmetric T waves that resolved on follow-up).²² In 13 of these cases, the electrocardiogram was interpreted as showing no T-wave changes even when read by a cardiologist. In addition, electrocardiographic criteria for hyperkalemia were noted in only 1 of 14 patients who manifested arrhythmias or cardiac arrest attributed to increased plasma potassium concentration.

The treatment of hyperkalemia depends on the magnitude of increase in the plasma potassium concentration and the presence or absence of electrocardiographic changes or neuromuscular symptoms.²³ Acute treatment is indicated for marked electrocardiographic changes and severe muscle weakness.

Intravenous calcium rapidly normalizes membrane excitability by antagonizing the potassium-induced decrease in membrane excitability but does not alter the plasma potassium concentration.

Insulin lowers the plasma potassium concentration by promoting its entry into cells. To avoid hypoglycemia, 10 units of short-acting insulin should be accompanied by a 50-g infusion of glucose, increased to 60 g if 20 units of insulin are given.²⁴

Beta-2 receptor agonists produce a similar effect. The shift of potassium into cells with insulin and beta-2-adrenergic receptor stimulation is brought about by increases in sodium-potassium ATPase pump activity, primarily in skeletal muscle cells.

Sodium bicarbonate, in the absence of acidosis, lowers the plasma potassium concentration only slightly. It should be reserved for hyperkalemic patients who have coexisting metabolic acidosis after the patient has received insulin and glucose, an adrenergic agent, and calcium.

These acute treatments need to be followed by therapies designed to lower the total body potassium content such as diuretics, potassium-binding drugs, and dialysis.

TREATMENT OF CHRONIC HYPERKALEMIA

Review medications. Once the diagnosis of hyperkalemia has been made, the initial approach should be to review the patient’s medications and make every effort to discontinue drugs that can impair renal potassium excretion.¹⁶ Patients should be asked about their use of over-the-counter nonsteroidal anti-inflammatory drugs and herbal remedies, since herbs may be a hidden source of dietary potassium.

Dietary counseling. Patients should be instructed to reduce their dietary intake of potassium and to avoid salt substitutes that contain potassium.

Diuretic therapy is beneficial in minimizing hyperkalemia in patients with chronic kidney disease. Thiazide and loop diuretics enhance renal potassium excretion by increasing flow and delivery of sodium to the collecting duct. Thiazide diuretics are effective when the estimated glomerular filtration rate is greater than 30 mL/min, while loop diuretics should be used in patients with more severe renal insufficiency (Table 2).

Sodium bicarbonate is an effective agent to minimize increases in the plasma potassium concentration in patients with chronic kidney disease and metabolic acidosis. This drug increases renal potassium excretion by increasing distal sodium delivery and shifts potassium into cells as the acidosis is corrected. The likelihood of developing volume overload as a complication of sodium bicarbonate administration can be minimized with effective diuretic therapy.

Avoiding hyperkalemia if renin-angiotensin-aldosterone system blockers are needed

Renin-angiotensin-aldosterone system blockers can be problematic, as these drugs cause hyperkalemia, often in the very patients who derive the greatest cardiovascular benefit from them.¹⁶ A number of steps can reduce the risk of hyperkalemia and allow these drugs to be used.

The initial dose should be low and the plasma potassium should be measured within 1 to 2 weeks after drug initiation. If the potassium level is normal, the dose can be titrated upwards with remeasurement of the plasma potassium after each dose titration. If the plasma potassium concentration rises to 5.5 mmol/L, in some cases lowering the dose will reduce the potassium concentration and allow the patient to remain on the drug.

In patients at risk of hyperkalemia, angiotensin II receptor blockers and direct renin inhibitors should be used with the same caution as angiotensin-converting enzyme inhibitors.

If the plasma potassium concentration exceeds 5.5 mmol/L despite the above precautions, one can consider using a potassium-binding drug (see below) before deciding to avoid renin-angiotensin-aldosterone system blockers.

Sodium polystyrene sulfonate binds potassium in the gastrointestinal tract in exchange for sodium and has been used to manage hyperkalemia. This drug is most commonly given along with sorbitol as a therapy for acute hyperkalemia. Although the drug is widely used, most of the potassium-lowering effect is due to an increase in stool volume caused by sorbitol.^25,26 In addition, long-term use is poorly tolerated, and the drug has been linked to gastrointestinal toxicity in rare cases.

Patiromer and sodium zirconium cyclosilicate are two new potassium-binding drugs that have been shown to be effective in reducing plasma potassium concentration in the setting of ongoing use of renin-angiotensin-aldosterone system blockers.

Patiromer is a nonabsorbed polymer approved for clinical use to treat hyperkalemia. The drug binds potassium in exchange for calcium in the gastrointestinal tract, predominantly in the colon, and lowers the plasma potassium concentration in a dose-dependent manner, with the greatest reduction in those with higher starting values.^27,28

Patiromer effectively controlled plasma potassium concentrations in a 1-year randomized trial in high-risk patients on renin-angiotensin-aldosterone system blockers.²⁹ The main adverse events in clinical trials have been constipation and hypomagnesemia, which required magnesium replacement in a small number of patients, but overall, the drug is well tolerated.

Sodium zirconium cyclosilicate is a nonabsorbed microporous compound that binds potassium in exchange for sodium throughout the gastrointestinal tract. It has been found effective in lowering plasma potassium concentration in a dose-dependent fashion in high-risk patients, most of whom were receiving renin-angiotensin-aldosterone system blockers.^30–32 Adverse events were generally comparable to those with placebo in clinical trials; however, edema occurred more frequently when higher doses were used. This drug is not yet approved for clinical use.

Hyperkalemia is common in patients with cardiovascular disease. Its consequences can be severe and life-threatening, and its management and prevention require a multidisciplinary approach that entails reducing intake of high-potassium foods, adjusting medications that cause hyperkalemia, and adding medications that reduce the plasma potassium concentration. With this approach, patients at high risk can receive the cardiorenal benefits of drugs that block the renin-angiotensin-aldosterone system without developing hyperkalemia.

98% OF POTASSIUM IS INSIDE CELLS

The body of a typical 70-kg man contains about 3,500 mmol of potassium, 98% of which is in the intracellular space; the remaining 2% is in the extracellular space. This large intracellular-to-extracellular gradient determines the cell voltage and explains why disorders in plasma potassium give rise to manifestations in excitable tissues such as the heart and nervous system.

The most important determinants of potassium distribution between the intracellular and extracellular space are insulin and beta-adrenergic receptor stimulation.

Maintenance of total-body potassium content is primarily the job of the kidneys, with a small contribution by the gastrointestinal tract.^1,2 Hyperkalemia is most commonly encountered in patients with decreased kidney function.

The normal kidney can secrete a large amount of potassium, making hyperkalemia uncommon in the absence of kidney disease. This large capacity may have evolved to handle the diet of Paleolithic humans, which contained 4 times as much potassium as contemporary diets.^3,4 With the onset of agriculture, dietary intake of potassium has progressively declined while sodium intake has risen. A popular theory suggests this mismatch between the modern diet and the nutritional requirements encoded in the human genome during evolution may contribute to chronic diseases such as hypertension, stroke, kidney stones, and bone disease.⁵

MANY POTENTIAL CAUSES OF HYPERKALEMIA

Causes of hyperkalemia are outlined in Table 1. Shifting of potassium from the cells to the extracellular space is a cause of transient hyperkalemia, while chronic hyperkalemia indicates an impairment in renal potassium secretion. The following discussion is a guide to the approach to the hyperkalemic patient.

Is the patient’s hyperkalemia really pseudohyperkalemia?

Pseudohyperkalemia, an artifact of measurement, occurs due to mechanical release of potassium from cells during phlebotomy or specimen processing.⁶ This diagnosis is made when the serum potassium concentration exceeds the plasma potassium concentration by more than 0.5 mmol/L, and should be considered when hyperkalemia occurs in the absence of a clinical risk factor. Fist-clenching, application of a tight-fitting tourniquet, or use of small-bore needles during phlebotomy can all cause pseudohyperkalemia.

Mechanism of pseudohyperkalemia. Since serum is the liquid part of blood remaining after coagulation, release of potassium from cells injured during the process of coagulation raises the potassium level in the serum. Plasma is the cell-free part of blood that has been treated with anticoagulants; it has no cells that can be injured and release potassium. Thus, the serum potassium level will be higher than that in the plasma.

Reverse pseudohyperkalemia, in contrast, occurs when the plasma potassium level is falsely elevated but the serum value is normal. This situation has been described in hematologic disorders characterized by pronounced leukocytosis in which malignant cells are prone to lysis with minimal mechanical stress due to increased fragility or altered sodium-potassium ATPase pump activity.⁷ This phenomenon is unusual but occurs because the cells are so fragile.

A spurious increase in plasma potassium concentration along with a low plasma calcium concentration raises the possibility of calcium chelation and release of potassium in a sample tube contaminated with the anticoagulant ethylenediaminetetraacetic acid.

Is there increased potassium intake?

Increased potassium intake is a potential cause of hyperkalemia in patients with decreased kidney function or adrenal disease.

Foods naturally rich in potassium include bananas (a medium-sized banana contains 451 mg or 12 mmol of potassium) and potatoes (844 mg or 22 mmol in a large baked potato with skin). Other potassium-rich foods are melons, citrus juice, and avocados. Less-obvious food sources include raw coconut juice (potassium concentration 44.3 mmol/L) and noni juice (56 mmol/L).

Salt substitutes, recommended to hypertensive patients with chronic kidney disease, can be a hidden source of dietary potassium.

Clay ingestion is a potential cause of dyskalemia. White clay consumption causes hypokalemia due to potassium binding in the gastrointestinal tract. Red clay or river bed clay, on the other hand, is enriched in potassium (100 mmol of potassium in 100 g of clay) and can cause life-threatening hyperkalemia in patients with chronic kidney disease.⁸

Eating burnt match heads. Some individuals chew and ingest burnt match heads, a condition called cautopyreiophagia. In one reported case,⁹ this activity contributed an additional 80 mmol of daily potassium intake in a dialysis patient, resulting in a plasma potassium concentration of 8 mmol/L.

Acute hyperkalemia can be the result of redistribution of cellular potassium. Shifting of as little as 2% of the body’s potassium from the intracellular to the extracellular space can double the plasma potassium concentration.

Tissue injury. Hyperkalemia frequently occurs in diseases that cause tissue injury such as rhabdomyolysis, trauma, massive hemolysis, and tumor lysis.

Insulin deficiency. Insulin and catecholamines are major regulators of potassium distribution within the body. After a meal, release of insulin not only regulates the plasma glucose concentration, it also causes potassium to move into cells until the kidneys have had sufficient time to excrete the dietary potassium load and reestablish total-body potassium content.

Exercise, beta-blockers. During exercise, potassium is released from skeletal muscle cells and accumulates in the interstitial compartment, where it exerts a vasodilatory effect. The simultaneous increase in circulating catecholamines regulates this release by promoting cell potassium uptake through beta-adrenergic receptor stimulation.

Metabolic acidosis can facilitate exit (ie, shift) of potassium from cells, but this effect depends on the type of acidosis. Hyperchloremic normal anion gap acidosis (mineral acidosis) most commonly causes this effect due to the relative impermeability of the cell membrane to the chloride anion. As hydrogen ions move into the cell due to accumulation of ammonium chloride or hydrogen chloride, electrical neutrality is maintained by potassium exit.

In contrast, organic acidosis (due to lactic, beta-hydroxybutyric, or methylmalonic acid) tends not to cause a potassium shift, since most organic anions readily cross the cell membrane along with hydrogen. Lactic acidosis is often associated with potassium shift, but this effect is due to loss of cell integrity as a result of cell ischemia. The hyperkalemia typically present on admission in patients with diabetic ketoacidosis is the result of insulin deficiency and hypertonicity and not the underlying organic acidosis.¹⁰

Hypertonic states can cause hyperkalemia due to cell shift. For example, hyperglycemia, as in diabetic ketoacidosis, pulls water from the intracellular into the extracellular compartment, thereby concentrating intracellular potassium and creating a more favorable gradient for potassium efflux through membrane channels. This same effect can occur in neurosurgical patients given large amounts of hypertonic mannitol. Repetitive doses of immunoglobulin can lead to extracellular accumulation of sorbitol, maltose, or sucrose, since these sugars are added to the preparations to prevent immunoglobulin aggregation.¹¹

Is a disturbance in renal potassium excretion present?

Sustained hyperkalemia is more commonly associated with decreases in renal potassium excretion than with a cellular shift. In most instances the clinician can distinguish between cell shift and impaired renal excretion based on the available clinical data.

The transtubular potassium gradient has been used to determine whether there is a disturbance in renal potassium excretion and to assess renal potassium handling.¹²

This calculation is based on the assumption that only water is reabsorbed past the cortical collecting duct, and not solutes. It has fallen out of favor since we have found this assumption to be incorrect; a large amount of urea is reabsorbed daily in the downstream medullary collecting duct as a result of intrarenal recycling of urea.

The one situation in which the transtubular potassium gradient may be of use is determining whether hyperkalemia is a result of low aldosterone levels as opposed to aldosterone resistance. One can compare the transtubular potassium gradient before and after a physiologic dose (0.05 mg) of 9-alpha fludrocortisone. An increase of more than 6 over a 4-hour period favors aldosterone deficiency, whereas smaller changes would indicate aldosterone resistance.

24-hour potassium excretion, spot urine potassium-creatinine ratio.  A better way to assess renal potassium handling is to measure the amount of potassium in a 24-hour urine collection or determine a spot urine potassium-creatinine ratio. A 24-hour urinary potassium excretion of less than 15 mmol or a potassium-creatinine ratio less than 1 suggests an extrarenal cause of hypokalemia. A ratio greater than 20 would be an appropriate renal response to hyperkalemia.

One or more of 3 abnormalities should be considered in the hyperkalemic patient with impaired renal excretion of potassium:

• Decreased distal delivery of sodium
• Mineralocorticoid deficiency
• Abnormal cortical collecting tubule function.¹³

Under normal circumstances, potassium is freely filtered across the glomerulus and then mostly reabsorbed in the proximal tubule and thick ascending limb. Potassium secretion begins in the distal convoluted tubule and increases in magnitude into the collecting duct. Tubular secretion is the component of potassium handling that varies and is regulated according to physiologic needs.

In acute kidney injury, the rapid decline in glomerular filtration rate and reduction in functioning nephron mass lead to decreased distal potassium secretion.

Hyperkalemia is a frequent problem when oliguria is present, since the reduction in distal delivery of sodium and water further impairs potassium secretion. Patients with oliguric acute kidney injury are more likely to have a more severe underlying disease state, and therefore tissue breakdown and catabolism further increase the risk of hyperkalemia.

In contrast, in nonoliguric patients, the renal injury tends to be less severe, and enough sodium and water are usually delivered distally to prevent hyperkalemia.

In chronic kidney disease, nephron dropout and reduction in collecting tubule mass also lead to a global decline in distal potassium secretion. However, this is countered by an increased capacity of the remaining individual nephrons for potassium secretion. High flow, increased distal sodium delivery, and increased activity and number of sodium-potassium ATPase pumps in the remaining nephrons account for this increased secretory capacity.¹⁴ As renal function declines over time, colonic potassium secretion progressively increases.¹⁵

These adaptive changes help to keep the plasma potassium concentration within the normal range until the glomerular filtration rate falls to less than 10 or 15 mL/min. Development of hyperkalemia with more modest reductions in the glomerular filtration rate suggest decreased mineralocorticoid activity or a specific lesion of the tubule.

Mineralocorticoid deficiency

Aldosterone deficiency can occur alone or in combination with decreased cortisol levels. Destruction of the adrenal glands is suggested when both hormones are reduced. Enzyme defects in cortisol metabolism can result in either isolated deficiency of aldosterone or adrenogenital syndromes associated with decreased mineralocorticoid activity.

Heparin administration leads to a reversible defect in adrenal synthesis of aldosterone. Drugs that block the stimulatory effect of angiotensin II on the zona glomerulosa cells of the adrenal gland will lower aldosterone.

Renin-angiotensin-aldosterone system blockers. Angiotensin-converting enzyme inhibitors block the formation of angiotensin II, whereas angiotensin II receptor blockers prevent angiotensin II from binding to its adrenal receptor. The direct renin inhibitor aliskiren lowers angiotensin II levels by blocking the enzymatic activity of renin and lowers the circulating levels of both angiotensin I and II.¹⁶

The syndrome of hyporeninemic hypoaldosteronism is a common cause of hyperkalemia in patients who have a glomerular filtration rate between 40 and 60 mL/min. Diabetic nephropathy and interstitial renal disease are the most common clinical entities associated with this syndrome.¹⁰ Other causes include analgesic nephropathy, urinary tract obstruction, sickle cell disease, systemic lupus erythematosus, and amyloidosis.

Nonsteroidal anti-inflammatory drugs can cause hyperkalemia by suppressing renin release and reducing delivery of sodium to the distal nephron.¹⁸

Calcineurin inhibitors impair potassium secretion by suppressing renin release and by direct tubular effects.¹⁹

Beta-blockers. Beta-1 and to a lesser extent beta-2 receptor blockade can also result in a hyporeninemic state.

Distal tubular defect

Hyperkalemia can result from interstitial renal diseases that specifically affect the distal nephron. In this setting, the glomerular filtration rate is only mildly reduced, and circulating aldosterone levels are normal.

Renal transplant, lupus erythematosus, amyloidosis, urinary obstruction, and sickle cell disease are conditions in which an impairment in renin release may coexist with a defect in tubular secretion.

Potassium-sparing diuretics impair the ability of the cortical collecting tubule to secrete potassium. Specifically, amiloride and triamterene inhibit sodium reabsorption mediated by the epithelial sodium channel located on the apical membrane of the principal cell. This effect abolishes the lumen’s negative potential and thereby removes a driving force for potassium secretion.

Trimethoprim and pentamidine cause similar effects.

Spironolactone and eplerenone compete with aldosterone at the level of the mineralocorticoid receptor and can result in hyperkalemia.

Drospirenone, a non-testosterone-derived progestin contained in certain oral contraceptives, possesses mineralocorticoid-blocking effects similar to those of spironolactone.

The plasma potassium level should be monitored when these drugs are prescribed in patients receiving potassium supplements, renin-angiotensin-aldosterone system blockers, or nonsteroidal anti-inflammatory drugs.²⁰

CLINICAL FEATURES OF HYPERKALEMIA

Neuromuscular manifestations of hyperkalemia include paresthesias and fasciculations in the arms and legs. Severe elevation in potassium can give rise to an ascending paralysis with eventual flaccid quadriplegia. Typically, the trunk, head, and respiratory muscles are spared, and respiratory failure is rare.

Cardiac signs

Hyperkalemia has depolarizing effects on the heart that are manifested by changes in the electrocardiogram (Figure 2). The progressive changes of hyperkalemia are classically listed as:

• Peaked T waves that are tall, narrow, and symmetrical and can occasionally be confused with the hyperacute T-wave change associated with an ST-segment elevation myocardial infarction.²¹ However, in the latter condition, the T waves tend to be more broad-based and asymmetric in shape.
• ST-segment depression
• Widening of the PR interval
• Widening of the QRS interval
• Loss of the P wave
• A sine-wave pattern—an ominous development and a harbinger of impending ventricular fibrillation and asystole.

The plasma potassium concentration often correlates poorly with cardiac manifestations. In a retrospective review, only 16 of 90 cases met strict criteria for electrocardiographic changes reflective of hyperkalemia (defined as new peaked and symmetric T waves that resolved on follow-up).²² In 13 of these cases, the electrocardiogram was interpreted as showing no T-wave changes even when read by a cardiologist. In addition, electrocardiographic criteria for hyperkalemia were noted in only 1 of 14 patients who manifested arrhythmias or cardiac arrest attributed to increased plasma potassium concentration.

The treatment of hyperkalemia depends on the magnitude of increase in the plasma potassium concentration and the presence or absence of electrocardiographic changes or neuromuscular symptoms.²³ Acute treatment is indicated for marked electrocardiographic changes and severe muscle weakness.

Intravenous calcium rapidly normalizes membrane excitability by antagonizing the potassium-induced decrease in membrane excitability but does not alter the plasma potassium concentration.

Insulin lowers the plasma potassium concentration by promoting its entry into cells. To avoid hypoglycemia, 10 units of short-acting insulin should be accompanied by a 50-g infusion of glucose, increased to 60 g if 20 units of insulin are given.²⁴

Beta-2 receptor agonists produce a similar effect. The shift of potassium into cells with insulin and beta-2-adrenergic receptor stimulation is brought about by increases in sodium-potassium ATPase pump activity, primarily in skeletal muscle cells.

Sodium bicarbonate, in the absence of acidosis, lowers the plasma potassium concentration only slightly. It should be reserved for hyperkalemic patients who have coexisting metabolic acidosis after the patient has received insulin and glucose, an adrenergic agent, and calcium.

These acute treatments need to be followed by therapies designed to lower the total body potassium content such as diuretics, potassium-binding drugs, and dialysis.

TREATMENT OF CHRONIC HYPERKALEMIA

Review medications. Once the diagnosis of hyperkalemia has been made, the initial approach should be to review the patient’s medications and make every effort to discontinue drugs that can impair renal potassium excretion.¹⁶ Patients should be asked about their use of over-the-counter nonsteroidal anti-inflammatory drugs and herbal remedies, since herbs may be a hidden source of dietary potassium.

Dietary counseling. Patients should be instructed to reduce their dietary intake of potassium and to avoid salt substitutes that contain potassium.

Diuretic therapy is beneficial in minimizing hyperkalemia in patients with chronic kidney disease. Thiazide and loop diuretics enhance renal potassium excretion by increasing flow and delivery of sodium to the collecting duct. Thiazide diuretics are effective when the estimated glomerular filtration rate is greater than 30 mL/min, while loop diuretics should be used in patients with more severe renal insufficiency (Table 2).

Sodium bicarbonate is an effective agent to minimize increases in the plasma potassium concentration in patients with chronic kidney disease and metabolic acidosis. This drug increases renal potassium excretion by increasing distal sodium delivery and shifts potassium into cells as the acidosis is corrected. The likelihood of developing volume overload as a complication of sodium bicarbonate administration can be minimized with effective diuretic therapy.

Avoiding hyperkalemia if renin-angiotensin-aldosterone system blockers are needed

Renin-angiotensin-aldosterone system blockers can be problematic, as these drugs cause hyperkalemia, often in the very patients who derive the greatest cardiovascular benefit from them.¹⁶ A number of steps can reduce the risk of hyperkalemia and allow these drugs to be used.

The initial dose should be low and the plasma potassium should be measured within 1 to 2 weeks after drug initiation. If the potassium level is normal, the dose can be titrated upwards with remeasurement of the plasma potassium after each dose titration. If the plasma potassium concentration rises to 5.5 mmol/L, in some cases lowering the dose will reduce the potassium concentration and allow the patient to remain on the drug.

In patients at risk of hyperkalemia, angiotensin II receptor blockers and direct renin inhibitors should be used with the same caution as angiotensin-converting enzyme inhibitors.

If the plasma potassium concentration exceeds 5.5 mmol/L despite the above precautions, one can consider using a potassium-binding drug (see below) before deciding to avoid renin-angiotensin-aldosterone system blockers.

Sodium polystyrene sulfonate binds potassium in the gastrointestinal tract in exchange for sodium and has been used to manage hyperkalemia. This drug is most commonly given along with sorbitol as a therapy for acute hyperkalemia. Although the drug is widely used, most of the potassium-lowering effect is due to an increase in stool volume caused by sorbitol.^25,26 In addition, long-term use is poorly tolerated, and the drug has been linked to gastrointestinal toxicity in rare cases.

Patiromer and sodium zirconium cyclosilicate are two new potassium-binding drugs that have been shown to be effective in reducing plasma potassium concentration in the setting of ongoing use of renin-angiotensin-aldosterone system blockers.

Patiromer is a nonabsorbed polymer approved for clinical use to treat hyperkalemia. The drug binds potassium in exchange for calcium in the gastrointestinal tract, predominantly in the colon, and lowers the plasma potassium concentration in a dose-dependent manner, with the greatest reduction in those with higher starting values.^27,28

Patiromer effectively controlled plasma potassium concentrations in a 1-year randomized trial in high-risk patients on renin-angiotensin-aldosterone system blockers.²⁹ The main adverse events in clinical trials have been constipation and hypomagnesemia, which required magnesium replacement in a small number of patients, but overall, the drug is well tolerated.

Sodium zirconium cyclosilicate is a nonabsorbed microporous compound that binds potassium in exchange for sodium throughout the gastrointestinal tract. It has been found effective in lowering plasma potassium concentration in a dose-dependent fashion in high-risk patients, most of whom were receiving renin-angiotensin-aldosterone system blockers.^30–32 Adverse events were generally comparable to those with placebo in clinical trials; however, edema occurred more frequently when higher doses were used. This drug is not yet approved for clinical use.

Hyperkalemia is common in patients with cardiovascular disease. Its consequences can be severe and life-threatening, and its management and prevention require a multidisciplinary approach that entails reducing intake of high-potassium foods, adjusting medications that cause hyperkalemia, and adding medications that reduce the plasma potassium concentration. With this approach, patients at high risk can receive the cardiorenal benefits of drugs that block the renin-angiotensin-aldosterone system without developing hyperkalemia.

98% OF POTASSIUM IS INSIDE CELLS

The body of a typical 70-kg man contains about 3,500 mmol of potassium, 98% of which is in the intracellular space; the remaining 2% is in the extracellular space. This large intracellular-to-extracellular gradient determines the cell voltage and explains why disorders in plasma potassium give rise to manifestations in excitable tissues such as the heart and nervous system.

The most important determinants of potassium distribution between the intracellular and extracellular space are insulin and beta-adrenergic receptor stimulation.

Maintenance of total-body potassium content is primarily the job of the kidneys, with a small contribution by the gastrointestinal tract.^1,2 Hyperkalemia is most commonly encountered in patients with decreased kidney function.

The normal kidney can secrete a large amount of potassium, making hyperkalemia uncommon in the absence of kidney disease. This large capacity may have evolved to handle the diet of Paleolithic humans, which contained 4 times as much potassium as contemporary diets.^3,4 With the onset of agriculture, dietary intake of potassium has progressively declined while sodium intake has risen. A popular theory suggests this mismatch between the modern diet and the nutritional requirements encoded in the human genome during evolution may contribute to chronic diseases such as hypertension, stroke, kidney stones, and bone disease.⁵

MANY POTENTIAL CAUSES OF HYPERKALEMIA

Causes of hyperkalemia are outlined in Table 1. Shifting of potassium from the cells to the extracellular space is a cause of transient hyperkalemia, while chronic hyperkalemia indicates an impairment in renal potassium secretion. The following discussion is a guide to the approach to the hyperkalemic patient.

Is the patient’s hyperkalemia really pseudohyperkalemia?

Pseudohyperkalemia, an artifact of measurement, occurs due to mechanical release of potassium from cells during phlebotomy or specimen processing.⁶ This diagnosis is made when the serum potassium concentration exceeds the plasma potassium concentration by more than 0.5 mmol/L, and should be considered when hyperkalemia occurs in the absence of a clinical risk factor. Fist-clenching, application of a tight-fitting tourniquet, or use of small-bore needles during phlebotomy can all cause pseudohyperkalemia.

Mechanism of pseudohyperkalemia. Since serum is the liquid part of blood remaining after coagulation, release of potassium from cells injured during the process of coagulation raises the potassium level in the serum. Plasma is the cell-free part of blood that has been treated with anticoagulants; it has no cells that can be injured and release potassium. Thus, the serum potassium level will be higher than that in the plasma.

Reverse pseudohyperkalemia, in contrast, occurs when the plasma potassium level is falsely elevated but the serum value is normal. This situation has been described in hematologic disorders characterized by pronounced leukocytosis in which malignant cells are prone to lysis with minimal mechanical stress due to increased fragility or altered sodium-potassium ATPase pump activity.⁷ This phenomenon is unusual but occurs because the cells are so fragile.

A spurious increase in plasma potassium concentration along with a low plasma calcium concentration raises the possibility of calcium chelation and release of potassium in a sample tube contaminated with the anticoagulant ethylenediaminetetraacetic acid.

Is there increased potassium intake?

Increased potassium intake is a potential cause of hyperkalemia in patients with decreased kidney function or adrenal disease.

Foods naturally rich in potassium include bananas (a medium-sized banana contains 451 mg or 12 mmol of potassium) and potatoes (844 mg or 22 mmol in a large baked potato with skin). Other potassium-rich foods are melons, citrus juice, and avocados. Less-obvious food sources include raw coconut juice (potassium concentration 44.3 mmol/L) and noni juice (56 mmol/L).

Salt substitutes, recommended to hypertensive patients with chronic kidney disease, can be a hidden source of dietary potassium.

Clay ingestion is a potential cause of dyskalemia. White clay consumption causes hypokalemia due to potassium binding in the gastrointestinal tract. Red clay or river bed clay, on the other hand, is enriched in potassium (100 mmol of potassium in 100 g of clay) and can cause life-threatening hyperkalemia in patients with chronic kidney disease.⁸

Eating burnt match heads. Some individuals chew and ingest burnt match heads, a condition called cautopyreiophagia. In one reported case,⁹ this activity contributed an additional 80 mmol of daily potassium intake in a dialysis patient, resulting in a plasma potassium concentration of 8 mmol/L.

Acute hyperkalemia can be the result of redistribution of cellular potassium. Shifting of as little as 2% of the body’s potassium from the intracellular to the extracellular space can double the plasma potassium concentration.

Tissue injury. Hyperkalemia frequently occurs in diseases that cause tissue injury such as rhabdomyolysis, trauma, massive hemolysis, and tumor lysis.

Insulin deficiency. Insulin and catecholamines are major regulators of potassium distribution within the body. After a meal, release of insulin not only regulates the plasma glucose concentration, it also causes potassium to move into cells until the kidneys have had sufficient time to excrete the dietary potassium load and reestablish total-body potassium content.

Exercise, beta-blockers. During exercise, potassium is released from skeletal muscle cells and accumulates in the interstitial compartment, where it exerts a vasodilatory effect. The simultaneous increase in circulating catecholamines regulates this release by promoting cell potassium uptake through beta-adrenergic receptor stimulation.

Metabolic acidosis can facilitate exit (ie, shift) of potassium from cells, but this effect depends on the type of acidosis. Hyperchloremic normal anion gap acidosis (mineral acidosis) most commonly causes this effect due to the relative impermeability of the cell membrane to the chloride anion. As hydrogen ions move into the cell due to accumulation of ammonium chloride or hydrogen chloride, electrical neutrality is maintained by potassium exit.

In contrast, organic acidosis (due to lactic, beta-hydroxybutyric, or methylmalonic acid) tends not to cause a potassium shift, since most organic anions readily cross the cell membrane along with hydrogen. Lactic acidosis is often associated with potassium shift, but this effect is due to loss of cell integrity as a result of cell ischemia. The hyperkalemia typically present on admission in patients with diabetic ketoacidosis is the result of insulin deficiency and hypertonicity and not the underlying organic acidosis.¹⁰

Hypertonic states can cause hyperkalemia due to cell shift. For example, hyperglycemia, as in diabetic ketoacidosis, pulls water from the intracellular into the extracellular compartment, thereby concentrating intracellular potassium and creating a more favorable gradient for potassium efflux through membrane channels. This same effect can occur in neurosurgical patients given large amounts of hypertonic mannitol. Repetitive doses of immunoglobulin can lead to extracellular accumulation of sorbitol, maltose, or sucrose, since these sugars are added to the preparations to prevent immunoglobulin aggregation.¹¹

Is a disturbance in renal potassium excretion present?

Sustained hyperkalemia is more commonly associated with decreases in renal potassium excretion than with a cellular shift. In most instances the clinician can distinguish between cell shift and impaired renal excretion based on the available clinical data.

The transtubular potassium gradient has been used to determine whether there is a disturbance in renal potassium excretion and to assess renal potassium handling.¹²

This calculation is based on the assumption that only water is reabsorbed past the cortical collecting duct, and not solutes. It has fallen out of favor since we have found this assumption to be incorrect; a large amount of urea is reabsorbed daily in the downstream medullary collecting duct as a result of intrarenal recycling of urea.

The one situation in which the transtubular potassium gradient may be of use is determining whether hyperkalemia is a result of low aldosterone levels as opposed to aldosterone resistance. One can compare the transtubular potassium gradient before and after a physiologic dose (0.05 mg) of 9-alpha fludrocortisone. An increase of more than 6 over a 4-hour period favors aldosterone deficiency, whereas smaller changes would indicate aldosterone resistance.

24-hour potassium excretion, spot urine potassium-creatinine ratio.  A better way to assess renal potassium handling is to measure the amount of potassium in a 24-hour urine collection or determine a spot urine potassium-creatinine ratio. A 24-hour urinary potassium excretion of less than 15 mmol or a potassium-creatinine ratio less than 1 suggests an extrarenal cause of hypokalemia. A ratio greater than 20 would be an appropriate renal response to hyperkalemia.

One or more of 3 abnormalities should be considered in the hyperkalemic patient with impaired renal excretion of potassium:

• Decreased distal delivery of sodium
• Mineralocorticoid deficiency
• Abnormal cortical collecting tubule function.¹³

Under normal circumstances, potassium is freely filtered across the glomerulus and then mostly reabsorbed in the proximal tubule and thick ascending limb. Potassium secretion begins in the distal convoluted tubule and increases in magnitude into the collecting duct. Tubular secretion is the component of potassium handling that varies and is regulated according to physiologic needs.

In acute kidney injury, the rapid decline in glomerular filtration rate and reduction in functioning nephron mass lead to decreased distal potassium secretion.

Hyperkalemia is a frequent problem when oliguria is present, since the reduction in distal delivery of sodium and water further impairs potassium secretion. Patients with oliguric acute kidney injury are more likely to have a more severe underlying disease state, and therefore tissue breakdown and catabolism further increase the risk of hyperkalemia.

In contrast, in nonoliguric patients, the renal injury tends to be less severe, and enough sodium and water are usually delivered distally to prevent hyperkalemia.

In chronic kidney disease, nephron dropout and reduction in collecting tubule mass also lead to a global decline in distal potassium secretion. However, this is countered by an increased capacity of the remaining individual nephrons for potassium secretion. High flow, increased distal sodium delivery, and increased activity and number of sodium-potassium ATPase pumps in the remaining nephrons account for this increased secretory capacity.¹⁴ As renal function declines over time, colonic potassium secretion progressively increases.¹⁵

These adaptive changes help to keep the plasma potassium concentration within the normal range until the glomerular filtration rate falls to less than 10 or 15 mL/min. Development of hyperkalemia with more modest reductions in the glomerular filtration rate suggest decreased mineralocorticoid activity or a specific lesion of the tubule.

Mineralocorticoid deficiency

Aldosterone deficiency can occur alone or in combination with decreased cortisol levels. Destruction of the adrenal glands is suggested when both hormones are reduced. Enzyme defects in cortisol metabolism can result in either isolated deficiency of aldosterone or adrenogenital syndromes associated with decreased mineralocorticoid activity.

Heparin administration leads to a reversible defect in adrenal synthesis of aldosterone. Drugs that block the stimulatory effect of angiotensin II on the zona glomerulosa cells of the adrenal gland will lower aldosterone.

Renin-angiotensin-aldosterone system blockers. Angiotensin-converting enzyme inhibitors block the formation of angiotensin II, whereas angiotensin II receptor blockers prevent angiotensin II from binding to its adrenal receptor. The direct renin inhibitor aliskiren lowers angiotensin II levels by blocking the enzymatic activity of renin and lowers the circulating levels of both angiotensin I and II.¹⁶

The syndrome of hyporeninemic hypoaldosteronism is a common cause of hyperkalemia in patients who have a glomerular filtration rate between 40 and 60 mL/min. Diabetic nephropathy and interstitial renal disease are the most common clinical entities associated with this syndrome.¹⁰ Other causes include analgesic nephropathy, urinary tract obstruction, sickle cell disease, systemic lupus erythematosus, and amyloidosis.

Nonsteroidal anti-inflammatory drugs can cause hyperkalemia by suppressing renin release and reducing delivery of sodium to the distal nephron.¹⁸

Calcineurin inhibitors impair potassium secretion by suppressing renin release and by direct tubular effects.¹⁹

Beta-blockers. Beta-1 and to a lesser extent beta-2 receptor blockade can also result in a hyporeninemic state.

Distal tubular defect

Hyperkalemia can result from interstitial renal diseases that specifically affect the distal nephron. In this setting, the glomerular filtration rate is only mildly reduced, and circulating aldosterone levels are normal.

Renal transplant, lupus erythematosus, amyloidosis, urinary obstruction, and sickle cell disease are conditions in which an impairment in renin release may coexist with a defect in tubular secretion.

Potassium-sparing diuretics impair the ability of the cortical collecting tubule to secrete potassium. Specifically, amiloride and triamterene inhibit sodium reabsorption mediated by the epithelial sodium channel located on the apical membrane of the principal cell. This effect abolishes the lumen’s negative potential and thereby removes a driving force for potassium secretion.

Trimethoprim and pentamidine cause similar effects.

Spironolactone and eplerenone compete with aldosterone at the level of the mineralocorticoid receptor and can result in hyperkalemia.

Drospirenone, a non-testosterone-derived progestin contained in certain oral contraceptives, possesses mineralocorticoid-blocking effects similar to those of spironolactone.

The plasma potassium level should be monitored when these drugs are prescribed in patients receiving potassium supplements, renin-angiotensin-aldosterone system blockers, or nonsteroidal anti-inflammatory drugs.²⁰

CLINICAL FEATURES OF HYPERKALEMIA

Neuromuscular manifestations of hyperkalemia include paresthesias and fasciculations in the arms and legs. Severe elevation in potassium can give rise to an ascending paralysis with eventual flaccid quadriplegia. Typically, the trunk, head, and respiratory muscles are spared, and respiratory failure is rare.

Cardiac signs

Hyperkalemia has depolarizing effects on the heart that are manifested by changes in the electrocardiogram (Figure 2). The progressive changes of hyperkalemia are classically listed as:

• Peaked T waves that are tall, narrow, and symmetrical and can occasionally be confused with the hyperacute T-wave change associated with an ST-segment elevation myocardial infarction.²¹ However, in the latter condition, the T waves tend to be more broad-based and asymmetric in shape.
• ST-segment depression
• Widening of the PR interval
• Widening of the QRS interval
• Loss of the P wave
• A sine-wave pattern—an ominous development and a harbinger of impending ventricular fibrillation and asystole.

The plasma potassium concentration often correlates poorly with cardiac manifestations. In a retrospective review, only 16 of 90 cases met strict criteria for electrocardiographic changes reflective of hyperkalemia (defined as new peaked and symmetric T waves that resolved on follow-up).²² In 13 of these cases, the electrocardiogram was interpreted as showing no T-wave changes even when read by a cardiologist. In addition, electrocardiographic criteria for hyperkalemia were noted in only 1 of 14 patients who manifested arrhythmias or cardiac arrest attributed to increased plasma potassium concentration.

The treatment of hyperkalemia depends on the magnitude of increase in the plasma potassium concentration and the presence or absence of electrocardiographic changes or neuromuscular symptoms.²³ Acute treatment is indicated for marked electrocardiographic changes and severe muscle weakness.

Intravenous calcium rapidly normalizes membrane excitability by antagonizing the potassium-induced decrease in membrane excitability but does not alter the plasma potassium concentration.

Insulin lowers the plasma potassium concentration by promoting its entry into cells. To avoid hypoglycemia, 10 units of short-acting insulin should be accompanied by a 50-g infusion of glucose, increased to 60 g if 20 units of insulin are given.²⁴

Beta-2 receptor agonists produce a similar effect. The shift of potassium into cells with insulin and beta-2-adrenergic receptor stimulation is brought about by increases in sodium-potassium ATPase pump activity, primarily in skeletal muscle cells.

Sodium bicarbonate, in the absence of acidosis, lowers the plasma potassium concentration only slightly. It should be reserved for hyperkalemic patients who have coexisting metabolic acidosis after the patient has received insulin and glucose, an adrenergic agent, and calcium.

These acute treatments need to be followed by therapies designed to lower the total body potassium content such as diuretics, potassium-binding drugs, and dialysis.

TREATMENT OF CHRONIC HYPERKALEMIA

Review medications. Once the diagnosis of hyperkalemia has been made, the initial approach should be to review the patient’s medications and make every effort to discontinue drugs that can impair renal potassium excretion.¹⁶ Patients should be asked about their use of over-the-counter nonsteroidal anti-inflammatory drugs and herbal remedies, since herbs may be a hidden source of dietary potassium.

Dietary counseling. Patients should be instructed to reduce their dietary intake of potassium and to avoid salt substitutes that contain potassium.

Diuretic therapy is beneficial in minimizing hyperkalemia in patients with chronic kidney disease. Thiazide and loop diuretics enhance renal potassium excretion by increasing flow and delivery of sodium to the collecting duct. Thiazide diuretics are effective when the estimated glomerular filtration rate is greater than 30 mL/min, while loop diuretics should be used in patients with more severe renal insufficiency (Table 2).

Sodium bicarbonate is an effective agent to minimize increases in the plasma potassium concentration in patients with chronic kidney disease and metabolic acidosis. This drug increases renal potassium excretion by increasing distal sodium delivery and shifts potassium into cells as the acidosis is corrected. The likelihood of developing volume overload as a complication of sodium bicarbonate administration can be minimized with effective diuretic therapy.

Avoiding hyperkalemia if renin-angiotensin-aldosterone system blockers are needed

Renin-angiotensin-aldosterone system blockers can be problematic, as these drugs cause hyperkalemia, often in the very patients who derive the greatest cardiovascular benefit from them.¹⁶ A number of steps can reduce the risk of hyperkalemia and allow these drugs to be used.

The initial dose should be low and the plasma potassium should be measured within 1 to 2 weeks after drug initiation. If the potassium level is normal, the dose can be titrated upwards with remeasurement of the plasma potassium after each dose titration. If the plasma potassium concentration rises to 5.5 mmol/L, in some cases lowering the dose will reduce the potassium concentration and allow the patient to remain on the drug.

In patients at risk of hyperkalemia, angiotensin II receptor blockers and direct renin inhibitors should be used with the same caution as angiotensin-converting enzyme inhibitors.

If the plasma potassium concentration exceeds 5.5 mmol/L despite the above precautions, one can consider using a potassium-binding drug (see below) before deciding to avoid renin-angiotensin-aldosterone system blockers.

Sodium polystyrene sulfonate binds potassium in the gastrointestinal tract in exchange for sodium and has been used to manage hyperkalemia. This drug is most commonly given along with sorbitol as a therapy for acute hyperkalemia. Although the drug is widely used, most of the potassium-lowering effect is due to an increase in stool volume caused by sorbitol.^25,26 In addition, long-term use is poorly tolerated, and the drug has been linked to gastrointestinal toxicity in rare cases.

Patiromer and sodium zirconium cyclosilicate are two new potassium-binding drugs that have been shown to be effective in reducing plasma potassium concentration in the setting of ongoing use of renin-angiotensin-aldosterone system blockers.

Patiromer is a nonabsorbed polymer approved for clinical use to treat hyperkalemia. The drug binds potassium in exchange for calcium in the gastrointestinal tract, predominantly in the colon, and lowers the plasma potassium concentration in a dose-dependent manner, with the greatest reduction in those with higher starting values.^27,28

Patiromer effectively controlled plasma potassium concentrations in a 1-year randomized trial in high-risk patients on renin-angiotensin-aldosterone system blockers.²⁹ The main adverse events in clinical trials have been constipation and hypomagnesemia, which required magnesium replacement in a small number of patients, but overall, the drug is well tolerated.

Sodium zirconium cyclosilicate is a nonabsorbed microporous compound that binds potassium in exchange for sodium throughout the gastrointestinal tract. It has been found effective in lowering plasma potassium concentration in a dose-dependent fashion in high-risk patients, most of whom were receiving renin-angiotensin-aldosterone system blockers.^30–32 Adverse events were generally comparable to those with placebo in clinical trials; however, edema occurred more frequently when higher doses were used. This drug is not yet approved for clinical use.

Laennec’s stethoscope has survived more than 200 years, much longer than some of his contemporaries predicted. But will it survive the challenge of bedside ultrasonography and other technologic advances?

The physical examination, with its roots extending at least as far back as Hippocrates, may be at a crossroads as the mainstay of diagnosis. Physical signs can be subjective and lack sensitivity and specificity. Modern imaging and laboratory studies may already be more trusted.

If the physical examination is to survive, it must be accurate, reproducible, and efficient. Needed is a simple, evidence-based approach to the physical examination that enhances its diagnostic accuracy while maintaining bedside efficiency.

Here, we analyze the accuracy of the physical signs that are most effective in the clinical diagnosis of 4 common cardiopulmonary conditions that often present with dyspnea: pneumonia, pleural effusion, chronic obstructive pulmonary disease (COPD), and congestive heart failure.

LIKELIHOOD RATIOS

To grasp the significance of physical findings, it is necessary to understand the concept of likelihood ratios, which are widely accepted measures of the accuracy of a test or clinical finding.^1,2 The positive likelihood ratio is the probability of a disease being present when the test is positive or the clinical finding is present, while the negative likelihood ratio is the probability that the disease is present when the test is negative or the clinical finding is absent. They are calculated as follows¹:

Positive likelihood ratio = sensitivity / (1 – specificity)

Negative likelihood ratio = (1 – sensitivity) / specificity

Table 1 shows how the likelihood ratio of a test changes the posttest probability that a condition is present or absent, according to an analysis by McGee.²

STANDARDIZED TERMINOLOGY

PNEUMONIA

Pneumonia is a common disease, with more than 2 million cases annually in the United States. It is most often diagnosed by standard chest radiography, although computed tomography can identify it earlier and with higher sensitivity and specificity.⁵ The amount of published data on physical examination findings in pneumonia is surprisingly small.

Asymmetry in chest expansion: Specific, reproducible, but not sensitive

The physical finding with the highest positive likelihood ratio for diagnosing pneumonia is asymmetry in chest expansion.^6,7

From Diaz-Guzman E, Budev MM. Accuracy of the physical examination in evaluating pleural effusion. Cleve Clin J Med 2008; 75:297–303.

In a 1984 study of 1,819 patients presenting to an emergency department with acute cough, Diehr et al⁶ evaluated several physical signs of pneumonia. Asymmetric chest expansion had a specificity and positive predictive value of 100%, but its sensitivity was only 4.3%. Thus, it is not a good screening test, but it is a good diagnostic or confirmatory test. From these numbers, Metlay et al⁸ calculated that the positive likelihood ratio was infinity and the negative likelihood ratio was 0.96.

McGee,⁷ on the other hand, calculated the positive likelihood ratio of asymmetric chest expansion at 44.1. McGee also found chest expansion to be a highly reproducible finding, with an interobserver agreement kappa score of 0.85.⁷ (A kappa score of 1.0 would indicate perfect interobserver agreement.) Interestingly, chest radiographs interpreted for pulmonary infiltrates have an interobserver kappa score of only 0.38.⁷ Further studies of this physical sign could shed more light upon this area of uncertainty.

Other signs of pneumonia

None of the other physical signs studied for the diagnosis of pneumonia has as high a positive likelihood ratio as asymmetric chest expansion.^6–12

Egophony is a high-pitched or nasal quality of the patient’s voice heard on auscultation over lung tissue that is consolidated or fibrosed, due to enhanced transmission of high-frequency sound across fluid. It is often described as the “E-to-A change.” Although listening for egophony is widely done and easy to do, we calculate that this sign has a positive likelihood ratio of only 6.8 based on pooled data from 3 trials with a total of 3,245 patients.^6,10,11

Faring less favorably, in descending order of diagnostic accuracy, are:

Percussion dullness (positive likelihood ratio 5.7 based on 4 studies with 3,653 patients)^6,10–12

Bronchophony or bronchial breath sounds (positive likelihood ratio 3.3 based on 1,118 patients)¹⁰

Crackles have long been taught as a common physical finding in pneumonia. Bohadana et al pointed out that “crackle” can be defined acoustically but does not suggest any means or site of generation.⁴ Pooled data from 4 studies in 3,647 patients^6,10–12 result in a positive likelihood ratio for crackles in the diagnosis of pneumonia of only 3.2.

Diminished breath sounds (positive likelihood ratio 2.5 based on 3 studies with 1,828 patients).^10–12

These physical examination maneuvers are time-honored and part of the rite of training for medical students and residents. As we have shown, they are not extremely helpful as individual tests in diagnosing pneumonia; however, they may be useful when used in combination as a clinical prediction rule or diagnostic algorithm. These rules often have higher diagnostic accuracy but drawbacks of taking more time and not being easily reproducible.

PLEURAL EFFUSION

Pleural effusion commonly occurs in patients with congestive heart failure, pneumonia, and malignancies. The following are signs of effusion.

Dullness to percussion had a positive likelihood ratio of 5.7 from pooled data from 3 studies analyzed by Wong et al.¹³

Asymmetric chest expansion, in a study by Kalantri et al,¹⁴ had a positive likelihood ratio of 8.1 and a negative likelihood ratio of 0.29, the latter making it a reasonably good test to help rule out a pleural effusion.

Negative signs. Since a pleural effusion is an abnormal fluid collection in the pleural space and not the lung parenchyma, one would not expect it to cause loud breath sounds, adventitious sounds, or vocal resonance. Since these 3 findings emanate from the lung, their absence would be expected to support the presence of a pleural effusion.

Tactile fremitus, also known as vocal fremitus, is the vibration felt on the chest wall while the patient is speaking. Traditionally, the patient says “ninety-nine” as the examiner feels for asymmetry in vibration. A consolidation such as pneumonia increases the vibration, while fluid in a pleural effusion diminishes it.

DIAGNOSTIC ALGORITHM FOR PNEUMONIA OR PLEURAL EFFUSION

Patients presenting with cough or dyspnea will most likely be evaluated for pneumonia and pleural effusion, among other diagnoses. We propose the following physical examination strategy in this setting.

First, evaluate the patient for asymmetric chest expansion. The positive likelihood ratio for this sign is excellent for pneumonia (44.1) and moderate for pleural effusion (8.1); therefore, both conditions are possible with a positive test.

Second, percuss the chest. Dullness to percussion has a low positive likelihood ratio for pneumonia but a moderate one for pleural effusion.¹³ The absence of this sign is only modest in excluding a pleural effusion (negative likelihood ratio 0.31 in pooled data analyzed by Wong et al).¹³

Third, auscultate the chest to elicit normal, diminished, or adventitious breath sounds. Diminished breath sounds may be noted in both conditions, but vocal resonance (egophony or bronchophony) and tactile fremitus should not be present directly over a pleural effusion. Either vocal resonance or tactile fremitus in a patient with asymmetric chest expansion would strongly support the diagnosis of pneumonia.

Figure 2 summarizes our proposed diagnostic algorithm for pneumonia and pleural effusion.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD imposes a heavy burden on public health worldwide in terms of cost and mortality. It is the third leading cause of death in the United States, after heart disease and cancer.¹⁵

Spirometry remains the gold standard for diagnosis. The Global Initiative for Chronic Obstructive Lung Disease standard for diagnosing COPD was the better of 2 spirometry test results, showing a forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity ratio less than 70%.¹⁶

Unfortunately, there is little evidence that physical signs aid in the early diagnosis of COPD, as physical signs of airflow limitation may not manifest until lung function is substantially impaired.^17,18

Early inspiratory crackles had a positive likelihood ratio of 14.6 based on 2 small studies.^19,20

Percussion dullness over the left sternal border in the fifth intercostal space should be present in the normal situation and is known as cardiac dullness. Absent cardiac dullness had a positive likelihood ratio of 16 and a negative likelihood ratio of 0.8 for diagnosing COPD in a study in 92 patients with a history of smoking or self-reported COPD.²¹ The kappa score was 0.49, signifying moderate interobserver  agreement.

A combined strategy using the history and physical examination may have the highest diagnostic accuracy. Many of these combinations are too cumbersome for practical clinical use. However, 1 of them is based on only 3 questions²¹:

• Has the patient smoked for more than 70-pack years?
• Has the patient been previously diagnosed with chronic bronchitis or emphysema?
• Are breath sounds diminished in intensity?

Answering yes to 2 of these questions gives a positive likelihood ratio of a diagnosis of COPD of 33.5.

Early detection of COPD may improve outcomes and lower healthcare costs and thus would be clinically useful. Unfortunately, a diagnostic approach using the history and physical in the early diagnosis of COPD remains uncertain at this time.

The clinical presentation of acute congestive heart failure has much in common with pneumonia, pleural effusion, and COPD.

Echocardiography, the gold standard for diagnosis, is costly and may not be immediately available for most patients evaluated for cardiorespiratory complaints. The American College of Cardiology reports the cost of standard echocardiography to be between $1,000 and $2,000.²² A physical examination approach in the assessment of dyspnea can be very useful.

Height of jugular venous distention approximates central venous pressure

Assessing the central venous pressure by estimating the vertical height of distention of the right internal or external jugular vein is validated and easily reproducible.^23,24 The use of the external jugular vein is supported by correlation with catheter-measured central venous pressure in critically ill patients.^25,26 The central venous pressure reflects the right atrial pressure, and in the absence of tricuspid stenosis, the right ventricular end-diastolic pressure. An elevation in central venous pressure can be seen in patients with congestive heart failure, pulmonary hypertension, and pulmonary valve stenosis.

The right side is preferred due to its anatomically direct route to the heart. In contrast, the left internal jugular vein crosses the mediastinum and can be compressed by the aorta, causing a false elevation.

In summary, an elevated jugular venous pressure on examination is a good test to rule in an elevated central venous pressure, and its absence is a good sign in ruling out an elevated central venous pressure. When using jugular venous pressure specifically for the diagnosis of congestive heart failure with reduced ejection fraction (ie, ejection fraction < 50%), the positive likelihood ratio is 6.3 based on 3 studies.^25–27

Heart failure with preserved ejection fraction has not been well studied for physical examination. The Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-Preserve)²⁸ looked only at the sensitivity of elevated jugular venous pressure in 4,128 patients, which was 8%. Specificity was not reported.

The abdominojugular reflux

Another way to gauge the jugular venous pressure is to examine the neck veins while firmly pressing on the mid-abdomen for 10 to 15 seconds to look for the abdominojugular reflux, also known as the hepatojugular reflux. An increase in the jugular venous pressure of 3 cm from baseline constitutes a positive abdominojugular reflux. It has a positive likelihood ratio of 8.0 and a negative likelihood ratio of 0.3 for the diagnosis of congestive heart failure by the assessment of end-diastolic pressure of the left ventricle (Table 5).^29–31

The abdominojugular reflux is a much more reliable test than examination of neck veins for jugular venous pressure. The interobserver agreement for examining neck veins has a wide range of kappa scores (0.08–0.81), whereas the abdominojugular reflux has a very high kappa score of 0.92.⁷ Interestingly, chest radiography showing interstitial edema has a kappa of 0.83.⁷

Displaced apical impulse

An evaluation of the apical impulse of the heart is also a very good and quick test in the examination of patients suspected of having congestive heart failure. An abnormal finding is defined by an apical impulse displaced laterally (to the left of the midclavicular line).

Using data from several studies,^32–35 a displaced apical impulse has a positive likelihood ratio of 10.3. The absence of this finding, however, is not very good for ruling out congestive heart failure, with a negative likelihood ratio of 0.7. Interobserver agreement is moderate to excellent (kappa score 0.43–0.86).⁷

A third heart sound

Auscultation to assess the third heart sound is much more difficult. A systematic review found that likelihood ratios vary widely and confidence intervals are wide.³⁶ Interobserver agreement also varies widely (kappa scores –0.17 to 0.84).⁷ In a primary care study,³⁷ a third heart sound had a very low sensitivity (4.3%) but a specificity of 99.8%.

Therefore, we are uncertain about a conclusion for this physical finding based on the concern for wide ranges in likelihood ratio and poor interobserver reliability.

PHYSICAL EXAMINATION STILL HAS A FUTURE

The physical examination has a long and distinguished place in the history of medicine. Technologic advances have changed the manner in which clinicians practice the art of healing. Modern technology in US healthcare has become a double-edged sword, with many benefits as well as detriments.³ Reproducibility and accuracy are paramount for the physical examination to remain a core component of medical diagnosis. Advances in the diagnostic accuracy of laboratory and imaging studies challenge the importance of the physical examination. However, we firmly believe that the traditional techniques have stood the test of time and have a future in the clinical practice of medicine.

Acknowledgments: The authors thank Ruby Marr, MD, Mohammed Nabhan, MD, Rajiv Doddamani, MD, and Sohaib Galani, MD, for their important contributions to this article, which included research assistance and editorial advice.

Laennec’s stethoscope has survived more than 200 years, much longer than some of his contemporaries predicted. But will it survive the challenge of bedside ultrasonography and other technologic advances?

The physical examination, with its roots extending at least as far back as Hippocrates, may be at a crossroads as the mainstay of diagnosis. Physical signs can be subjective and lack sensitivity and specificity. Modern imaging and laboratory studies may already be more trusted.

If the physical examination is to survive, it must be accurate, reproducible, and efficient. Needed is a simple, evidence-based approach to the physical examination that enhances its diagnostic accuracy while maintaining bedside efficiency.

Here, we analyze the accuracy of the physical signs that are most effective in the clinical diagnosis of 4 common cardiopulmonary conditions that often present with dyspnea: pneumonia, pleural effusion, chronic obstructive pulmonary disease (COPD), and congestive heart failure.

LIKELIHOOD RATIOS

To grasp the significance of physical findings, it is necessary to understand the concept of likelihood ratios, which are widely accepted measures of the accuracy of a test or clinical finding.^1,2 The positive likelihood ratio is the probability of a disease being present when the test is positive or the clinical finding is present, while the negative likelihood ratio is the probability that the disease is present when the test is negative or the clinical finding is absent. They are calculated as follows¹:

Positive likelihood ratio = sensitivity / (1 – specificity)

Negative likelihood ratio = (1 – sensitivity) / specificity

Table 1 shows how the likelihood ratio of a test changes the posttest probability that a condition is present or absent, according to an analysis by McGee.²

STANDARDIZED TERMINOLOGY

PNEUMONIA

Pneumonia is a common disease, with more than 2 million cases annually in the United States. It is most often diagnosed by standard chest radiography, although computed tomography can identify it earlier and with higher sensitivity and specificity.⁵ The amount of published data on physical examination findings in pneumonia is surprisingly small.

Asymmetry in chest expansion: Specific, reproducible, but not sensitive

The physical finding with the highest positive likelihood ratio for diagnosing pneumonia is asymmetry in chest expansion.^6,7

From Diaz-Guzman E, Budev MM. Accuracy of the physical examination in evaluating pleural effusion. Cleve Clin J Med 2008; 75:297–303.

In a 1984 study of 1,819 patients presenting to an emergency department with acute cough, Diehr et al⁶ evaluated several physical signs of pneumonia. Asymmetric chest expansion had a specificity and positive predictive value of 100%, but its sensitivity was only 4.3%. Thus, it is not a good screening test, but it is a good diagnostic or confirmatory test. From these numbers, Metlay et al⁸ calculated that the positive likelihood ratio was infinity and the negative likelihood ratio was 0.96.

McGee,⁷ on the other hand, calculated the positive likelihood ratio of asymmetric chest expansion at 44.1. McGee also found chest expansion to be a highly reproducible finding, with an interobserver agreement kappa score of 0.85.⁷ (A kappa score of 1.0 would indicate perfect interobserver agreement.) Interestingly, chest radiographs interpreted for pulmonary infiltrates have an interobserver kappa score of only 0.38.⁷ Further studies of this physical sign could shed more light upon this area of uncertainty.

Other signs of pneumonia

None of the other physical signs studied for the diagnosis of pneumonia has as high a positive likelihood ratio as asymmetric chest expansion.^6–12

Egophony is a high-pitched or nasal quality of the patient’s voice heard on auscultation over lung tissue that is consolidated or fibrosed, due to enhanced transmission of high-frequency sound across fluid. It is often described as the “E-to-A change.” Although listening for egophony is widely done and easy to do, we calculate that this sign has a positive likelihood ratio of only 6.8 based on pooled data from 3 trials with a total of 3,245 patients.^6,10,11

Faring less favorably, in descending order of diagnostic accuracy, are:

Percussion dullness (positive likelihood ratio 5.7 based on 4 studies with 3,653 patients)^6,10–12

Bronchophony or bronchial breath sounds (positive likelihood ratio 3.3 based on 1,118 patients)¹⁰

Crackles have long been taught as a common physical finding in pneumonia. Bohadana et al pointed out that “crackle” can be defined acoustically but does not suggest any means or site of generation.⁴ Pooled data from 4 studies in 3,647 patients^6,10–12 result in a positive likelihood ratio for crackles in the diagnosis of pneumonia of only 3.2.

Diminished breath sounds (positive likelihood ratio 2.5 based on 3 studies with 1,828 patients).^10–12

These physical examination maneuvers are time-honored and part of the rite of training for medical students and residents. As we have shown, they are not extremely helpful as individual tests in diagnosing pneumonia; however, they may be useful when used in combination as a clinical prediction rule or diagnostic algorithm. These rules often have higher diagnostic accuracy but drawbacks of taking more time and not being easily reproducible.

PLEURAL EFFUSION

Pleural effusion commonly occurs in patients with congestive heart failure, pneumonia, and malignancies. The following are signs of effusion.

Dullness to percussion had a positive likelihood ratio of 5.7 from pooled data from 3 studies analyzed by Wong et al.¹³

Asymmetric chest expansion, in a study by Kalantri et al,¹⁴ had a positive likelihood ratio of 8.1 and a negative likelihood ratio of 0.29, the latter making it a reasonably good test to help rule out a pleural effusion.

Negative signs. Since a pleural effusion is an abnormal fluid collection in the pleural space and not the lung parenchyma, one would not expect it to cause loud breath sounds, adventitious sounds, or vocal resonance. Since these 3 findings emanate from the lung, their absence would be expected to support the presence of a pleural effusion.

Tactile fremitus, also known as vocal fremitus, is the vibration felt on the chest wall while the patient is speaking. Traditionally, the patient says “ninety-nine” as the examiner feels for asymmetry in vibration. A consolidation such as pneumonia increases the vibration, while fluid in a pleural effusion diminishes it.

DIAGNOSTIC ALGORITHM FOR PNEUMONIA OR PLEURAL EFFUSION

Patients presenting with cough or dyspnea will most likely be evaluated for pneumonia and pleural effusion, among other diagnoses. We propose the following physical examination strategy in this setting.

First, evaluate the patient for asymmetric chest expansion. The positive likelihood ratio for this sign is excellent for pneumonia (44.1) and moderate for pleural effusion (8.1); therefore, both conditions are possible with a positive test.

Second, percuss the chest. Dullness to percussion has a low positive likelihood ratio for pneumonia but a moderate one for pleural effusion.¹³ The absence of this sign is only modest in excluding a pleural effusion (negative likelihood ratio 0.31 in pooled data analyzed by Wong et al).¹³

Third, auscultate the chest to elicit normal, diminished, or adventitious breath sounds. Diminished breath sounds may be noted in both conditions, but vocal resonance (egophony or bronchophony) and tactile fremitus should not be present directly over a pleural effusion. Either vocal resonance or tactile fremitus in a patient with asymmetric chest expansion would strongly support the diagnosis of pneumonia.

Figure 2 summarizes our proposed diagnostic algorithm for pneumonia and pleural effusion.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD imposes a heavy burden on public health worldwide in terms of cost and mortality. It is the third leading cause of death in the United States, after heart disease and cancer.¹⁵

Spirometry remains the gold standard for diagnosis. The Global Initiative for Chronic Obstructive Lung Disease standard for diagnosing COPD was the better of 2 spirometry test results, showing a forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity ratio less than 70%.¹⁶

Unfortunately, there is little evidence that physical signs aid in the early diagnosis of COPD, as physical signs of airflow limitation may not manifest until lung function is substantially impaired.^17,18

Early inspiratory crackles had a positive likelihood ratio of 14.6 based on 2 small studies.^19,20

Percussion dullness over the left sternal border in the fifth intercostal space should be present in the normal situation and is known as cardiac dullness. Absent cardiac dullness had a positive likelihood ratio of 16 and a negative likelihood ratio of 0.8 for diagnosing COPD in a study in 92 patients with a history of smoking or self-reported COPD.²¹ The kappa score was 0.49, signifying moderate interobserver  agreement.

A combined strategy using the history and physical examination may have the highest diagnostic accuracy. Many of these combinations are too cumbersome for practical clinical use. However, 1 of them is based on only 3 questions²¹:

• Has the patient smoked for more than 70-pack years?
• Has the patient been previously diagnosed with chronic bronchitis or emphysema?
• Are breath sounds diminished in intensity?

Answering yes to 2 of these questions gives a positive likelihood ratio of a diagnosis of COPD of 33.5.

Early detection of COPD may improve outcomes and lower healthcare costs and thus would be clinically useful. Unfortunately, a diagnostic approach using the history and physical in the early diagnosis of COPD remains uncertain at this time.

The clinical presentation of acute congestive heart failure has much in common with pneumonia, pleural effusion, and COPD.

Echocardiography, the gold standard for diagnosis, is costly and may not be immediately available for most patients evaluated for cardiorespiratory complaints. The American College of Cardiology reports the cost of standard echocardiography to be between $1,000 and $2,000.²² A physical examination approach in the assessment of dyspnea can be very useful.

Height of jugular venous distention approximates central venous pressure

Assessing the central venous pressure by estimating the vertical height of distention of the right internal or external jugular vein is validated and easily reproducible.^23,24 The use of the external jugular vein is supported by correlation with catheter-measured central venous pressure in critically ill patients.^25,26 The central venous pressure reflects the right atrial pressure, and in the absence of tricuspid stenosis, the right ventricular end-diastolic pressure. An elevation in central venous pressure can be seen in patients with congestive heart failure, pulmonary hypertension, and pulmonary valve stenosis.

The right side is preferred due to its anatomically direct route to the heart. In contrast, the left internal jugular vein crosses the mediastinum and can be compressed by the aorta, causing a false elevation.

In summary, an elevated jugular venous pressure on examination is a good test to rule in an elevated central venous pressure, and its absence is a good sign in ruling out an elevated central venous pressure. When using jugular venous pressure specifically for the diagnosis of congestive heart failure with reduced ejection fraction (ie, ejection fraction < 50%), the positive likelihood ratio is 6.3 based on 3 studies.^25–27

Heart failure with preserved ejection fraction has not been well studied for physical examination. The Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-Preserve)²⁸ looked only at the sensitivity of elevated jugular venous pressure in 4,128 patients, which was 8%. Specificity was not reported.

The abdominojugular reflux

Another way to gauge the jugular venous pressure is to examine the neck veins while firmly pressing on the mid-abdomen for 10 to 15 seconds to look for the abdominojugular reflux, also known as the hepatojugular reflux. An increase in the jugular venous pressure of 3 cm from baseline constitutes a positive abdominojugular reflux. It has a positive likelihood ratio of 8.0 and a negative likelihood ratio of 0.3 for the diagnosis of congestive heart failure by the assessment of end-diastolic pressure of the left ventricle (Table 5).^29–31

The abdominojugular reflux is a much more reliable test than examination of neck veins for jugular venous pressure. The interobserver agreement for examining neck veins has a wide range of kappa scores (0.08–0.81), whereas the abdominojugular reflux has a very high kappa score of 0.92.⁷ Interestingly, chest radiography showing interstitial edema has a kappa of 0.83.⁷

Displaced apical impulse

An evaluation of the apical impulse of the heart is also a very good and quick test in the examination of patients suspected of having congestive heart failure. An abnormal finding is defined by an apical impulse displaced laterally (to the left of the midclavicular line).

Using data from several studies,^32–35 a displaced apical impulse has a positive likelihood ratio of 10.3. The absence of this finding, however, is not very good for ruling out congestive heart failure, with a negative likelihood ratio of 0.7. Interobserver agreement is moderate to excellent (kappa score 0.43–0.86).⁷

A third heart sound

Auscultation to assess the third heart sound is much more difficult. A systematic review found that likelihood ratios vary widely and confidence intervals are wide.³⁶ Interobserver agreement also varies widely (kappa scores –0.17 to 0.84).⁷ In a primary care study,³⁷ a third heart sound had a very low sensitivity (4.3%) but a specificity of 99.8%.

Therefore, we are uncertain about a conclusion for this physical finding based on the concern for wide ranges in likelihood ratio and poor interobserver reliability.

PHYSICAL EXAMINATION STILL HAS A FUTURE

The physical examination has a long and distinguished place in the history of medicine. Technologic advances have changed the manner in which clinicians practice the art of healing. Modern technology in US healthcare has become a double-edged sword, with many benefits as well as detriments.³ Reproducibility and accuracy are paramount for the physical examination to remain a core component of medical diagnosis. Advances in the diagnostic accuracy of laboratory and imaging studies challenge the importance of the physical examination. However, we firmly believe that the traditional techniques have stood the test of time and have a future in the clinical practice of medicine.

Acknowledgments: The authors thank Ruby Marr, MD, Mohammed Nabhan, MD, Rajiv Doddamani, MD, and Sohaib Galani, MD, for their important contributions to this article, which included research assistance and editorial advice.

Laennec’s stethoscope has survived more than 200 years, much longer than some of his contemporaries predicted. But will it survive the challenge of bedside ultrasonography and other technologic advances?

The physical examination, with its roots extending at least as far back as Hippocrates, may be at a crossroads as the mainstay of diagnosis. Physical signs can be subjective and lack sensitivity and specificity. Modern imaging and laboratory studies may already be more trusted.

If the physical examination is to survive, it must be accurate, reproducible, and efficient. Needed is a simple, evidence-based approach to the physical examination that enhances its diagnostic accuracy while maintaining bedside efficiency.

Here, we analyze the accuracy of the physical signs that are most effective in the clinical diagnosis of 4 common cardiopulmonary conditions that often present with dyspnea: pneumonia, pleural effusion, chronic obstructive pulmonary disease (COPD), and congestive heart failure.

LIKELIHOOD RATIOS

To grasp the significance of physical findings, it is necessary to understand the concept of likelihood ratios, which are widely accepted measures of the accuracy of a test or clinical finding.^1,2 The positive likelihood ratio is the probability of a disease being present when the test is positive or the clinical finding is present, while the negative likelihood ratio is the probability that the disease is present when the test is negative or the clinical finding is absent. They are calculated as follows¹:

Positive likelihood ratio = sensitivity / (1 – specificity)

Negative likelihood ratio = (1 – sensitivity) / specificity

Table 1 shows how the likelihood ratio of a test changes the posttest probability that a condition is present or absent, according to an analysis by McGee.²

STANDARDIZED TERMINOLOGY

PNEUMONIA

Pneumonia is a common disease, with more than 2 million cases annually in the United States. It is most often diagnosed by standard chest radiography, although computed tomography can identify it earlier and with higher sensitivity and specificity.⁵ The amount of published data on physical examination findings in pneumonia is surprisingly small.

Asymmetry in chest expansion: Specific, reproducible, but not sensitive

The physical finding with the highest positive likelihood ratio for diagnosing pneumonia is asymmetry in chest expansion.^6,7

From Diaz-Guzman E, Budev MM. Accuracy of the physical examination in evaluating pleural effusion. Cleve Clin J Med 2008; 75:297–303.

In a 1984 study of 1,819 patients presenting to an emergency department with acute cough, Diehr et al⁶ evaluated several physical signs of pneumonia. Asymmetric chest expansion had a specificity and positive predictive value of 100%, but its sensitivity was only 4.3%. Thus, it is not a good screening test, but it is a good diagnostic or confirmatory test. From these numbers, Metlay et al⁸ calculated that the positive likelihood ratio was infinity and the negative likelihood ratio was 0.96.

McGee,⁷ on the other hand, calculated the positive likelihood ratio of asymmetric chest expansion at 44.1. McGee also found chest expansion to be a highly reproducible finding, with an interobserver agreement kappa score of 0.85.⁷ (A kappa score of 1.0 would indicate perfect interobserver agreement.) Interestingly, chest radiographs interpreted for pulmonary infiltrates have an interobserver kappa score of only 0.38.⁷ Further studies of this physical sign could shed more light upon this area of uncertainty.

Other signs of pneumonia

None of the other physical signs studied for the diagnosis of pneumonia has as high a positive likelihood ratio as asymmetric chest expansion.^6–12

Egophony is a high-pitched or nasal quality of the patient’s voice heard on auscultation over lung tissue that is consolidated or fibrosed, due to enhanced transmission of high-frequency sound across fluid. It is often described as the “E-to-A change.” Although listening for egophony is widely done and easy to do, we calculate that this sign has a positive likelihood ratio of only 6.8 based on pooled data from 3 trials with a total of 3,245 patients.^6,10,11

Faring less favorably, in descending order of diagnostic accuracy, are:

Percussion dullness (positive likelihood ratio 5.7 based on 4 studies with 3,653 patients)^6,10–12

Bronchophony or bronchial breath sounds (positive likelihood ratio 3.3 based on 1,118 patients)¹⁰

Crackles have long been taught as a common physical finding in pneumonia. Bohadana et al pointed out that “crackle” can be defined acoustically but does not suggest any means or site of generation.⁴ Pooled data from 4 studies in 3,647 patients^6,10–12 result in a positive likelihood ratio for crackles in the diagnosis of pneumonia of only 3.2.

Diminished breath sounds (positive likelihood ratio 2.5 based on 3 studies with 1,828 patients).^10–12

These physical examination maneuvers are time-honored and part of the rite of training for medical students and residents. As we have shown, they are not extremely helpful as individual tests in diagnosing pneumonia; however, they may be useful when used in combination as a clinical prediction rule or diagnostic algorithm. These rules often have higher diagnostic accuracy but drawbacks of taking more time and not being easily reproducible.

PLEURAL EFFUSION

Pleural effusion commonly occurs in patients with congestive heart failure, pneumonia, and malignancies. The following are signs of effusion.

Dullness to percussion had a positive likelihood ratio of 5.7 from pooled data from 3 studies analyzed by Wong et al.¹³

Asymmetric chest expansion, in a study by Kalantri et al,¹⁴ had a positive likelihood ratio of 8.1 and a negative likelihood ratio of 0.29, the latter making it a reasonably good test to help rule out a pleural effusion.

Negative signs. Since a pleural effusion is an abnormal fluid collection in the pleural space and not the lung parenchyma, one would not expect it to cause loud breath sounds, adventitious sounds, or vocal resonance. Since these 3 findings emanate from the lung, their absence would be expected to support the presence of a pleural effusion.

Tactile fremitus, also known as vocal fremitus, is the vibration felt on the chest wall while the patient is speaking. Traditionally, the patient says “ninety-nine” as the examiner feels for asymmetry in vibration. A consolidation such as pneumonia increases the vibration, while fluid in a pleural effusion diminishes it.

DIAGNOSTIC ALGORITHM FOR PNEUMONIA OR PLEURAL EFFUSION

Patients presenting with cough or dyspnea will most likely be evaluated for pneumonia and pleural effusion, among other diagnoses. We propose the following physical examination strategy in this setting.

First, evaluate the patient for asymmetric chest expansion. The positive likelihood ratio for this sign is excellent for pneumonia (44.1) and moderate for pleural effusion (8.1); therefore, both conditions are possible with a positive test.

Second, percuss the chest. Dullness to percussion has a low positive likelihood ratio for pneumonia but a moderate one for pleural effusion.¹³ The absence of this sign is only modest in excluding a pleural effusion (negative likelihood ratio 0.31 in pooled data analyzed by Wong et al).¹³

Third, auscultate the chest to elicit normal, diminished, or adventitious breath sounds. Diminished breath sounds may be noted in both conditions, but vocal resonance (egophony or bronchophony) and tactile fremitus should not be present directly over a pleural effusion. Either vocal resonance or tactile fremitus in a patient with asymmetric chest expansion would strongly support the diagnosis of pneumonia.

Figure 2 summarizes our proposed diagnostic algorithm for pneumonia and pleural effusion.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

COPD imposes a heavy burden on public health worldwide in terms of cost and mortality. It is the third leading cause of death in the United States, after heart disease and cancer.¹⁵

Spirometry remains the gold standard for diagnosis. The Global Initiative for Chronic Obstructive Lung Disease standard for diagnosing COPD was the better of 2 spirometry test results, showing a forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity ratio less than 70%.¹⁶

Unfortunately, there is little evidence that physical signs aid in the early diagnosis of COPD, as physical signs of airflow limitation may not manifest until lung function is substantially impaired.^17,18

Early inspiratory crackles had a positive likelihood ratio of 14.6 based on 2 small studies.^19,20

Percussion dullness over the left sternal border in the fifth intercostal space should be present in the normal situation and is known as cardiac dullness. Absent cardiac dullness had a positive likelihood ratio of 16 and a negative likelihood ratio of 0.8 for diagnosing COPD in a study in 92 patients with a history of smoking or self-reported COPD.²¹ The kappa score was 0.49, signifying moderate interobserver  agreement.

A combined strategy using the history and physical examination may have the highest diagnostic accuracy. Many of these combinations are too cumbersome for practical clinical use. However, 1 of them is based on only 3 questions²¹:

• Has the patient smoked for more than 70-pack years?
• Has the patient been previously diagnosed with chronic bronchitis or emphysema?
• Are breath sounds diminished in intensity?

Answering yes to 2 of these questions gives a positive likelihood ratio of a diagnosis of COPD of 33.5.

Early detection of COPD may improve outcomes and lower healthcare costs and thus would be clinically useful. Unfortunately, a diagnostic approach using the history and physical in the early diagnosis of COPD remains uncertain at this time.

The clinical presentation of acute congestive heart failure has much in common with pneumonia, pleural effusion, and COPD.

Echocardiography, the gold standard for diagnosis, is costly and may not be immediately available for most patients evaluated for cardiorespiratory complaints. The American College of Cardiology reports the cost of standard echocardiography to be between $1,000 and $2,000.²² A physical examination approach in the assessment of dyspnea can be very useful.

Height of jugular venous distention approximates central venous pressure

Assessing the central venous pressure by estimating the vertical height of distention of the right internal or external jugular vein is validated and easily reproducible.^23,24 The use of the external jugular vein is supported by correlation with catheter-measured central venous pressure in critically ill patients.^25,26 The central venous pressure reflects the right atrial pressure, and in the absence of tricuspid stenosis, the right ventricular end-diastolic pressure. An elevation in central venous pressure can be seen in patients with congestive heart failure, pulmonary hypertension, and pulmonary valve stenosis.

The right side is preferred due to its anatomically direct route to the heart. In contrast, the left internal jugular vein crosses the mediastinum and can be compressed by the aorta, causing a false elevation.

In summary, an elevated jugular venous pressure on examination is a good test to rule in an elevated central venous pressure, and its absence is a good sign in ruling out an elevated central venous pressure. When using jugular venous pressure specifically for the diagnosis of congestive heart failure with reduced ejection fraction (ie, ejection fraction < 50%), the positive likelihood ratio is 6.3 based on 3 studies.^25–27

Heart failure with preserved ejection fraction has not been well studied for physical examination. The Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-Preserve)²⁸ looked only at the sensitivity of elevated jugular venous pressure in 4,128 patients, which was 8%. Specificity was not reported.

The abdominojugular reflux

Another way to gauge the jugular venous pressure is to examine the neck veins while firmly pressing on the mid-abdomen for 10 to 15 seconds to look for the abdominojugular reflux, also known as the hepatojugular reflux. An increase in the jugular venous pressure of 3 cm from baseline constitutes a positive abdominojugular reflux. It has a positive likelihood ratio of 8.0 and a negative likelihood ratio of 0.3 for the diagnosis of congestive heart failure by the assessment of end-diastolic pressure of the left ventricle (Table 5).^29–31

The abdominojugular reflux is a much more reliable test than examination of neck veins for jugular venous pressure. The interobserver agreement for examining neck veins has a wide range of kappa scores (0.08–0.81), whereas the abdominojugular reflux has a very high kappa score of 0.92.⁷ Interestingly, chest radiography showing interstitial edema has a kappa of 0.83.⁷

Displaced apical impulse

An evaluation of the apical impulse of the heart is also a very good and quick test in the examination of patients suspected of having congestive heart failure. An abnormal finding is defined by an apical impulse displaced laterally (to the left of the midclavicular line).

Using data from several studies,^32–35 a displaced apical impulse has a positive likelihood ratio of 10.3. The absence of this finding, however, is not very good for ruling out congestive heart failure, with a negative likelihood ratio of 0.7. Interobserver agreement is moderate to excellent (kappa score 0.43–0.86).⁷

A third heart sound

Auscultation to assess the third heart sound is much more difficult. A systematic review found that likelihood ratios vary widely and confidence intervals are wide.³⁶ Interobserver agreement also varies widely (kappa scores –0.17 to 0.84).⁷ In a primary care study,³⁷ a third heart sound had a very low sensitivity (4.3%) but a specificity of 99.8%.

Therefore, we are uncertain about a conclusion for this physical finding based on the concern for wide ranges in likelihood ratio and poor interobserver reliability.

PHYSICAL EXAMINATION STILL HAS A FUTURE

The physical examination has a long and distinguished place in the history of medicine. Technologic advances have changed the manner in which clinicians practice the art of healing. Modern technology in US healthcare has become a double-edged sword, with many benefits as well as detriments.³ Reproducibility and accuracy are paramount for the physical examination to remain a core component of medical diagnosis. Advances in the diagnostic accuracy of laboratory and imaging studies challenge the importance of the physical examination. However, we firmly believe that the traditional techniques have stood the test of time and have a future in the clinical practice of medicine.

Acknowledgments: The authors thank Ruby Marr, MD, Mohammed Nabhan, MD, Rajiv Doddamani, MD, and Sohaib Galani, MD, for their important contributions to this article, which included research assistance and editorial advice.

Case

A 50-year-old Hispanic woman with a history of rheumatoid arthritis (RA), for which she was not currently taking medication, was referred to the ED by her primary care physician (PCP) for evaluation of generalized pruritus and jaundice, and an abnormal hepatic function panel.

The patient’s recent history was significant for a positive tuberculosis test (purified protein derivative [PPD], 13 mm), for which she had been on prophylactic medication. Laboratory evaluation taken during the patient’s recent follow-up visit with her PCP revealed the following significant hepatic abnormalities: total bilirubin, 20.0 mg/dL; direct bilirubin, 16.4 mg/dL; international normalized ratio, 2.9; aspartate aminotransferase, greater than 2,000 IU/L; and alanine aminotransferase, greater than 2,000 IU/L. The patient had no history of hepatic disease, and a hepatitis panel obtained in the ED was unremarkable.

Can this be drug-induced liver injury?

Drug-induced liver injury (DILI) accounts for nearly 50% of cases of acute liver failure in the United States.¹ According to the National Institutes of Health database of drugs, supplements, and herbal medications acetaminophen is the most common drug associated with hepatotoxicity in the United States, whereas amoxicillin-clavulanate is the most common implicated drug worldwide.^1,2 The histological pattern of DILI varies by drug (Table).³

Who is susceptible to drug-induced liver injury?

The factors that help predict DILI include drug pharmacokinetics and metabolism, as well as patient age, sex, and comorbidities. Although some patients are at an increased risk of DILI, it is extraordinarily difficult to accurately predict which patients will develop it. In general, there is a positive correlation between age and risk of developing DILI. For example, in a large US-based tuberculosis study, the incidence of isoniazid (INH)-induced hepatotoxicity was 4.4 per 1,000 patients aged 25 to 34 years. Patients older than age 50 years had a 20.83 per 1,000 incidence of DILI, and women also appear to be at increased risk.⁴

Pharmacogenetic factors affecting drug metabolism such as the specific cytochrome profile and acetylator status of an individual also influence a patient’s risk of developing DILI. Although our understanding of these issues is growing rapidly, our ability to apply this knowledge to the clinical venue is limited by the available technology, regulatory requirements, and cost.

Case Continuation

A detailed, careful history-taking in the ED revealed that, 2 months prior, the patient had been started on INH, rifampin, and pyridoxine for latent tuberculosis. She had been taking methotrexate for the RA but discontinued it 3 months ago because of the positive PPD. When routine outpatient laboratory testing results demonstrated significant hepatic dysfunction, the patient’s PCP advised her to immediately discontinue her medications and referred her to the ED for further evaluation and management.

By what mechanism does INH cause DILI?

Acute INH-associated hepatitis primarily results from the direct hepatotoxic effects of INH metabolites. Isoniazid is metabolized in the liver via N-acetylation to acetylisoniazid (Figure). Oxidation of this compound in the liver leads to an accumulation of the hepatotoxic metabolites acetylhydrazine and hydrazine.^5,6

Is there a role for N-acetylcysteine in INH hepatotoxicity?

No antidote is specifically designed to treat INH-induced hepatotoxicity, and management is largely supportive. Observation for progressive liver failure is indicated and evaluation for liver transplant may become necessary.

N-acetylcysteine (NAC) has a clear role in preventing hepatotoxicity from acetaminophen overdose through its ability to act as a precursor for the synthesis of glutathione—a compound that protects hepatocytes from oxidative damage. In advanced acetaminophen-toxic patients and those with non-acetaminophen toxicity, NAC has nonspecific effects that promote healing through several mechanisms, including anti-inflammatory effect and enhanced hepatic perfusion. Though there are no studies that specifically evaluate the role of NAC in patients with INH-induced hepatotoxicity, it is commonly and appropriately administered for its aforementioned nonspecific effects.⁸ Common side effects from NAC administration include nausea, vomiting, and diarrhea, which are generally treatable with symptomatic and supportive care.

Case Conclusion

The patient was admitted to the hepatology service for continued clinical care. Although she received NAC, hepatic function testing showed only mild improvement. Additional etiologies of liver failure were investigated, including a computed tomography scan of the abdomen/pelvis and an abdominal ultrasound with Doppler. Both studies were negative for any pathology, and autoimmune laboratory studies were likewise unremarkable.

The patient underwent a liver biopsy, which revealed inflammation and scattered eosinophils suggestive of drug-induced hepatic injury. Her clinical condition continued to deteriorate, and she was transferred to another hospital for transplant evaluation.

Case

A 50-year-old Hispanic woman with a history of rheumatoid arthritis (RA), for which she was not currently taking medication, was referred to the ED by her primary care physician (PCP) for evaluation of generalized pruritus and jaundice, and an abnormal hepatic function panel.

The patient’s recent history was significant for a positive tuberculosis test (purified protein derivative [PPD], 13 mm), for which she had been on prophylactic medication. Laboratory evaluation taken during the patient’s recent follow-up visit with her PCP revealed the following significant hepatic abnormalities: total bilirubin, 20.0 mg/dL; direct bilirubin, 16.4 mg/dL; international normalized ratio, 2.9; aspartate aminotransferase, greater than 2,000 IU/L; and alanine aminotransferase, greater than 2,000 IU/L. The patient had no history of hepatic disease, and a hepatitis panel obtained in the ED was unremarkable.

Can this be drug-induced liver injury?

Drug-induced liver injury (DILI) accounts for nearly 50% of cases of acute liver failure in the United States.¹ According to the National Institutes of Health database of drugs, supplements, and herbal medications acetaminophen is the most common drug associated with hepatotoxicity in the United States, whereas amoxicillin-clavulanate is the most common implicated drug worldwide.^1,2 The histological pattern of DILI varies by drug (Table).³

Who is susceptible to drug-induced liver injury?

The factors that help predict DILI include drug pharmacokinetics and metabolism, as well as patient age, sex, and comorbidities. Although some patients are at an increased risk of DILI, it is extraordinarily difficult to accurately predict which patients will develop it. In general, there is a positive correlation between age and risk of developing DILI. For example, in a large US-based tuberculosis study, the incidence of isoniazid (INH)-induced hepatotoxicity was 4.4 per 1,000 patients aged 25 to 34 years. Patients older than age 50 years had a 20.83 per 1,000 incidence of DILI, and women also appear to be at increased risk.⁴

Pharmacogenetic factors affecting drug metabolism such as the specific cytochrome profile and acetylator status of an individual also influence a patient’s risk of developing DILI. Although our understanding of these issues is growing rapidly, our ability to apply this knowledge to the clinical venue is limited by the available technology, regulatory requirements, and cost.

Case Continuation

A detailed, careful history-taking in the ED revealed that, 2 months prior, the patient had been started on INH, rifampin, and pyridoxine for latent tuberculosis. She had been taking methotrexate for the RA but discontinued it 3 months ago because of the positive PPD. When routine outpatient laboratory testing results demonstrated significant hepatic dysfunction, the patient’s PCP advised her to immediately discontinue her medications and referred her to the ED for further evaluation and management.

By what mechanism does INH cause DILI?

Acute INH-associated hepatitis primarily results from the direct hepatotoxic effects of INH metabolites. Isoniazid is metabolized in the liver via N-acetylation to acetylisoniazid (Figure). Oxidation of this compound in the liver leads to an accumulation of the hepatotoxic metabolites acetylhydrazine and hydrazine.^5,6

Is there a role for N-acetylcysteine in INH hepatotoxicity?

No antidote is specifically designed to treat INH-induced hepatotoxicity, and management is largely supportive. Observation for progressive liver failure is indicated and evaluation for liver transplant may become necessary.

N-acetylcysteine (NAC) has a clear role in preventing hepatotoxicity from acetaminophen overdose through its ability to act as a precursor for the synthesis of glutathione—a compound that protects hepatocytes from oxidative damage. In advanced acetaminophen-toxic patients and those with non-acetaminophen toxicity, NAC has nonspecific effects that promote healing through several mechanisms, including anti-inflammatory effect and enhanced hepatic perfusion. Though there are no studies that specifically evaluate the role of NAC in patients with INH-induced hepatotoxicity, it is commonly and appropriately administered for its aforementioned nonspecific effects.⁸ Common side effects from NAC administration include nausea, vomiting, and diarrhea, which are generally treatable with symptomatic and supportive care.

Case Conclusion

The patient was admitted to the hepatology service for continued clinical care. Although she received NAC, hepatic function testing showed only mild improvement. Additional etiologies of liver failure were investigated, including a computed tomography scan of the abdomen/pelvis and an abdominal ultrasound with Doppler. Both studies were negative for any pathology, and autoimmune laboratory studies were likewise unremarkable.

The patient underwent a liver biopsy, which revealed inflammation and scattered eosinophils suggestive of drug-induced hepatic injury. Her clinical condition continued to deteriorate, and she was transferred to another hospital for transplant evaluation.

Case

A 50-year-old Hispanic woman with a history of rheumatoid arthritis (RA), for which she was not currently taking medication, was referred to the ED by her primary care physician (PCP) for evaluation of generalized pruritus and jaundice, and an abnormal hepatic function panel.

The patient’s recent history was significant for a positive tuberculosis test (purified protein derivative [PPD], 13 mm), for which she had been on prophylactic medication. Laboratory evaluation taken during the patient’s recent follow-up visit with her PCP revealed the following significant hepatic abnormalities: total bilirubin, 20.0 mg/dL; direct bilirubin, 16.4 mg/dL; international normalized ratio, 2.9; aspartate aminotransferase, greater than 2,000 IU/L; and alanine aminotransferase, greater than 2,000 IU/L. The patient had no history of hepatic disease, and a hepatitis panel obtained in the ED was unremarkable.

Can this be drug-induced liver injury?

Drug-induced liver injury (DILI) accounts for nearly 50% of cases of acute liver failure in the United States.¹ According to the National Institutes of Health database of drugs, supplements, and herbal medications acetaminophen is the most common drug associated with hepatotoxicity in the United States, whereas amoxicillin-clavulanate is the most common implicated drug worldwide.^1,2 The histological pattern of DILI varies by drug (Table).³

Who is susceptible to drug-induced liver injury?

The factors that help predict DILI include drug pharmacokinetics and metabolism, as well as patient age, sex, and comorbidities. Although some patients are at an increased risk of DILI, it is extraordinarily difficult to accurately predict which patients will develop it. In general, there is a positive correlation between age and risk of developing DILI. For example, in a large US-based tuberculosis study, the incidence of isoniazid (INH)-induced hepatotoxicity was 4.4 per 1,000 patients aged 25 to 34 years. Patients older than age 50 years had a 20.83 per 1,000 incidence of DILI, and women also appear to be at increased risk.⁴

Pharmacogenetic factors affecting drug metabolism such as the specific cytochrome profile and acetylator status of an individual also influence a patient’s risk of developing DILI. Although our understanding of these issues is growing rapidly, our ability to apply this knowledge to the clinical venue is limited by the available technology, regulatory requirements, and cost.

Case Continuation

A detailed, careful history-taking in the ED revealed that, 2 months prior, the patient had been started on INH, rifampin, and pyridoxine for latent tuberculosis. She had been taking methotrexate for the RA but discontinued it 3 months ago because of the positive PPD. When routine outpatient laboratory testing results demonstrated significant hepatic dysfunction, the patient’s PCP advised her to immediately discontinue her medications and referred her to the ED for further evaluation and management.

By what mechanism does INH cause DILI?

Acute INH-associated hepatitis primarily results from the direct hepatotoxic effects of INH metabolites. Isoniazid is metabolized in the liver via N-acetylation to acetylisoniazid (Figure). Oxidation of this compound in the liver leads to an accumulation of the hepatotoxic metabolites acetylhydrazine and hydrazine.^5,6

Is there a role for N-acetylcysteine in INH hepatotoxicity?

No antidote is specifically designed to treat INH-induced hepatotoxicity, and management is largely supportive. Observation for progressive liver failure is indicated and evaluation for liver transplant may become necessary.

N-acetylcysteine (NAC) has a clear role in preventing hepatotoxicity from acetaminophen overdose through its ability to act as a precursor for the synthesis of glutathione—a compound that protects hepatocytes from oxidative damage. In advanced acetaminophen-toxic patients and those with non-acetaminophen toxicity, NAC has nonspecific effects that promote healing through several mechanisms, including anti-inflammatory effect and enhanced hepatic perfusion. Though there are no studies that specifically evaluate the role of NAC in patients with INH-induced hepatotoxicity, it is commonly and appropriately administered for its aforementioned nonspecific effects.⁸ Common side effects from NAC administration include nausea, vomiting, and diarrhea, which are generally treatable with symptomatic and supportive care.

Case Conclusion

The patient was admitted to the hepatology service for continued clinical care. Although she received NAC, hepatic function testing showed only mild improvement. Additional etiologies of liver failure were investigated, including a computed tomography scan of the abdomen/pelvis and an abdominal ultrasound with Doppler. Both studies were negative for any pathology, and autoimmune laboratory studies were likewise unremarkable.

The patient underwent a liver biopsy, which revealed inflammation and scattered eosinophils suggestive of drug-induced hepatic injury. Her clinical condition continued to deteriorate, and she was transferred to another hospital for transplant evaluation.

ANSWER

The radiograph shows two fractures: one within the distal ulna and one within the fifth metacarpal. On closer examination, you can see that a bony callous surrounds each of the fracture lines, making these injuries more likely to be subacute or remote than acute.

Review of the patient's electronic health record showed he had presented three months earlier for a left hand and wrist injury, at which time an acute fracture was diagnosed. Nonetheless, he was placed in a splint and referred to orthopedics for outpatient follow-up.

ANSWER

The radiograph shows two fractures: one within the distal ulna and one within the fifth metacarpal. On closer examination, you can see that a bony callous surrounds each of the fracture lines, making these injuries more likely to be subacute or remote than acute.

Review of the patient's electronic health record showed he had presented three months earlier for a left hand and wrist injury, at which time an acute fracture was diagnosed. Nonetheless, he was placed in a splint and referred to orthopedics for outpatient follow-up.

ANSWER

The radiograph shows two fractures: one within the distal ulna and one within the fifth metacarpal. On closer examination, you can see that a bony callous surrounds each of the fracture lines, making these injuries more likely to be subacute or remote than acute.

Review of the patient's electronic health record showed he had presented three months earlier for a left hand and wrist injury, at which time an acute fracture was diagnosed. Nonetheless, he was placed in a splint and referred to orthopedics for outpatient follow-up.

From Tampa General Hospital, Tampa, FL.

Abstract

• Objective: To decrease insertion-related catheter-associated urinary tract infections (CAUTIs) attributed to the emergency department (ED) as well as facility-wide within a large teaching hospital.
• Methods: Recommendations from the Agency for Healthcare Research and Quality (AHRQ) toolkit for reducing CAUTIs in hospital units were used to implement both technical and socioadaptive changes focused on prevention of insertion-related CAUTIs in the ED through a trial that required 2 licensed personnel for insertion of all urinary catheters. The process would include a safety time-out to confirm catheter appropriateness and review of the proper steps for insertion as a means to encompass and hardwire both the technical and socioadaptive aspects of the Comprehensive Unit-based Safety Project methodology into ED practice.
• Results: There was a 75% decrease in CAUTI rates following the intervention (P = 0.05). This reduction was sustained for at least 1 year following implementation.
• Conclusion: Using AHRQ recommendations to implement socioadaptive and technical changes through 2-person insertion of urinary catheters yielded a significant and sustainable decrease in insertion-related CAUTI rates and utilization of indwelling urinary catheters in the ED at Tampa General Hospital.

Key words: catheter-associated urinary tract infections; infection prevention; quality improvement; change model.

Each year an estimated 721,800 health care–associated infections occur in U.S. acute care hospitals, resulting in approximately 75,000 deaths [1]. Catheter-associated urinary tract infections (CAUTIs) account for an estimated 449,334 of health care–associated infections s annually [2]. The direct medical cost per CAUTI ranges from $749 to $1007, resulting in direct costs to U.S. facilities of over $340 million annually [2]. Although CAUTIs are one of the most common health care–associated infections, the literature has shown that following well established prevention guidelines can greatly reduce their incidence.

Since most health care–associated infections are preventable and cause unnecessary patient harm, there is pressure from regulatory bodies to prevent such events during a patient’s hospitalization. Prevention of CAUTIs is a Joint Commission National Patient Safety Goal, and as of 2008 the Centers for Medicare and Medicaid Services (CMS) does not reimburse hospitals for the cost of additional care as a result of a CAUTI. Additionally, facility CAUTI data is included in the CMS value-based purchasing program, which can withhold payments to hospitals based on performance, as well as the inpatient quality reporting program, which requires public reporting of CAUTI to receive a higher annual payment.

Even before the external pressures of regulatory bodies, Tampa General Hospital has strived to protect patients by preventing infections through implementing best practices via multidisciplinary committees to maximize impact. Tampa General Hospital, a private not-for-profit level 1 trauma center located in downtown Tampa, Florida, is a teaching facility affiliated with the University of South Florida Morsani College of Medicine. It is licensed for more than 1000 beds and serves 12 surrounding counties with a population in excess of 4 million.

Background

CAUTI data had been collected in all of the intensive care units at the hospital for several years, benchmarked against national unit-specific rates, with feedback provided to committees and the hospital board. However, in 2006, a multidisciplinary committee chaired by the chief operating officer known as Committee Targeting Zero (CTZ) was formed to review best practices and analyze all device-associated infection rates in an effort to reduce hospital-acquired infections. To target reduction of the CAUTI rate, a Foley stabilization device and renewed focus on hand hygiene were implemented, and CAUTI rates were reduced by over 50% by the end of 2007.

When CAUTI rates began to climb in 2008, additional interventions were implemented under the direction of CTZ, including a literature review for CAUTI prevention for any new or novel prevention strategies, reporting of each CAUTI to leadership of the attributed unit at the time of identification, ongoing surveillance of the appropriateness of indwelling urinary catheters at the unit level with feedback to CTZ, and mandatory education focused on infection of CAUTI and proper insertion for all staff inserting indwelling urinary catheters. Additionally, in 2009 an evaluation of an antibiotic-coated Foley catheter was implemented to further decrease rates, resulting in a statistically significant 42% reduction in the CAUTI rate as compared to 2008. Other prevention strategies instituted between 2010 and 2012 included increased availability of condom catheters, a closed system urine culture collection kit, and computer-based learning module for all staff inserting indwelling urinary catheters.

In 2013, the hospital included CAUTI prevention as part of a facility-wide initiative to decrease patient harm. A CAUTI committee led by senior leadership was convened to address CAUTI rates that exceeded national benchmarks. The multidisciplinary team began as a subcommittee of CTZ and was chaired by the chief nursing officer with the support of the chief operations officer and included representation from the infection prevention department and nursing unit leadership. After reviewing the Healthcare Infection Control Practices Advisory Committee’s (HICPAC) guideline for prevention of CAUTIs [3], the committee focused its efforts on appropriate indications for insertion and timely removal, aseptic insertion, and proper maintenance of indwelling urinary catheters.

The key accomplishments of the CAUTI committee during 2014 included development of a comprehensive genitourinary management policy, incorporation of CAUTI prevention into new employee orientation for all patient care staff, aseptic indwelling urinary catheter insertion competency check-off with return demonstration (teachback methodology) for all nursing staff, and reinforcement of insertion criteria and daily assessment for necessity with documentation of indications, and removal via nurse-driven protocol when necessary. Additionally, a requirement to document indications for ordering urine cultures and a pop-up reminder in the electronic medical record for patients with an indwelling urinary catheter requiring indications to continue, both targeted towards physicians and advanced practice providers, were implemented.

In conjunction with the technical changes, additional strategies were executed with the intent of facilitating a culture of patient safety and reinforcing the aforementioned technical changes. In 2014, the hospital implemented Franklin Covey’s “The Speed of Trust” methodology [4] and its associated 13 behaviors hospital-wide. Additionally, several of the inpatient units participated in a quality improvement project with either the Florida Hospital Engagement Network (HEN) [5] or the Agency for Healthcare Research and Quality (AHRQ) Comprehensive Unit-based Safety Program (CUSP) [6] national project. Physician engagement and education was accomplished through a white paper written by the infection prevention department, summarizing the current state of CAUTI within the facility and highlighting strategies to reduce infection, including evidence-based guidelines on ordering urine cultures.

In an attempt to target ongoing improvement strategies, CAUTIs were categorized as either insertion-related, occurring within 7 days of insertion, or maintenance-related, occurring greater than 7 days of insertion; the date of insertion was considered day 1. A review of the facility CAUTI data demonstrated that an opportunity to reduce insertion-related CAUTIs existed and a high volume of urinary catheters were inserted in the emergency department (ED). Therefore, ED leadership agreed to participate in the CUSP initiative for EDs beginning April 2014. The goals of the CUSP initiative include using best practices for CAUTI prevention through the implementation of both technical and socioadaptive changes.

Methods

CUSP Initiative

The CUSP initiative focuses specifically on improving processes for determining catheter appropriateness and promoting proper insertion techniques in addition to changes in culture to facilitate teamwork and communication amongst frontline staff and improve collaboration between the ED and inpatient units. To participate in the project, a multidisciplinary team that included ED leadership, infection prevention department, and nursing clinical quality and research specialists was established.

The team designed an intervention that required 2 licensed personnel for insertion of all urinary catheters. The process would include a safety time-out consisting of a pause before inserting the indwelling urinary catheter to confirm catheter appropriateness and review of the proper steps for insertion as a means to encompass and hardwire both the technical and socioadaptive aspects of the CUSP methodology into ED practice.

Rollout Using 4Es

January through March 2015 was the implementation period during which education and validation of practices were conducted. The 4Es model created by the Johns Hopkins University Quality and Safety Research Group was used to roll out the changes in practice to the ED staff; the 4Es are Engagement, Education, Execution, and Evaluation [7]. To engage staff, the scope of CAUTIs, including the implications to both patients and to the health care system as a whole, were presented from a local (hospital) and a national perspective. Education was achieved by outlining the new process in ED staff education sessions, as well as through handouts, emails, and during shift change huddles. The content included a checklist (Figure 1) staff would use to follow proper aseptic technique as well as reminders of the intent of the project.

The process was executed through the use of a safety time-out completed by the 2 personnel (nurses) involved in the procedure prior to insertion of an indwelling urinary catheter. The time-out consisted of reviewing the insertion criteria to determine appropriateness for placement and the proper steps for insertion per hospital policy. The catheter was then inserted by one person while the second was solely responsible to assure compliance with proper aseptic technique. The procedure was stopped if aseptic technique was compromised. The indications for insertion and/or maintaining the urinary catheter are based on the HICPAC guidelines [3] and include the following:

• Acute urinary retention/obstruction
• Urologic, urethral or extensive abdominal surgical procedure
• Critically ill patient with unstable vital signs and requires close urine output monitoring (ICU patient receiving aggressive diuretic therapy, vasopressor/inotropic therapy, paralytic therapy, aggressive fluid management or titrated vasoactive medications)
• Stage 3 or 4 sacral or perineal pressure ulcer in a patient with incontinence
• End of life comfort
• Prevention of further trauma due to a difficult insertion
• Prolonged immobility due to unstable spinal fracture or pelvic fracture and inability to use bedpan.

During the implementation period, a process measure was used to evaluate the rollout. The compliance rate of returned insertion checklists versus the total number of insertions was calculated weekly and tracked over time. Although compliance was low at first, through several Plan-Do-Study-Act (PDSA) cycles conducted on a weekly basis, compliance steadily increased during the implementation period. Staff were also kept abreast of the compliance rates and progress of the project with weekly email updates and periodically in daily huddles during shift change.

Rollout Using 4Es

In parallel to the CUSP framework, the ED leadership team discretely used 6 of “The Speed of Trust” behaviors most relevant to the project to help drive the new process including get better, practice accountability, keep commitments, clarify expectations, deliver results, and create transparency. Get better was used to motivate staff to action in order to deliver the highest quality of care to our patients. Practice accountability was exercised by having the staff sign the checklist used in the new process. Deliver results was supported by the timely feedback of data to frontline staff to show whether the goal was being met. Clarifying expectations was demonstrated through feedback from weekly PDSA rapid cycles and constant reinforcement that all insertions must involve 2 personnel. Keeping commitments was established with an agreement amongst the staff and leadership to keep patients safe and deliver high quality care. Creating transparency was exemplified by explaining the initiative clearly to each patient and their family and allowing for any questions.

Outcomes Measurement

During the post-intervention period, progress was evaluated using 2 outcome measures: the insertion-related CAUTI rate and the catheter utilization ratio. National Healthcare Safety Network (NHSN) 2014 and 2015 criteria was used to identify any CAUTI [8] and for the purposes of this project, the insertion-related CAUTI rate was defined as the number of CAUTIs occurring ≤ 7 days after insertion, with the date of insertion being day 1, per 1000 catheters inserted in the ED. The utilization ratio was calculated from the number of catheters inserted per patient ED visits. The insertion-related CAUTI rates for the pre- and post-intervention periods were compared after excluding 2014 yeast CAUTIs to adjust for changes in the 2015 National Healthcare Safety Network CAUTI criteria, which removed yeast as an organism for CAUTI. The utilization ratio was also calculated and compared between pre- and post-intervention periods. All statistical analysis was done using the NHSN statistics calculator.

Results

During the pre-intervention period (April–December 2014) there were 10 infections and 1450 catheters inserted, which equates to an insertion-related CAUTI rate of 6.9/1,000 catheters. In the post-intervention period (April–December 2015), there were 2 infections and 1180 catheters placed, or an insertion-related CAUTI rate of 1.7/1000 catheters (Table 1)—a 75% decrease from the pre-intervention rate (P = 0.05).

Additionally, the utilization ratio was calculated for 2014 and 2015 based on the number of catheter insertions per total patient ED visits in each year (Table 2). In 2014 the utilization ratio was 2.2 and in 2015 the utilization ratio was 1.7, representing a 23% reduction (P < 0.01).

Discussion

As highlighted in the AHRQ toolkit [5], the project confirmed that using both technical and socioadaptive methodologies yielded a significant and sustainable impact on CAUTIs and utilization of indwelling urinary catheters. Prior to initiating the project, a review of the literature did not show any previous studies involving the insertion of urinary catheters by 2 licensed personnel. Since then, an acute care facility published data demonstrating a sustainable 39% reduction of CAUTI rates in an inpatient post-surgical unit within 6 months after the implementation of 2-person urinary catheter insertion [9]. The facility had also done extensive education and training on the CAUTI prevention best-practices prior to implementing the new insertion practices.

A key measure of success in regards to implementing cultural and technical changes is the sustainability of the results yielded after implementation. According to the AHRQ CAUTI toolkit, several specific strategies are necessary to successfully sustain prevention efforts. Implementing changes in the ED at our hospital in alignment with the goal of creating a culture of safety, incorporating the changes into daily work flow, employing both technical and socioadaptive interventions, empowering staff to stop the procedure if there are any concerns, and monitoring and communicating outcomes all ensure that the changes in practice will be sustained. Additionally, there is an engaged interdisciplinary CAUTI committee that continues to meet regularly as well as required yearly computer-based education for all frontline staff, and a “Safety Day” education session for all newly hired nurses where competency is assessed and validated for proper insertion and maintenance of a urinary catheter.

Initially, barriers for implementation included limited staff to ensure the presence of 2 licensed personnel for every urinary catheter insertion, lack of ability to collect checklist data in the electronic medical record and run compliance reports, and availability of the checklists at the onset of implementation. The staffing limitation seemed to work in favor of meeting the goals of the project, as staff were less likely to insert indwelling urinary catheters for inappropriate indications. In regards to the checklists, the barriers identified via the PDSA rapid cycles included inadequate locations to obtain checklists for use during insertion and drop-off locations for checklists after use. To increase availability and convenience, brightly colored folders labeled “FOLEY!” containing the checklists were placed both on the outside of the supply management stations and on the doors exiting the supply rooms where indwelling urinary catheter kits were located. Rounds were made on these folders approximately 1 to 2 times per week to be sure they remained full. In addition, more locations for dropping off completed forms were placed at all nursing stations as opposed to a single drop off location.

A limitation of the project is that there are not established metrics for infection rates in any outpatient setting nor are there established criteria to differentiate between insertion- and maintenance-related infections. While the metrics were created for the purposes of the project, they are easily reproducible within other health care facilities to track infection rates associated with outpatient areas. Additionally, by ensuring indications are met and proper insertion occurs in ED patients, the overall hospital’s CAUTI infection rate and standardized infection ratio are impacted, which are comparable across facilities. The criteria for differentiating between insertion and maintenance related infections was established in an attempt to define where the biggest vulnerabilities were with insertion versus maintenance. Days from insertion to infection were tracked for all infections, and arbitrarily a 7-day cutoff was used to consider the infection potentially insertion-related, as no evidence has been published to define this previously.

The lessons learned both during implementation of the changes in practice and the impact it can have on infection rates are valuable. Moving forward, Tampa General Hospital plans to spread dual personnel indwelling urinary catheter insertion as a best practice, first targeting inpatient units identified with the highest number of insertion-related infections as well as high device utilization ratios.

From Tampa General Hospital, Tampa, FL.

Abstract

• Objective: To decrease insertion-related catheter-associated urinary tract infections (CAUTIs) attributed to the emergency department (ED) as well as facility-wide within a large teaching hospital.
• Methods: Recommendations from the Agency for Healthcare Research and Quality (AHRQ) toolkit for reducing CAUTIs in hospital units were used to implement both technical and socioadaptive changes focused on prevention of insertion-related CAUTIs in the ED through a trial that required 2 licensed personnel for insertion of all urinary catheters. The process would include a safety time-out to confirm catheter appropriateness and review of the proper steps for insertion as a means to encompass and hardwire both the technical and socioadaptive aspects of the Comprehensive Unit-based Safety Project methodology into ED practice.
• Results: There was a 75% decrease in CAUTI rates following the intervention (P = 0.05). This reduction was sustained for at least 1 year following implementation.
• Conclusion: Using AHRQ recommendations to implement socioadaptive and technical changes through 2-person insertion of urinary catheters yielded a significant and sustainable decrease in insertion-related CAUTI rates and utilization of indwelling urinary catheters in the ED at Tampa General Hospital.

Key words: catheter-associated urinary tract infections; infection prevention; quality improvement; change model.

Each year an estimated 721,800 health care–associated infections occur in U.S. acute care hospitals, resulting in approximately 75,000 deaths [1]. Catheter-associated urinary tract infections (CAUTIs) account for an estimated 449,334 of health care–associated infections s annually [2]. The direct medical cost per CAUTI ranges from $749 to $1007, resulting in direct costs to U.S. facilities of over $340 million annually [2]. Although CAUTIs are one of the most common health care–associated infections, the literature has shown that following well established prevention guidelines can greatly reduce their incidence.

Since most health care–associated infections are preventable and cause unnecessary patient harm, there is pressure from regulatory bodies to prevent such events during a patient’s hospitalization. Prevention of CAUTIs is a Joint Commission National Patient Safety Goal, and as of 2008 the Centers for Medicare and Medicaid Services (CMS) does not reimburse hospitals for the cost of additional care as a result of a CAUTI. Additionally, facility CAUTI data is included in the CMS value-based purchasing program, which can withhold payments to hospitals based on performance, as well as the inpatient quality reporting program, which requires public reporting of CAUTI to receive a higher annual payment.

Even before the external pressures of regulatory bodies, Tampa General Hospital has strived to protect patients by preventing infections through implementing best practices via multidisciplinary committees to maximize impact. Tampa General Hospital, a private not-for-profit level 1 trauma center located in downtown Tampa, Florida, is a teaching facility affiliated with the University of South Florida Morsani College of Medicine. It is licensed for more than 1000 beds and serves 12 surrounding counties with a population in excess of 4 million.

Background

CAUTI data had been collected in all of the intensive care units at the hospital for several years, benchmarked against national unit-specific rates, with feedback provided to committees and the hospital board. However, in 2006, a multidisciplinary committee chaired by the chief operating officer known as Committee Targeting Zero (CTZ) was formed to review best practices and analyze all device-associated infection rates in an effort to reduce hospital-acquired infections. To target reduction of the CAUTI rate, a Foley stabilization device and renewed focus on hand hygiene were implemented, and CAUTI rates were reduced by over 50% by the end of 2007.

When CAUTI rates began to climb in 2008, additional interventions were implemented under the direction of CTZ, including a literature review for CAUTI prevention for any new or novel prevention strategies, reporting of each CAUTI to leadership of the attributed unit at the time of identification, ongoing surveillance of the appropriateness of indwelling urinary catheters at the unit level with feedback to CTZ, and mandatory education focused on infection of CAUTI and proper insertion for all staff inserting indwelling urinary catheters. Additionally, in 2009 an evaluation of an antibiotic-coated Foley catheter was implemented to further decrease rates, resulting in a statistically significant 42% reduction in the CAUTI rate as compared to 2008. Other prevention strategies instituted between 2010 and 2012 included increased availability of condom catheters, a closed system urine culture collection kit, and computer-based learning module for all staff inserting indwelling urinary catheters.

In 2013, the hospital included CAUTI prevention as part of a facility-wide initiative to decrease patient harm. A CAUTI committee led by senior leadership was convened to address CAUTI rates that exceeded national benchmarks. The multidisciplinary team began as a subcommittee of CTZ and was chaired by the chief nursing officer with the support of the chief operations officer and included representation from the infection prevention department and nursing unit leadership. After reviewing the Healthcare Infection Control Practices Advisory Committee’s (HICPAC) guideline for prevention of CAUTIs [3], the committee focused its efforts on appropriate indications for insertion and timely removal, aseptic insertion, and proper maintenance of indwelling urinary catheters.

The key accomplishments of the CAUTI committee during 2014 included development of a comprehensive genitourinary management policy, incorporation of CAUTI prevention into new employee orientation for all patient care staff, aseptic indwelling urinary catheter insertion competency check-off with return demonstration (teachback methodology) for all nursing staff, and reinforcement of insertion criteria and daily assessment for necessity with documentation of indications, and removal via nurse-driven protocol when necessary. Additionally, a requirement to document indications for ordering urine cultures and a pop-up reminder in the electronic medical record for patients with an indwelling urinary catheter requiring indications to continue, both targeted towards physicians and advanced practice providers, were implemented.

In conjunction with the technical changes, additional strategies were executed with the intent of facilitating a culture of patient safety and reinforcing the aforementioned technical changes. In 2014, the hospital implemented Franklin Covey’s “The Speed of Trust” methodology [4] and its associated 13 behaviors hospital-wide. Additionally, several of the inpatient units participated in a quality improvement project with either the Florida Hospital Engagement Network (HEN) [5] or the Agency for Healthcare Research and Quality (AHRQ) Comprehensive Unit-based Safety Program (CUSP) [6] national project. Physician engagement and education was accomplished through a white paper written by the infection prevention department, summarizing the current state of CAUTI within the facility and highlighting strategies to reduce infection, including evidence-based guidelines on ordering urine cultures.

In an attempt to target ongoing improvement strategies, CAUTIs were categorized as either insertion-related, occurring within 7 days of insertion, or maintenance-related, occurring greater than 7 days of insertion; the date of insertion was considered day 1. A review of the facility CAUTI data demonstrated that an opportunity to reduce insertion-related CAUTIs existed and a high volume of urinary catheters were inserted in the emergency department (ED). Therefore, ED leadership agreed to participate in the CUSP initiative for EDs beginning April 2014. The goals of the CUSP initiative include using best practices for CAUTI prevention through the implementation of both technical and socioadaptive changes.

Methods

CUSP Initiative

The CUSP initiative focuses specifically on improving processes for determining catheter appropriateness and promoting proper insertion techniques in addition to changes in culture to facilitate teamwork and communication amongst frontline staff and improve collaboration between the ED and inpatient units. To participate in the project, a multidisciplinary team that included ED leadership, infection prevention department, and nursing clinical quality and research specialists was established.

The team designed an intervention that required 2 licensed personnel for insertion of all urinary catheters. The process would include a safety time-out consisting of a pause before inserting the indwelling urinary catheter to confirm catheter appropriateness and review of the proper steps for insertion as a means to encompass and hardwire both the technical and socioadaptive aspects of the CUSP methodology into ED practice.

Rollout Using 4Es

January through March 2015 was the implementation period during which education and validation of practices were conducted. The 4Es model created by the Johns Hopkins University Quality and Safety Research Group was used to roll out the changes in practice to the ED staff; the 4Es are Engagement, Education, Execution, and Evaluation [7]. To engage staff, the scope of CAUTIs, including the implications to both patients and to the health care system as a whole, were presented from a local (hospital) and a national perspective. Education was achieved by outlining the new process in ED staff education sessions, as well as through handouts, emails, and during shift change huddles. The content included a checklist (Figure 1) staff would use to follow proper aseptic technique as well as reminders of the intent of the project.

The process was executed through the use of a safety time-out completed by the 2 personnel (nurses) involved in the procedure prior to insertion of an indwelling urinary catheter. The time-out consisted of reviewing the insertion criteria to determine appropriateness for placement and the proper steps for insertion per hospital policy. The catheter was then inserted by one person while the second was solely responsible to assure compliance with proper aseptic technique. The procedure was stopped if aseptic technique was compromised. The indications for insertion and/or maintaining the urinary catheter are based on the HICPAC guidelines [3] and include the following:

• Acute urinary retention/obstruction
• Urologic, urethral or extensive abdominal surgical procedure
• Critically ill patient with unstable vital signs and requires close urine output monitoring (ICU patient receiving aggressive diuretic therapy, vasopressor/inotropic therapy, paralytic therapy, aggressive fluid management or titrated vasoactive medications)
• Stage 3 or 4 sacral or perineal pressure ulcer in a patient with incontinence
• End of life comfort
• Prevention of further trauma due to a difficult insertion
• Prolonged immobility due to unstable spinal fracture or pelvic fracture and inability to use bedpan.

During the implementation period, a process measure was used to evaluate the rollout. The compliance rate of returned insertion checklists versus the total number of insertions was calculated weekly and tracked over time. Although compliance was low at first, through several Plan-Do-Study-Act (PDSA) cycles conducted on a weekly basis, compliance steadily increased during the implementation period. Staff were also kept abreast of the compliance rates and progress of the project with weekly email updates and periodically in daily huddles during shift change.

Rollout Using 4Es

In parallel to the CUSP framework, the ED leadership team discretely used 6 of “The Speed of Trust” behaviors most relevant to the project to help drive the new process including get better, practice accountability, keep commitments, clarify expectations, deliver results, and create transparency. Get better was used to motivate staff to action in order to deliver the highest quality of care to our patients. Practice accountability was exercised by having the staff sign the checklist used in the new process. Deliver results was supported by the timely feedback of data to frontline staff to show whether the goal was being met. Clarifying expectations was demonstrated through feedback from weekly PDSA rapid cycles and constant reinforcement that all insertions must involve 2 personnel. Keeping commitments was established with an agreement amongst the staff and leadership to keep patients safe and deliver high quality care. Creating transparency was exemplified by explaining the initiative clearly to each patient and their family and allowing for any questions.

Outcomes Measurement

During the post-intervention period, progress was evaluated using 2 outcome measures: the insertion-related CAUTI rate and the catheter utilization ratio. National Healthcare Safety Network (NHSN) 2014 and 2015 criteria was used to identify any CAUTI [8] and for the purposes of this project, the insertion-related CAUTI rate was defined as the number of CAUTIs occurring ≤ 7 days after insertion, with the date of insertion being day 1, per 1000 catheters inserted in the ED. The utilization ratio was calculated from the number of catheters inserted per patient ED visits. The insertion-related CAUTI rates for the pre- and post-intervention periods were compared after excluding 2014 yeast CAUTIs to adjust for changes in the 2015 National Healthcare Safety Network CAUTI criteria, which removed yeast as an organism for CAUTI. The utilization ratio was also calculated and compared between pre- and post-intervention periods. All statistical analysis was done using the NHSN statistics calculator.

Results

During the pre-intervention period (April–December 2014) there were 10 infections and 1450 catheters inserted, which equates to an insertion-related CAUTI rate of 6.9/1,000 catheters. In the post-intervention period (April–December 2015), there were 2 infections and 1180 catheters placed, or an insertion-related CAUTI rate of 1.7/1000 catheters (Table 1)—a 75% decrease from the pre-intervention rate (P = 0.05).

Additionally, the utilization ratio was calculated for 2014 and 2015 based on the number of catheter insertions per total patient ED visits in each year (Table 2). In 2014 the utilization ratio was 2.2 and in 2015 the utilization ratio was 1.7, representing a 23% reduction (P < 0.01).

Discussion

As highlighted in the AHRQ toolkit [5], the project confirmed that using both technical and socioadaptive methodologies yielded a significant and sustainable impact on CAUTIs and utilization of indwelling urinary catheters. Prior to initiating the project, a review of the literature did not show any previous studies involving the insertion of urinary catheters by 2 licensed personnel. Since then, an acute care facility published data demonstrating a sustainable 39% reduction of CAUTI rates in an inpatient post-surgical unit within 6 months after the implementation of 2-person urinary catheter insertion [9]. The facility had also done extensive education and training on the CAUTI prevention best-practices prior to implementing the new insertion practices.

A key measure of success in regards to implementing cultural and technical changes is the sustainability of the results yielded after implementation. According to the AHRQ CAUTI toolkit, several specific strategies are necessary to successfully sustain prevention efforts. Implementing changes in the ED at our hospital in alignment with the goal of creating a culture of safety, incorporating the changes into daily work flow, employing both technical and socioadaptive interventions, empowering staff to stop the procedure if there are any concerns, and monitoring and communicating outcomes all ensure that the changes in practice will be sustained. Additionally, there is an engaged interdisciplinary CAUTI committee that continues to meet regularly as well as required yearly computer-based education for all frontline staff, and a “Safety Day” education session for all newly hired nurses where competency is assessed and validated for proper insertion and maintenance of a urinary catheter.

Initially, barriers for implementation included limited staff to ensure the presence of 2 licensed personnel for every urinary catheter insertion, lack of ability to collect checklist data in the electronic medical record and run compliance reports, and availability of the checklists at the onset of implementation. The staffing limitation seemed to work in favor of meeting the goals of the project, as staff were less likely to insert indwelling urinary catheters for inappropriate indications. In regards to the checklists, the barriers identified via the PDSA rapid cycles included inadequate locations to obtain checklists for use during insertion and drop-off locations for checklists after use. To increase availability and convenience, brightly colored folders labeled “FOLEY!” containing the checklists were placed both on the outside of the supply management stations and on the doors exiting the supply rooms where indwelling urinary catheter kits were located. Rounds were made on these folders approximately 1 to 2 times per week to be sure they remained full. In addition, more locations for dropping off completed forms were placed at all nursing stations as opposed to a single drop off location.

A limitation of the project is that there are not established metrics for infection rates in any outpatient setting nor are there established criteria to differentiate between insertion- and maintenance-related infections. While the metrics were created for the purposes of the project, they are easily reproducible within other health care facilities to track infection rates associated with outpatient areas. Additionally, by ensuring indications are met and proper insertion occurs in ED patients, the overall hospital’s CAUTI infection rate and standardized infection ratio are impacted, which are comparable across facilities. The criteria for differentiating between insertion and maintenance related infections was established in an attempt to define where the biggest vulnerabilities were with insertion versus maintenance. Days from insertion to infection were tracked for all infections, and arbitrarily a 7-day cutoff was used to consider the infection potentially insertion-related, as no evidence has been published to define this previously.

The lessons learned both during implementation of the changes in practice and the impact it can have on infection rates are valuable. Moving forward, Tampa General Hospital plans to spread dual personnel indwelling urinary catheter insertion as a best practice, first targeting inpatient units identified with the highest number of insertion-related infections as well as high device utilization ratios.

From Tampa General Hospital, Tampa, FL.

Abstract

• Objective: To decrease insertion-related catheter-associated urinary tract infections (CAUTIs) attributed to the emergency department (ED) as well as facility-wide within a large teaching hospital.
• Methods: Recommendations from the Agency for Healthcare Research and Quality (AHRQ) toolkit for reducing CAUTIs in hospital units were used to implement both technical and socioadaptive changes focused on prevention of insertion-related CAUTIs in the ED through a trial that required 2 licensed personnel for insertion of all urinary catheters. The process would include a safety time-out to confirm catheter appropriateness and review of the proper steps for insertion as a means to encompass and hardwire both the technical and socioadaptive aspects of the Comprehensive Unit-based Safety Project methodology into ED practice.
• Results: There was a 75% decrease in CAUTI rates following the intervention (P = 0.05). This reduction was sustained for at least 1 year following implementation.
• Conclusion: Using AHRQ recommendations to implement socioadaptive and technical changes through 2-person insertion of urinary catheters yielded a significant and sustainable decrease in insertion-related CAUTI rates and utilization of indwelling urinary catheters in the ED at Tampa General Hospital.

Key words: catheter-associated urinary tract infections; infection prevention; quality improvement; change model.

Each year an estimated 721,800 health care–associated infections occur in U.S. acute care hospitals, resulting in approximately 75,000 deaths [1]. Catheter-associated urinary tract infections (CAUTIs) account for an estimated 449,334 of health care–associated infections s annually [2]. The direct medical cost per CAUTI ranges from $749 to $1007, resulting in direct costs to U.S. facilities of over $340 million annually [2]. Although CAUTIs are one of the most common health care–associated infections, the literature has shown that following well established prevention guidelines can greatly reduce their incidence.

Since most health care–associated infections are preventable and cause unnecessary patient harm, there is pressure from regulatory bodies to prevent such events during a patient’s hospitalization. Prevention of CAUTIs is a Joint Commission National Patient Safety Goal, and as of 2008 the Centers for Medicare and Medicaid Services (CMS) does not reimburse hospitals for the cost of additional care as a result of a CAUTI. Additionally, facility CAUTI data is included in the CMS value-based purchasing program, which can withhold payments to hospitals based on performance, as well as the inpatient quality reporting program, which requires public reporting of CAUTI to receive a higher annual payment.

Even before the external pressures of regulatory bodies, Tampa General Hospital has strived to protect patients by preventing infections through implementing best practices via multidisciplinary committees to maximize impact. Tampa General Hospital, a private not-for-profit level 1 trauma center located in downtown Tampa, Florida, is a teaching facility affiliated with the University of South Florida Morsani College of Medicine. It is licensed for more than 1000 beds and serves 12 surrounding counties with a population in excess of 4 million.

Background

CAUTI data had been collected in all of the intensive care units at the hospital for several years, benchmarked against national unit-specific rates, with feedback provided to committees and the hospital board. However, in 2006, a multidisciplinary committee chaired by the chief operating officer known as Committee Targeting Zero (CTZ) was formed to review best practices and analyze all device-associated infection rates in an effort to reduce hospital-acquired infections. To target reduction of the CAUTI rate, a Foley stabilization device and renewed focus on hand hygiene were implemented, and CAUTI rates were reduced by over 50% by the end of 2007.

When CAUTI rates began to climb in 2008, additional interventions were implemented under the direction of CTZ, including a literature review for CAUTI prevention for any new or novel prevention strategies, reporting of each CAUTI to leadership of the attributed unit at the time of identification, ongoing surveillance of the appropriateness of indwelling urinary catheters at the unit level with feedback to CTZ, and mandatory education focused on infection of CAUTI and proper insertion for all staff inserting indwelling urinary catheters. Additionally, in 2009 an evaluation of an antibiotic-coated Foley catheter was implemented to further decrease rates, resulting in a statistically significant 42% reduction in the CAUTI rate as compared to 2008. Other prevention strategies instituted between 2010 and 2012 included increased availability of condom catheters, a closed system urine culture collection kit, and computer-based learning module for all staff inserting indwelling urinary catheters.

In 2013, the hospital included CAUTI prevention as part of a facility-wide initiative to decrease patient harm. A CAUTI committee led by senior leadership was convened to address CAUTI rates that exceeded national benchmarks. The multidisciplinary team began as a subcommittee of CTZ and was chaired by the chief nursing officer with the support of the chief operations officer and included representation from the infection prevention department and nursing unit leadership. After reviewing the Healthcare Infection Control Practices Advisory Committee’s (HICPAC) guideline for prevention of CAUTIs [3], the committee focused its efforts on appropriate indications for insertion and timely removal, aseptic insertion, and proper maintenance of indwelling urinary catheters.

The key accomplishments of the CAUTI committee during 2014 included development of a comprehensive genitourinary management policy, incorporation of CAUTI prevention into new employee orientation for all patient care staff, aseptic indwelling urinary catheter insertion competency check-off with return demonstration (teachback methodology) for all nursing staff, and reinforcement of insertion criteria and daily assessment for necessity with documentation of indications, and removal via nurse-driven protocol when necessary. Additionally, a requirement to document indications for ordering urine cultures and a pop-up reminder in the electronic medical record for patients with an indwelling urinary catheter requiring indications to continue, both targeted towards physicians and advanced practice providers, were implemented.

In conjunction with the technical changes, additional strategies were executed with the intent of facilitating a culture of patient safety and reinforcing the aforementioned technical changes. In 2014, the hospital implemented Franklin Covey’s “The Speed of Trust” methodology [4] and its associated 13 behaviors hospital-wide. Additionally, several of the inpatient units participated in a quality improvement project with either the Florida Hospital Engagement Network (HEN) [5] or the Agency for Healthcare Research and Quality (AHRQ) Comprehensive Unit-based Safety Program (CUSP) [6] national project. Physician engagement and education was accomplished through a white paper written by the infection prevention department, summarizing the current state of CAUTI within the facility and highlighting strategies to reduce infection, including evidence-based guidelines on ordering urine cultures.

In an attempt to target ongoing improvement strategies, CAUTIs were categorized as either insertion-related, occurring within 7 days of insertion, or maintenance-related, occurring greater than 7 days of insertion; the date of insertion was considered day 1. A review of the facility CAUTI data demonstrated that an opportunity to reduce insertion-related CAUTIs existed and a high volume of urinary catheters were inserted in the emergency department (ED). Therefore, ED leadership agreed to participate in the CUSP initiative for EDs beginning April 2014. The goals of the CUSP initiative include using best practices for CAUTI prevention through the implementation of both technical and socioadaptive changes.

Methods

CUSP Initiative

The CUSP initiative focuses specifically on improving processes for determining catheter appropriateness and promoting proper insertion techniques in addition to changes in culture to facilitate teamwork and communication amongst frontline staff and improve collaboration between the ED and inpatient units. To participate in the project, a multidisciplinary team that included ED leadership, infection prevention department, and nursing clinical quality and research specialists was established.

The team designed an intervention that required 2 licensed personnel for insertion of all urinary catheters. The process would include a safety time-out consisting of a pause before inserting the indwelling urinary catheter to confirm catheter appropriateness and review of the proper steps for insertion as a means to encompass and hardwire both the technical and socioadaptive aspects of the CUSP methodology into ED practice.

Rollout Using 4Es

January through March 2015 was the implementation period during which education and validation of practices were conducted. The 4Es model created by the Johns Hopkins University Quality and Safety Research Group was used to roll out the changes in practice to the ED staff; the 4Es are Engagement, Education, Execution, and Evaluation [7]. To engage staff, the scope of CAUTIs, including the implications to both patients and to the health care system as a whole, were presented from a local (hospital) and a national perspective. Education was achieved by outlining the new process in ED staff education sessions, as well as through handouts, emails, and during shift change huddles. The content included a checklist (Figure 1) staff would use to follow proper aseptic technique as well as reminders of the intent of the project.

The process was executed through the use of a safety time-out completed by the 2 personnel (nurses) involved in the procedure prior to insertion of an indwelling urinary catheter. The time-out consisted of reviewing the insertion criteria to determine appropriateness for placement and the proper steps for insertion per hospital policy. The catheter was then inserted by one person while the second was solely responsible to assure compliance with proper aseptic technique. The procedure was stopped if aseptic technique was compromised. The indications for insertion and/or maintaining the urinary catheter are based on the HICPAC guidelines [3] and include the following:

• Acute urinary retention/obstruction
• Urologic, urethral or extensive abdominal surgical procedure
• Critically ill patient with unstable vital signs and requires close urine output monitoring (ICU patient receiving aggressive diuretic therapy, vasopressor/inotropic therapy, paralytic therapy, aggressive fluid management or titrated vasoactive medications)
• Stage 3 or 4 sacral or perineal pressure ulcer in a patient with incontinence
• End of life comfort
• Prevention of further trauma due to a difficult insertion
• Prolonged immobility due to unstable spinal fracture or pelvic fracture and inability to use bedpan.

During the implementation period, a process measure was used to evaluate the rollout. The compliance rate of returned insertion checklists versus the total number of insertions was calculated weekly and tracked over time. Although compliance was low at first, through several Plan-Do-Study-Act (PDSA) cycles conducted on a weekly basis, compliance steadily increased during the implementation period. Staff were also kept abreast of the compliance rates and progress of the project with weekly email updates and periodically in daily huddles during shift change.

Rollout Using 4Es

In parallel to the CUSP framework, the ED leadership team discretely used 6 of “The Speed of Trust” behaviors most relevant to the project to help drive the new process including get better, practice accountability, keep commitments, clarify expectations, deliver results, and create transparency. Get better was used to motivate staff to action in order to deliver the highest quality of care to our patients. Practice accountability was exercised by having the staff sign the checklist used in the new process. Deliver results was supported by the timely feedback of data to frontline staff to show whether the goal was being met. Clarifying expectations was demonstrated through feedback from weekly PDSA rapid cycles and constant reinforcement that all insertions must involve 2 personnel. Keeping commitments was established with an agreement amongst the staff and leadership to keep patients safe and deliver high quality care. Creating transparency was exemplified by explaining the initiative clearly to each patient and their family and allowing for any questions.

Outcomes Measurement

During the post-intervention period, progress was evaluated using 2 outcome measures: the insertion-related CAUTI rate and the catheter utilization ratio. National Healthcare Safety Network (NHSN) 2014 and 2015 criteria was used to identify any CAUTI [8] and for the purposes of this project, the insertion-related CAUTI rate was defined as the number of CAUTIs occurring ≤ 7 days after insertion, with the date of insertion being day 1, per 1000 catheters inserted in the ED. The utilization ratio was calculated from the number of catheters inserted per patient ED visits. The insertion-related CAUTI rates for the pre- and post-intervention periods were compared after excluding 2014 yeast CAUTIs to adjust for changes in the 2015 National Healthcare Safety Network CAUTI criteria, which removed yeast as an organism for CAUTI. The utilization ratio was also calculated and compared between pre- and post-intervention periods. All statistical analysis was done using the NHSN statistics calculator.

Results

During the pre-intervention period (April–December 2014) there were 10 infections and 1450 catheters inserted, which equates to an insertion-related CAUTI rate of 6.9/1,000 catheters. In the post-intervention period (April–December 2015), there were 2 infections and 1180 catheters placed, or an insertion-related CAUTI rate of 1.7/1000 catheters (Table 1)—a 75% decrease from the pre-intervention rate (P = 0.05).

Additionally, the utilization ratio was calculated for 2014 and 2015 based on the number of catheter insertions per total patient ED visits in each year (Table 2). In 2014 the utilization ratio was 2.2 and in 2015 the utilization ratio was 1.7, representing a 23% reduction (P < 0.01).

Discussion

As highlighted in the AHRQ toolkit [5], the project confirmed that using both technical and socioadaptive methodologies yielded a significant and sustainable impact on CAUTIs and utilization of indwelling urinary catheters. Prior to initiating the project, a review of the literature did not show any previous studies involving the insertion of urinary catheters by 2 licensed personnel. Since then, an acute care facility published data demonstrating a sustainable 39% reduction of CAUTI rates in an inpatient post-surgical unit within 6 months after the implementation of 2-person urinary catheter insertion [9]. The facility had also done extensive education and training on the CAUTI prevention best-practices prior to implementing the new insertion practices.

A key measure of success in regards to implementing cultural and technical changes is the sustainability of the results yielded after implementation. According to the AHRQ CAUTI toolkit, several specific strategies are necessary to successfully sustain prevention efforts. Implementing changes in the ED at our hospital in alignment with the goal of creating a culture of safety, incorporating the changes into daily work flow, employing both technical and socioadaptive interventions, empowering staff to stop the procedure if there are any concerns, and monitoring and communicating outcomes all ensure that the changes in practice will be sustained. Additionally, there is an engaged interdisciplinary CAUTI committee that continues to meet regularly as well as required yearly computer-based education for all frontline staff, and a “Safety Day” education session for all newly hired nurses where competency is assessed and validated for proper insertion and maintenance of a urinary catheter.

Initially, barriers for implementation included limited staff to ensure the presence of 2 licensed personnel for every urinary catheter insertion, lack of ability to collect checklist data in the electronic medical record and run compliance reports, and availability of the checklists at the onset of implementation. The staffing limitation seemed to work in favor of meeting the goals of the project, as staff were less likely to insert indwelling urinary catheters for inappropriate indications. In regards to the checklists, the barriers identified via the PDSA rapid cycles included inadequate locations to obtain checklists for use during insertion and drop-off locations for checklists after use. To increase availability and convenience, brightly colored folders labeled “FOLEY!” containing the checklists were placed both on the outside of the supply management stations and on the doors exiting the supply rooms where indwelling urinary catheter kits were located. Rounds were made on these folders approximately 1 to 2 times per week to be sure they remained full. In addition, more locations for dropping off completed forms were placed at all nursing stations as opposed to a single drop off location.

A limitation of the project is that there are not established metrics for infection rates in any outpatient setting nor are there established criteria to differentiate between insertion- and maintenance-related infections. While the metrics were created for the purposes of the project, they are easily reproducible within other health care facilities to track infection rates associated with outpatient areas. Additionally, by ensuring indications are met and proper insertion occurs in ED patients, the overall hospital’s CAUTI infection rate and standardized infection ratio are impacted, which are comparable across facilities. The criteria for differentiating between insertion and maintenance related infections was established in an attempt to define where the biggest vulnerabilities were with insertion versus maintenance. Days from insertion to infection were tracked for all infections, and arbitrarily a 7-day cutoff was used to consider the infection potentially insertion-related, as no evidence has been published to define this previously.

The lessons learned both during implementation of the changes in practice and the impact it can have on infection rates are valuable. Moving forward, Tampa General Hospital plans to spread dual personnel indwelling urinary catheter insertion as a best practice, first targeting inpatient units identified with the highest number of insertion-related infections as well as high device utilization ratios.

Case

A 45-year-old Chinese man with no known medical history presented to the ED with right-sided facial spasm and cheek swelling, which began immediately after he bit into a piece of taro root, approximately 2 hours prior to presentation. The patient stated that the root was an ingredient in a soup that a relative had made. According to the patient, after biting into the root, he immediately experienced a burning pain on the right side of his mouth. He further noted that he swallowed less than two bites of the root and stopped eating because the act of chewing was too painful.

Initial vital signs at presentation were: blood pressure, 140/100 mm Hg; heart rate, 84 beats/min; respiratory rate, 14 beats/min; and temperature, 97.6°F. Oxygen saturation was 98% on room air. The patient’s physical examination was remarkable for pain upon opening the mouth, as well as right-sided cheek and lip swelling and tenderness. The tongue and oropharynx were not erythematous or swollen. The patient was only able to speak in short sentences, secondary to oropharyngeal pain, but he was in no respiratory distress. No urticaria, pruritus, wheezing, or stridor was present.

During the patient’s workup, his 40-year-old wife also presented to the same ED for evaluation of burning pain and spasm on the left side of her mouth, which she stated also developed immediately after she bit into a piece of taro root contained in the same soup as that ingested by the patient.

The wife’s vital signs were unremarkable, and she was in no respiratory distress. Her physical examination was remarkable only for left-sided cheek and lip swelling and tenderness, associated with an erythematous oropharynx and pain with speaking.

What is taro? What are the manifestations of taro toxicity?

Taro commonly refers to plants from the Araceae family, usually Colocasia esculenta.¹ Taro is ubiquitous in Southern Asia and Southeast India. It is a widely naturalized and perennial tropical plant primarily grown as a root vegetable, and is a common flavor in boba (bubble) tea. All members of Araceae contain calcium oxalate crystals in the form of raphides, sharp needle-shaped crystals packaged in idioblasts and contained within the waxy leaf.² Pressure on the idioblasts, such as from mastication, triggers the release of the raphides. The needles pierce the surface of any tissue with which they come into contact, creating a gateway for proteolytic enzymes to enter the consumer.³ The leaves and root of Araceae must be cooked before eating to inactivate the raphides.

Oral exposure to uncooked taro leaves or taro root can result in mouth irritation and swelling that can progress to angioedema and airway obstruction. Although the traditional method of removing taro raphides is to soak the root in cold water overnight,^4,5 this does not fully remove all of the raphides. Instead, taro root should be thoroughly cooked in boiling water to draw-out oxalates from the root into the cooking water, which must then be discarded. Consuming taro with warm milk also reduces the effect of the oxalates by about 80%.⁶

Many other plants of the Araceae family, such as Dieffenbachia (dumbcane), share similar toxicity and are commonly kept in the home and office.

Patients with oral exposure to taro may experience a delayed (also termed biphasic) anaphylactic reaction, ie, the development of anaphylactic symptoms more than 4 hours after the inciting event. Delayed anaphylaxis is distinct from delayed hypersensitivity, though both may be immunoglobulin E-mediated. Delayed hypersensitivity presents later (2-14 days) and with less immediately life-threatening effects, most commonly dermatitis (eg, poison ivy dermatitis).

While both of the patients in this case presented with mild symptoms, life-threatening angioedema of the oropharynx, anaphylaxis, and hypocalcemia have been reported^7,8 and should be considered in any symptomatic patient with exposure to taro.

What is the differential diagnosis of plant-related mouth pain?

The oral mucosa is composed of superficial layers of mucin and epithelial cells that lie over the dermis and connective tissue. Local immune cells, including mast cells and Langerhans cells, reside in the deeper layers. The differential diagnosis of plant-based mouth pain can be divided into mechanical, chemical, and thermal causes.

Mechanical Causes. Causes of mechanical plant-based oral pain include structural damage when foreign matter, such as barbs, sharp leaves, or hard seeds, pierce the layers of the oral mucosa.

Chemical Causes. Chemical-related causes of oral pain include caustic ingestion, for example from detergents or cleaning agents that contaminate the broth. Araceae, such as taro or arum, have sharp calcium oxalate crystals tipped with phospholipases and proteases that cause mechanical pain on piercing mucous membranes, and chemical pain by enzymatically degrading epithelium and mucosa. Both chemical and mechanical irritation can lead to an inflammatory response. Raw taro can cause irritant contact stomatitis as the raphides pierce the oral mucosa. It can also cause allergic stomatitis if antigens related to the phospholipases or proteases are presented to Langerhans cells.⁹

Thermal Causes. The hot temperature of the ingested broth could cause thermal injury, but the injury is likely to be more diffuse.

How common is taro exposure, and how is it treated?

From 1995 to 1999, 15 cases of taro poisoning were reported to the Drug and Toxicology Information service in Zimbabwe.¹⁰ From 2005 to 2009, 21 out of 31 cases reported to the Hong Kong Poison Control Center involving gastrointestinal irritation involved the consumption of Colocasia fallax, a form of taro more common in Tibet, the Himalayas, and northern Indochina.⁷ Of the 31 cases, six patients were treated with diphenhydramine, epinephrine, and dexamethasone for angioedema.

From 2011 to 2013, two cases of mouth irritation and swelling after eating raw taro leaves were reported to the British Columbia Poison Control Center.¹¹ Those two patients were observed for 6 hours without specific treatment and discharged.

Case Conclusion

Due to concerns of the potential for anaphylaxis, both patients were treated intravenously with 50 mg diphenhydramine and 10 mg dexamethasone. The husband was also given 650 mg acetaminophen orally for pain relief; his wife declined pain medication. Laboratory evaluation, including a complete blood count, basic metabolic panel, liver function panel, and urinalysis were ordered for both patients; all results were within normal limits for both patients.

After an uneventful 6-hour observation period, both patients were discharged home with instructions to return to the ED if they develop any signs of allergic reaction and to call emergency medical services for any sign of anaphylaxis.

Case

A 45-year-old Chinese man with no known medical history presented to the ED with right-sided facial spasm and cheek swelling, which began immediately after he bit into a piece of taro root, approximately 2 hours prior to presentation. The patient stated that the root was an ingredient in a soup that a relative had made. According to the patient, after biting into the root, he immediately experienced a burning pain on the right side of his mouth. He further noted that he swallowed less than two bites of the root and stopped eating because the act of chewing was too painful.

Initial vital signs at presentation were: blood pressure, 140/100 mm Hg; heart rate, 84 beats/min; respiratory rate, 14 beats/min; and temperature, 97.6°F. Oxygen saturation was 98% on room air. The patient’s physical examination was remarkable for pain upon opening the mouth, as well as right-sided cheek and lip swelling and tenderness. The tongue and oropharynx were not erythematous or swollen. The patient was only able to speak in short sentences, secondary to oropharyngeal pain, but he was in no respiratory distress. No urticaria, pruritus, wheezing, or stridor was present.

During the patient’s workup, his 40-year-old wife also presented to the same ED for evaluation of burning pain and spasm on the left side of her mouth, which she stated also developed immediately after she bit into a piece of taro root contained in the same soup as that ingested by the patient.

The wife’s vital signs were unremarkable, and she was in no respiratory distress. Her physical examination was remarkable only for left-sided cheek and lip swelling and tenderness, associated with an erythematous oropharynx and pain with speaking.

What is taro? What are the manifestations of taro toxicity?

Taro commonly refers to plants from the Araceae family, usually Colocasia esculenta.¹ Taro is ubiquitous in Southern Asia and Southeast India. It is a widely naturalized and perennial tropical plant primarily grown as a root vegetable, and is a common flavor in boba (bubble) tea. All members of Araceae contain calcium oxalate crystals in the form of raphides, sharp needle-shaped crystals packaged in idioblasts and contained within the waxy leaf.² Pressure on the idioblasts, such as from mastication, triggers the release of the raphides. The needles pierce the surface of any tissue with which they come into contact, creating a gateway for proteolytic enzymes to enter the consumer.³ The leaves and root of Araceae must be cooked before eating to inactivate the raphides.

Oral exposure to uncooked taro leaves or taro root can result in mouth irritation and swelling that can progress to angioedema and airway obstruction. Although the traditional method of removing taro raphides is to soak the root in cold water overnight,^4,5 this does not fully remove all of the raphides. Instead, taro root should be thoroughly cooked in boiling water to draw-out oxalates from the root into the cooking water, which must then be discarded. Consuming taro with warm milk also reduces the effect of the oxalates by about 80%.⁶

Many other plants of the Araceae family, such as Dieffenbachia (dumbcane), share similar toxicity and are commonly kept in the home and office.

Patients with oral exposure to taro may experience a delayed (also termed biphasic) anaphylactic reaction, ie, the development of anaphylactic symptoms more than 4 hours after the inciting event. Delayed anaphylaxis is distinct from delayed hypersensitivity, though both may be immunoglobulin E-mediated. Delayed hypersensitivity presents later (2-14 days) and with less immediately life-threatening effects, most commonly dermatitis (eg, poison ivy dermatitis).

While both of the patients in this case presented with mild symptoms, life-threatening angioedema of the oropharynx, anaphylaxis, and hypocalcemia have been reported^7,8 and should be considered in any symptomatic patient with exposure to taro.

What is the differential diagnosis of plant-related mouth pain?

The oral mucosa is composed of superficial layers of mucin and epithelial cells that lie over the dermis and connective tissue. Local immune cells, including mast cells and Langerhans cells, reside in the deeper layers. The differential diagnosis of plant-based mouth pain can be divided into mechanical, chemical, and thermal causes.

Mechanical Causes. Causes of mechanical plant-based oral pain include structural damage when foreign matter, such as barbs, sharp leaves, or hard seeds, pierce the layers of the oral mucosa.

Chemical Causes. Chemical-related causes of oral pain include caustic ingestion, for example from detergents or cleaning agents that contaminate the broth. Araceae, such as taro or arum, have sharp calcium oxalate crystals tipped with phospholipases and proteases that cause mechanical pain on piercing mucous membranes, and chemical pain by enzymatically degrading epithelium and mucosa. Both chemical and mechanical irritation can lead to an inflammatory response. Raw taro can cause irritant contact stomatitis as the raphides pierce the oral mucosa. It can also cause allergic stomatitis if antigens related to the phospholipases or proteases are presented to Langerhans cells.⁹

Thermal Causes. The hot temperature of the ingested broth could cause thermal injury, but the injury is likely to be more diffuse.

How common is taro exposure, and how is it treated?

From 1995 to 1999, 15 cases of taro poisoning were reported to the Drug and Toxicology Information service in Zimbabwe.¹⁰ From 2005 to 2009, 21 out of 31 cases reported to the Hong Kong Poison Control Center involving gastrointestinal irritation involved the consumption of Colocasia fallax, a form of taro more common in Tibet, the Himalayas, and northern Indochina.⁷ Of the 31 cases, six patients were treated with diphenhydramine, epinephrine, and dexamethasone for angioedema.

From 2011 to 2013, two cases of mouth irritation and swelling after eating raw taro leaves were reported to the British Columbia Poison Control Center.¹¹ Those two patients were observed for 6 hours without specific treatment and discharged.

Case Conclusion

Due to concerns of the potential for anaphylaxis, both patients were treated intravenously with 50 mg diphenhydramine and 10 mg dexamethasone. The husband was also given 650 mg acetaminophen orally for pain relief; his wife declined pain medication. Laboratory evaluation, including a complete blood count, basic metabolic panel, liver function panel, and urinalysis were ordered for both patients; all results were within normal limits for both patients.

After an uneventful 6-hour observation period, both patients were discharged home with instructions to return to the ED if they develop any signs of allergic reaction and to call emergency medical services for any sign of anaphylaxis.

Case

A 45-year-old Chinese man with no known medical history presented to the ED with right-sided facial spasm and cheek swelling, which began immediately after he bit into a piece of taro root, approximately 2 hours prior to presentation. The patient stated that the root was an ingredient in a soup that a relative had made. According to the patient, after biting into the root, he immediately experienced a burning pain on the right side of his mouth. He further noted that he swallowed less than two bites of the root and stopped eating because the act of chewing was too painful.

Initial vital signs at presentation were: blood pressure, 140/100 mm Hg; heart rate, 84 beats/min; respiratory rate, 14 beats/min; and temperature, 97.6°F. Oxygen saturation was 98% on room air. The patient’s physical examination was remarkable for pain upon opening the mouth, as well as right-sided cheek and lip swelling and tenderness. The tongue and oropharynx were not erythematous or swollen. The patient was only able to speak in short sentences, secondary to oropharyngeal pain, but he was in no respiratory distress. No urticaria, pruritus, wheezing, or stridor was present.

During the patient’s workup, his 40-year-old wife also presented to the same ED for evaluation of burning pain and spasm on the left side of her mouth, which she stated also developed immediately after she bit into a piece of taro root contained in the same soup as that ingested by the patient.

The wife’s vital signs were unremarkable, and she was in no respiratory distress. Her physical examination was remarkable only for left-sided cheek and lip swelling and tenderness, associated with an erythematous oropharynx and pain with speaking.

What is taro? What are the manifestations of taro toxicity?

Taro commonly refers to plants from the Araceae family, usually Colocasia esculenta.¹ Taro is ubiquitous in Southern Asia and Southeast India. It is a widely naturalized and perennial tropical plant primarily grown as a root vegetable, and is a common flavor in boba (bubble) tea. All members of Araceae contain calcium oxalate crystals in the form of raphides, sharp needle-shaped crystals packaged in idioblasts and contained within the waxy leaf.² Pressure on the idioblasts, such as from mastication, triggers the release of the raphides. The needles pierce the surface of any tissue with which they come into contact, creating a gateway for proteolytic enzymes to enter the consumer.³ The leaves and root of Araceae must be cooked before eating to inactivate the raphides.

Oral exposure to uncooked taro leaves or taro root can result in mouth irritation and swelling that can progress to angioedema and airway obstruction. Although the traditional method of removing taro raphides is to soak the root in cold water overnight,^4,5 this does not fully remove all of the raphides. Instead, taro root should be thoroughly cooked in boiling water to draw-out oxalates from the root into the cooking water, which must then be discarded. Consuming taro with warm milk also reduces the effect of the oxalates by about 80%.⁶

Many other plants of the Araceae family, such as Dieffenbachia (dumbcane), share similar toxicity and are commonly kept in the home and office.

Patients with oral exposure to taro may experience a delayed (also termed biphasic) anaphylactic reaction, ie, the development of anaphylactic symptoms more than 4 hours after the inciting event. Delayed anaphylaxis is distinct from delayed hypersensitivity, though both may be immunoglobulin E-mediated. Delayed hypersensitivity presents later (2-14 days) and with less immediately life-threatening effects, most commonly dermatitis (eg, poison ivy dermatitis).

While both of the patients in this case presented with mild symptoms, life-threatening angioedema of the oropharynx, anaphylaxis, and hypocalcemia have been reported^7,8 and should be considered in any symptomatic patient with exposure to taro.

What is the differential diagnosis of plant-related mouth pain?

The oral mucosa is composed of superficial layers of mucin and epithelial cells that lie over the dermis and connective tissue. Local immune cells, including mast cells and Langerhans cells, reside in the deeper layers. The differential diagnosis of plant-based mouth pain can be divided into mechanical, chemical, and thermal causes.

Mechanical Causes. Causes of mechanical plant-based oral pain include structural damage when foreign matter, such as barbs, sharp leaves, or hard seeds, pierce the layers of the oral mucosa.

Chemical Causes. Chemical-related causes of oral pain include caustic ingestion, for example from detergents or cleaning agents that contaminate the broth. Araceae, such as taro or arum, have sharp calcium oxalate crystals tipped with phospholipases and proteases that cause mechanical pain on piercing mucous membranes, and chemical pain by enzymatically degrading epithelium and mucosa. Both chemical and mechanical irritation can lead to an inflammatory response. Raw taro can cause irritant contact stomatitis as the raphides pierce the oral mucosa. It can also cause allergic stomatitis if antigens related to the phospholipases or proteases are presented to Langerhans cells.⁹

Thermal Causes. The hot temperature of the ingested broth could cause thermal injury, but the injury is likely to be more diffuse.

How common is taro exposure, and how is it treated?

From 1995 to 1999, 15 cases of taro poisoning were reported to the Drug and Toxicology Information service in Zimbabwe.¹⁰ From 2005 to 2009, 21 out of 31 cases reported to the Hong Kong Poison Control Center involving gastrointestinal irritation involved the consumption of Colocasia fallax, a form of taro more common in Tibet, the Himalayas, and northern Indochina.⁷ Of the 31 cases, six patients were treated with diphenhydramine, epinephrine, and dexamethasone for angioedema.

From 2011 to 2013, two cases of mouth irritation and swelling after eating raw taro leaves were reported to the British Columbia Poison Control Center.¹¹ Those two patients were observed for 6 hours without specific treatment and discharged.

Case Conclusion

Due to concerns of the potential for anaphylaxis, both patients were treated intravenously with 50 mg diphenhydramine and 10 mg dexamethasone. The husband was also given 650 mg acetaminophen orally for pain relief; his wife declined pain medication. Laboratory evaluation, including a complete blood count, basic metabolic panel, liver function panel, and urinalysis were ordered for both patients; all results were within normal limits for both patients.

After an uneventful 6-hour observation period, both patients were discharged home with instructions to return to the ED if they develop any signs of allergic reaction and to call emergency medical services for any sign of anaphylaxis.

An 83-year-old man presented to the emergency department with acute, painless loss of vision in his left eye. His vision in that eye had been normal in the middle of the night when he woke to use the restroom, but on awakening 6 hours later he could perceive only light or darkness.

He denied headache, scalp tenderness, jaw claudication, fever, weight loss, myalgia, or other neurologic symptoms. He had not experienced any recent change in his vision before this presentation, including halos around lights, floaters, eye pain, or redness. However, 6 months ago he had undergone left cataract surgery (left phacoemulsification with intraocular implant) without complications. And he said that when he was 3 years old, he had sustained a serious injury to his right eye.

His medical history included ischemic heart disease and hypertension. His medications included losartan, furosemide, amlodi­pine, atorvastatin, and aspirin.

CAUSES OF ACUTE MONOCULAR VISION LOSS

1. Which of the following is the least likely cause of this patient’s acute monocular vision loss?

• Optic neuritis
• Retinal vein occlusion
• Retinal artery occlusion
• Pituitary apoplexy
• Retinal detachment

Acute vision loss is often so distressing to the patient that the emergency department may be the first step in evaluation. While its diagnosis and management often require an interdisciplinary effort, early evaluation and triage of this potential medical emergency is often done by clinicians without specialized training in ophthalmology.

The physiology of vision is complex and the list of possible causes of vision loss is long, but the differential diagnosis can be narrowed quickly by considering the time course of vision loss and the anatomic localization.¹

The time course (including onset and tempo) of vision loss can classified as:

• Transient (ie, vision returned to normal by the time seen by clinician)
• Acute (instantaneous onset, ie, within seconds to minutes)
• Subacute (progression over days to weeks)
• Chronic (insidious progression over months to years).

Although acute vision loss is usually dramatic, insidious vision loss may occasionally be unnoticed for a surprisingly long time until the normal eye is inadvertently shielded.

Anatomic localization. Lesions anterior to the optic chiasm cause monocular vision loss, whereas lesions at or posterior to the chiasm lead to bilateral visual field defects. Problems leading to monocular blindness can be broadly divided into 3 anatomic categories (Figure 1):

• Ocular medial (including the cornea, anterior chamber, and lens)
• Retinal
• Neurologic (including the optic nerve and chiasm).

Clues from the history

A careful ophthalmic history is an essential initial step in the evaluation (Table 1). In addition, nonvisual symptoms can help narrow the differential diagnosis.

Nausea and vomiting often accompany acute elevation of intraocular pressure.

Focal neurologic deficits or other neurologic symptoms can point to a demyelinating disease such as multiple sclerosis.

Risk factors for vascular atherosclerotic disease such as diabetes, hypertension, and coronary artery disease raise concern for retinal, optic nerve, or cerebral ischemia.

Medications with anticholinergic and adrenergic properties can also precipitate monocular vision loss with acute angle-closure glaucoma.

Can we rule out anything yet?

Our patient presented with painless monocular vision loss. As discussed, causes of monocular vision loss can be localized to ocular abnormalities and prechiasmatic neurologic ones. Retinal detachment, occlusion of a retinal artery or vein, and optic neuritis are all important potential causes of acute monocular vision loss.

Pituitary apoplexy, on the other hand, is characterized by an acute increase in pituitary volume, often leading to compression of the optic chiasm resulting in a visual-field defect. It is most often characterized by binocular deficits (eg, bitemporal hemianopia) but is less likely to cause monocular vision loss.¹

CASE CONTINUED: EXAMINATION

On examination, the patient appeared comfortable. His temperature was 97.6°F (36.4°C), pulse 59 beats per minute, respiratory rate 18 per minute, and blood pressure 153/56 mm Hg.

Heart and lung examinations were notable for a grade 3 of 6 midsystolic, low-pitched murmur in the aortic area radiating to the neck, bilateral carotid bruits, and clear lungs. The cardiac impulse was normal in location and character. There was no evidence of aortic insufficiency (including auscultation during exhalation phase while sitting upright).

Eye examination. Visual acuity in the right eye was 20/200 with correction (owing to his eye injury at age 3). With the left eye, he could see only light or darkness. The conjunctiva and sclera were normal.

The right pupil was irregular and measured 3 mm (baseline from his previous eye injury). The left pupil was 3.5 mm. The direct pupillary response was preserved, but a relative afferent pupillary defect was present: on the swinging flashlight test, the left pupil dilated when the flashlight was passed from the right to the left pupil. Extraocular movements were full and intact bilaterally. The rest of the neurologic examination was normal.

An ophthalmologist was urgently consulted. A dilated funduscopic examination of the left eye revealed peripapillary atrophy, tortuous vessels, a cherry red macular spot, and flame hemorrhages, but no disc edema or pallor (Figure 2).

FURTHER WORKUP

2. Which of the following investigations would be least useful and not indicated at this point for this patient?

• Carotid ultrasonography
• Electrocardiography and echocardiography
• Magnetic resonance angiography of the brain
• Computed tomographic (CT) angiography of the head and neck
• Testing for the factor V Leiden and prothrombin gene mutations

A systematic ocular physical examination can offer important diagnostic information (Table 2). Ophthalmoscopy directly examines the optic disc, macula, and retinal vasculature. To interpret the funduscopic examination, we need a basic understanding of the vascular supply to the eye (Figure 3).

Information from references 4 and 5.

For example, the cherry red spot within the macula in our patient is characteristic of central retinal artery occlusion and highlights the relationship between anatomy and pathophysiology. The retina’s blood supply is compromised, leading to an ischemic, white background (secondary to edema of the inner third of the retina), but the macula continues to be nourished by the posterior ciliary arteries. This contrast in color is accentuated by the underlying structures composing the fovea, which lacks the nerve fiber layer and ganglion cell layer, making the vascular bed more visible.^2,3

Also in our patient, the marked reduction in visual acuity and relative afferent pupillary defect in the left eye point to unilateral optic nerve (or retinal ganglion cell) dysfunction. The findings on direct funduscopy were consistent with acute central retinal artery ischemia or occlusion. Central retinal artery occlusion can be either arteritic (due to inflammation, most often giant cell arteritis) or nonarteritic (due to atherosclerotic vascular disease).

Thus, carotid ultrasonography, electrocardiography, and transthoracic and transesophageal echocardiography are important components of the further workup. In addition, urgent brain imaging including either CT angiography or magnetic resonance angiography of the head and neck is indicated in all patients with central retinal artery occlusion.

Thrombophilia testing, including tests for the factor V Leiden and prothrombin gene mutations, is indicated in specific cases when a hypercoagulable state is suggested by components of the history, physical examination, and laboratory and radiologic testing. Thrombophilia testing would be low-yield and should not be part of the first-line testing in elderly patients with several atherosclerotic risk factors, such as our patient.

CASE CONTINUED: LABORATORY AND IMAGING EVIDENCE

Initial laboratory work showed:

• Mild microcytic anemia
• Erythrocyte sedimentation rate 77 mm/hour (reference range 1–10)
• C-reactive protein 4.0 mg/dL (reference range < 0.9).

The rest of the complete blood cell count and metabolic profile were unremarkable. His hemoglobin A_1c value was 5.3% (reference range 4.8%–6.2%).

A neurologist was urgently consulted.

Magnetic resonance imaging of the brain without contrast revealed nonspecific white-matter disease with no evidence of ischemic stroke.

Magnetic resonance angiography of the head and neck with contrast demonstrated 20% to 40% stenosis in both carotid arteries with otherwise patent anterior and posterior circulation.

Continuous monitoring of the left carotid artery with transcranial Doppler ultrasonography was also ordered, and the study concluded there were no undetected microembolic events.

Transthoracic echocardiography showed aortic sclerosis with no other abnormalities.

Ophthalmic fluorescein angiography was performed and showed patchy choroidal hypoperfusion, severe delayed filling, and extensive pruning of the arterial circulation with no  involvement of the posterior ciliary arteries.

Given the elevated inflammatory markers, pulse-dose intravenous methylprednisolone was started, and a temporal artery biopsy was planned.

CENTRAL RETINAL ARTERY OCCLUSION: NONARTERITIC VS ARTERITIC CAUSES

3. Which of the following is least useful to differentiate arteritic from nonarteritic causes of central retinal artery occlusion?

• Finding emboli in the retinal vasculature on funduscopy
• Temporal artery biopsy
• Measuring the C-reactive protein level and the erythrocyte sedimentation rate
• Echocardiography
• Positron-emission tomography (PET)
• Retinal fluorescein angiography

In patients diagnosed with central retinal artery occlusion, the next step is to differentiate between nonarteritic and arteritic causes, since separating them has therapeutic relevance.

The carotid artery is the main culprit for embolic disease affecting the central retinal artery, leading to the nonarteritic subtype. Thus, evaluation of acute retinal ischemia secondary to nonarteritic central retinal artery occlusion is similar to the evaluation of patients with an acute cerebral stroke.⁴ Studies have shown that 25% of patients diagnosed with central retinal artery occlusion have an additional ischemic insult in the cerebrovascular system, and these patients are at high risk of recurrent ocular or cerebral infarction. Workup includes diffusion-weighted MRI, angiography, echocardiography, and telemetry.⁵

Arteritic central retinal artery occlusion is most often caused by giant cell arteritis. The American College of Rheumatology classification criteria for giant cell arteritis include 3 of the following 5:

• Age 50 or older
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• Erythrocyte sedimentation rate 50 mm/hour or greater
• Positive biopsy findings.⁶  

Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis and should be done whenever the disease is suspected.^7,8 However, the test is invasive and imperfect, as a negative result does not completely rule out giant cell arteritis.⁹

Although a unilateral temporal artery biopsy can be falsely negative, several studies evaluating the efficacy of bilateral biopsies did not show significant improvement in the diagnostic yield.^10,11

Ophthalmic fluorescein angiography is another helpful test for distinguishing nonarteritic from arteritic central retinal artery occlusion.¹² Involvement of the posterior ciliary arteries usually occurs in giant cell arteritis, and this leads to choroidal malperfusion with or without retinal involvement. The optic nerve may also be infarcted by closure of the paraoptic vessels fed by the posterior ciliary vessels.^12,13 Such involvement of multiple vessels would not be typical with nonarteritic central retinal artery occlusion. Thus, this finding is helpful in making the final diagnosis along with supplying possible prognostic information.¹³

PET-CT is emerging as a test for early inflammation in extracranial disease, but its utility for diagnosing intracranial disease is limited by high uptake of the tracer fluoro­deoxyglucose by the brain and low resolution.¹⁴ Currently, it has no established role in the evaluation of patients with central retinal artery occlusion and would have no utility in differentiating arteritic vs nonarteritic causes of central retinal artery occlusion.

If giant cell arteritis is suspected, it is essential to start intravenous pulse-dose methyl­prednisolone early to prevent further vision loss in the contralateral eye. Treatment should not be delayed for invasive testing or temporal artery biopsy. Improvement in headache, jaw claudication, or scalp tenderness once steroids are initiated also helps support the diagnosis of giant cell arteritis.⁷

Unfortunately, visual symptoms may be irreversible despite treatment.

Our patient’s central retinal artery occlusion

This case highlights how difficult it is in practice to distinguish nonarteritic from arteritic central retinal artery occlusion.

Our patient had numerous cardiovascular risk factors, including known carotid and coronary artery disease, favoring a nonarteritic diagnosis.

On the other hand, his elevated inflammatory markers suggested an underlying inflammatory response. He lacked the characteristic headache and other systemic signs of giant cell arteritis, but this has been described in about 25% of patients.¹⁵ If emboli are seen on funduscopy, further workup for arteritic central retinal artery occlusion is not warranted, but emboli are not always present. Then again, absence of posterior ciliary artery involvement on fluorescein angiography pointed away from giant cell arteritis.

CASE CONTINUED: FINAL DIAGNOSIS

Biopsy of the left temporal artery showed intimal thickening with focal destruction of the internal elastic lamina by dystrophic calcification with no evidence of inflammatory infiltrates, giant cells, or granulomata in the adventitia, media, or intima. Based on the results of biopsy study and fluorescein angiography, we concluded that this was nonarteritic central retinal artery occlusion related to atherosclerotic disease.

Methylprednisolone was discontinued. The patient was discharged on aspirin, losartan, furosemide, amlodipine, and high-dose atorvastatin for standard stroke prevention. He was followed by the medical team and the ophthalmology department. At 6 weeks, there was only marginal improvement in the visual acuity of the left eye.

4. Management of nonarteritic central retinal artery occlusion could include all of the following except which one?

• Ocular massage
• Intravenous thrombolysis
• Intra-arterial thrombolysis
• Risk-factor modification
• Intraocular steroid injection

In patients with acute vision loss from nonarteritic central retinal artery occlusion, acute strategies to restore retinal perfusion include noninvasive “standard” therapies and thrombolysis (intravenous or intra-arterial). Unfortunately, consensus and guidelines are lacking.

Traditional therapies include sublingual isosorbide dinitrate, systemic pentoxifylline, inhalation of a carbogen, hyperbaric oxygen, ocular massage, intravenous acetazolamide and mannitol, anterior chamber paracentesis, and systemic steroids. However, none of these have been shown to be more effective than placebo.¹⁶

Thrombolytic therapy, analogous to the treatment of patients with ischemic stroke or myocardial infarction, is more controversial in acute central retinal artery occlusion.¹³ Data from small case-series suggested that intra-arterial or intravenous thrombolysis might improve visual acuity with reasonable safety.¹⁷ On the other hand, a randomized study from the United Kingdom that compared intra-arterial thrombolysis within a 24-hour window and conservative measures concluded that thrombolysis should not be used.¹⁸

Thrombolysis is thus used only in selected patients on a case-specific basis with involvement of a multispecialty team including stroke neurologists, especially if patients present within hours of onset and have concomitant neurologic symptoms.

Treatment beyond the acute phase focuses on preventing complications of the eye ischemia and aggressively managing systemic atherosclerotic risk factors to decrease the incidence of further ischemic events. Other interventions  include endarterectomy for significant carotid stenosis and anticoagulation to prevent cardioembolic embolization (such as atrial fibrillation). Most experts agree on the addition of an antiplatelet agent.^13,19

Intraocular steroid injection can be used in the management of some retinal disorders but has no value in nonarteritic central retinal artery occlusion.

Vision recovery in nonarteritic central retinal artery occlusion is variable, but the prognosis is generally poor. The visual acuity on presentation, the onset of the symptoms, and collateral vessels are major factors influencing long-term recovery. Most of the recovery occurs within 7 days and involves peripheral vision rather than central vision. Several studies report some recovery in peripheral vision in approximately 30% to 35% of affected eyes.^20–22

PROMPT ACTION MAY SAVE SIGHT

Vision loss is a common presenting symptom in the emergency setting. A meticulous history and systematic physical examination can narrow the differential diagnosis of this neuro-ophthalmologic emergency. Acute retinal ischemia from central retinal artery occlusion is the ocular equivalent of an ischemic stroke, and they share risk factors, diagnostic workup, and management approaches.

Both etiologic subtypes (ie, arteritic and nonarteritic) require prompt intervention by front-line physicians. If giant cell arteritis is suspected, corticosteroid therapy must be initiated to save the contralateral retina from ischemia. Suspicion of central retinal artery occlusion warrants immediate evaluation by a neurologist to consider thrombolysis. Prompt action and interdisciplinary care involving an ophthalmologist, neurologist, and emergency or internal medicine physician may save a patient from permanent visual disability.

KEY POINTS

• Monocular vision loss requires urgent evaluation with a multidisciplinary management approach.
• There are no consensus treatment guidelines for nonarteritic central retinal artery occlusion, but the workup includes a comprehensive stroke evaluation.
• Arteritic central retinal artery occlusion is most often due to giant cell arteritis, and when it is suspected, the patient should be empirically treated with steroids.

An 83-year-old man presented to the emergency department with acute, painless loss of vision in his left eye. His vision in that eye had been normal in the middle of the night when he woke to use the restroom, but on awakening 6 hours later he could perceive only light or darkness.

He denied headache, scalp tenderness, jaw claudication, fever, weight loss, myalgia, or other neurologic symptoms. He had not experienced any recent change in his vision before this presentation, including halos around lights, floaters, eye pain, or redness. However, 6 months ago he had undergone left cataract surgery (left phacoemulsification with intraocular implant) without complications. And he said that when he was 3 years old, he had sustained a serious injury to his right eye.

His medical history included ischemic heart disease and hypertension. His medications included losartan, furosemide, amlodi­pine, atorvastatin, and aspirin.

CAUSES OF ACUTE MONOCULAR VISION LOSS

1. Which of the following is the least likely cause of this patient’s acute monocular vision loss?

• Optic neuritis
• Retinal vein occlusion
• Retinal artery occlusion
• Pituitary apoplexy
• Retinal detachment

Acute vision loss is often so distressing to the patient that the emergency department may be the first step in evaluation. While its diagnosis and management often require an interdisciplinary effort, early evaluation and triage of this potential medical emergency is often done by clinicians without specialized training in ophthalmology.

The physiology of vision is complex and the list of possible causes of vision loss is long, but the differential diagnosis can be narrowed quickly by considering the time course of vision loss and the anatomic localization.¹

The time course (including onset and tempo) of vision loss can classified as:

• Transient (ie, vision returned to normal by the time seen by clinician)
• Acute (instantaneous onset, ie, within seconds to minutes)
• Subacute (progression over days to weeks)
• Chronic (insidious progression over months to years).

Although acute vision loss is usually dramatic, insidious vision loss may occasionally be unnoticed for a surprisingly long time until the normal eye is inadvertently shielded.

Anatomic localization. Lesions anterior to the optic chiasm cause monocular vision loss, whereas lesions at or posterior to the chiasm lead to bilateral visual field defects. Problems leading to monocular blindness can be broadly divided into 3 anatomic categories (Figure 1):

• Ocular medial (including the cornea, anterior chamber, and lens)
• Retinal
• Neurologic (including the optic nerve and chiasm).

Clues from the history

A careful ophthalmic history is an essential initial step in the evaluation (Table 1). In addition, nonvisual symptoms can help narrow the differential diagnosis.

Nausea and vomiting often accompany acute elevation of intraocular pressure.

Focal neurologic deficits or other neurologic symptoms can point to a demyelinating disease such as multiple sclerosis.

Risk factors for vascular atherosclerotic disease such as diabetes, hypertension, and coronary artery disease raise concern for retinal, optic nerve, or cerebral ischemia.

Medications with anticholinergic and adrenergic properties can also precipitate monocular vision loss with acute angle-closure glaucoma.

Can we rule out anything yet?

Our patient presented with painless monocular vision loss. As discussed, causes of monocular vision loss can be localized to ocular abnormalities and prechiasmatic neurologic ones. Retinal detachment, occlusion of a retinal artery or vein, and optic neuritis are all important potential causes of acute monocular vision loss.

Pituitary apoplexy, on the other hand, is characterized by an acute increase in pituitary volume, often leading to compression of the optic chiasm resulting in a visual-field defect. It is most often characterized by binocular deficits (eg, bitemporal hemianopia) but is less likely to cause monocular vision loss.¹

CASE CONTINUED: EXAMINATION

On examination, the patient appeared comfortable. His temperature was 97.6°F (36.4°C), pulse 59 beats per minute, respiratory rate 18 per minute, and blood pressure 153/56 mm Hg.

Heart and lung examinations were notable for a grade 3 of 6 midsystolic, low-pitched murmur in the aortic area radiating to the neck, bilateral carotid bruits, and clear lungs. The cardiac impulse was normal in location and character. There was no evidence of aortic insufficiency (including auscultation during exhalation phase while sitting upright).

Eye examination. Visual acuity in the right eye was 20/200 with correction (owing to his eye injury at age 3). With the left eye, he could see only light or darkness. The conjunctiva and sclera were normal.

The right pupil was irregular and measured 3 mm (baseline from his previous eye injury). The left pupil was 3.5 mm. The direct pupillary response was preserved, but a relative afferent pupillary defect was present: on the swinging flashlight test, the left pupil dilated when the flashlight was passed from the right to the left pupil. Extraocular movements were full and intact bilaterally. The rest of the neurologic examination was normal.

An ophthalmologist was urgently consulted. A dilated funduscopic examination of the left eye revealed peripapillary atrophy, tortuous vessels, a cherry red macular spot, and flame hemorrhages, but no disc edema or pallor (Figure 2).

FURTHER WORKUP

2. Which of the following investigations would be least useful and not indicated at this point for this patient?

• Carotid ultrasonography
• Electrocardiography and echocardiography
• Magnetic resonance angiography of the brain
• Computed tomographic (CT) angiography of the head and neck
• Testing for the factor V Leiden and prothrombin gene mutations

A systematic ocular physical examination can offer important diagnostic information (Table 2). Ophthalmoscopy directly examines the optic disc, macula, and retinal vasculature. To interpret the funduscopic examination, we need a basic understanding of the vascular supply to the eye (Figure 3).

Information from references 4 and 5.

For example, the cherry red spot within the macula in our patient is characteristic of central retinal artery occlusion and highlights the relationship between anatomy and pathophysiology. The retina’s blood supply is compromised, leading to an ischemic, white background (secondary to edema of the inner third of the retina), but the macula continues to be nourished by the posterior ciliary arteries. This contrast in color is accentuated by the underlying structures composing the fovea, which lacks the nerve fiber layer and ganglion cell layer, making the vascular bed more visible.^2,3

Also in our patient, the marked reduction in visual acuity and relative afferent pupillary defect in the left eye point to unilateral optic nerve (or retinal ganglion cell) dysfunction. The findings on direct funduscopy were consistent with acute central retinal artery ischemia or occlusion. Central retinal artery occlusion can be either arteritic (due to inflammation, most often giant cell arteritis) or nonarteritic (due to atherosclerotic vascular disease).

Thus, carotid ultrasonography, electrocardiography, and transthoracic and transesophageal echocardiography are important components of the further workup. In addition, urgent brain imaging including either CT angiography or magnetic resonance angiography of the head and neck is indicated in all patients with central retinal artery occlusion.

Thrombophilia testing, including tests for the factor V Leiden and prothrombin gene mutations, is indicated in specific cases when a hypercoagulable state is suggested by components of the history, physical examination, and laboratory and radiologic testing. Thrombophilia testing would be low-yield and should not be part of the first-line testing in elderly patients with several atherosclerotic risk factors, such as our patient.

CASE CONTINUED: LABORATORY AND IMAGING EVIDENCE

Initial laboratory work showed:

• Mild microcytic anemia
• Erythrocyte sedimentation rate 77 mm/hour (reference range 1–10)
• C-reactive protein 4.0 mg/dL (reference range < 0.9).

The rest of the complete blood cell count and metabolic profile were unremarkable. His hemoglobin A_1c value was 5.3% (reference range 4.8%–6.2%).

A neurologist was urgently consulted.

Magnetic resonance imaging of the brain without contrast revealed nonspecific white-matter disease with no evidence of ischemic stroke.

Magnetic resonance angiography of the head and neck with contrast demonstrated 20% to 40% stenosis in both carotid arteries with otherwise patent anterior and posterior circulation.

Continuous monitoring of the left carotid artery with transcranial Doppler ultrasonography was also ordered, and the study concluded there were no undetected microembolic events.

Transthoracic echocardiography showed aortic sclerosis with no other abnormalities.

Ophthalmic fluorescein angiography was performed and showed patchy choroidal hypoperfusion, severe delayed filling, and extensive pruning of the arterial circulation with no  involvement of the posterior ciliary arteries.

Given the elevated inflammatory markers, pulse-dose intravenous methylprednisolone was started, and a temporal artery biopsy was planned.

CENTRAL RETINAL ARTERY OCCLUSION: NONARTERITIC VS ARTERITIC CAUSES

3. Which of the following is least useful to differentiate arteritic from nonarteritic causes of central retinal artery occlusion?

• Finding emboli in the retinal vasculature on funduscopy
• Temporal artery biopsy
• Measuring the C-reactive protein level and the erythrocyte sedimentation rate
• Echocardiography
• Positron-emission tomography (PET)
• Retinal fluorescein angiography

In patients diagnosed with central retinal artery occlusion, the next step is to differentiate between nonarteritic and arteritic causes, since separating them has therapeutic relevance.

The carotid artery is the main culprit for embolic disease affecting the central retinal artery, leading to the nonarteritic subtype. Thus, evaluation of acute retinal ischemia secondary to nonarteritic central retinal artery occlusion is similar to the evaluation of patients with an acute cerebral stroke.⁴ Studies have shown that 25% of patients diagnosed with central retinal artery occlusion have an additional ischemic insult in the cerebrovascular system, and these patients are at high risk of recurrent ocular or cerebral infarction. Workup includes diffusion-weighted MRI, angiography, echocardiography, and telemetry.⁵

Arteritic central retinal artery occlusion is most often caused by giant cell arteritis. The American College of Rheumatology classification criteria for giant cell arteritis include 3 of the following 5:

• Age 50 or older
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• Erythrocyte sedimentation rate 50 mm/hour or greater
• Positive biopsy findings.⁶  

Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis and should be done whenever the disease is suspected.^7,8 However, the test is invasive and imperfect, as a negative result does not completely rule out giant cell arteritis.⁹

Although a unilateral temporal artery biopsy can be falsely negative, several studies evaluating the efficacy of bilateral biopsies did not show significant improvement in the diagnostic yield.^10,11

Ophthalmic fluorescein angiography is another helpful test for distinguishing nonarteritic from arteritic central retinal artery occlusion.¹² Involvement of the posterior ciliary arteries usually occurs in giant cell arteritis, and this leads to choroidal malperfusion with or without retinal involvement. The optic nerve may also be infarcted by closure of the paraoptic vessels fed by the posterior ciliary vessels.^12,13 Such involvement of multiple vessels would not be typical with nonarteritic central retinal artery occlusion. Thus, this finding is helpful in making the final diagnosis along with supplying possible prognostic information.¹³

PET-CT is emerging as a test for early inflammation in extracranial disease, but its utility for diagnosing intracranial disease is limited by high uptake of the tracer fluoro­deoxyglucose by the brain and low resolution.¹⁴ Currently, it has no established role in the evaluation of patients with central retinal artery occlusion and would have no utility in differentiating arteritic vs nonarteritic causes of central retinal artery occlusion.

If giant cell arteritis is suspected, it is essential to start intravenous pulse-dose methyl­prednisolone early to prevent further vision loss in the contralateral eye. Treatment should not be delayed for invasive testing or temporal artery biopsy. Improvement in headache, jaw claudication, or scalp tenderness once steroids are initiated also helps support the diagnosis of giant cell arteritis.⁷

Unfortunately, visual symptoms may be irreversible despite treatment.

Our patient’s central retinal artery occlusion

This case highlights how difficult it is in practice to distinguish nonarteritic from arteritic central retinal artery occlusion.

Our patient had numerous cardiovascular risk factors, including known carotid and coronary artery disease, favoring a nonarteritic diagnosis.

On the other hand, his elevated inflammatory markers suggested an underlying inflammatory response. He lacked the characteristic headache and other systemic signs of giant cell arteritis, but this has been described in about 25% of patients.¹⁵ If emboli are seen on funduscopy, further workup for arteritic central retinal artery occlusion is not warranted, but emboli are not always present. Then again, absence of posterior ciliary artery involvement on fluorescein angiography pointed away from giant cell arteritis.

CASE CONTINUED: FINAL DIAGNOSIS

Biopsy of the left temporal artery showed intimal thickening with focal destruction of the internal elastic lamina by dystrophic calcification with no evidence of inflammatory infiltrates, giant cells, or granulomata in the adventitia, media, or intima. Based on the results of biopsy study and fluorescein angiography, we concluded that this was nonarteritic central retinal artery occlusion related to atherosclerotic disease.

Methylprednisolone was discontinued. The patient was discharged on aspirin, losartan, furosemide, amlodipine, and high-dose atorvastatin for standard stroke prevention. He was followed by the medical team and the ophthalmology department. At 6 weeks, there was only marginal improvement in the visual acuity of the left eye.

4. Management of nonarteritic central retinal artery occlusion could include all of the following except which one?

• Ocular massage
• Intravenous thrombolysis
• Intra-arterial thrombolysis
• Risk-factor modification
• Intraocular steroid injection

In patients with acute vision loss from nonarteritic central retinal artery occlusion, acute strategies to restore retinal perfusion include noninvasive “standard” therapies and thrombolysis (intravenous or intra-arterial). Unfortunately, consensus and guidelines are lacking.

Traditional therapies include sublingual isosorbide dinitrate, systemic pentoxifylline, inhalation of a carbogen, hyperbaric oxygen, ocular massage, intravenous acetazolamide and mannitol, anterior chamber paracentesis, and systemic steroids. However, none of these have been shown to be more effective than placebo.¹⁶

Thrombolytic therapy, analogous to the treatment of patients with ischemic stroke or myocardial infarction, is more controversial in acute central retinal artery occlusion.¹³ Data from small case-series suggested that intra-arterial or intravenous thrombolysis might improve visual acuity with reasonable safety.¹⁷ On the other hand, a randomized study from the United Kingdom that compared intra-arterial thrombolysis within a 24-hour window and conservative measures concluded that thrombolysis should not be used.¹⁸

Thrombolysis is thus used only in selected patients on a case-specific basis with involvement of a multispecialty team including stroke neurologists, especially if patients present within hours of onset and have concomitant neurologic symptoms.

Treatment beyond the acute phase focuses on preventing complications of the eye ischemia and aggressively managing systemic atherosclerotic risk factors to decrease the incidence of further ischemic events. Other interventions  include endarterectomy for significant carotid stenosis and anticoagulation to prevent cardioembolic embolization (such as atrial fibrillation). Most experts agree on the addition of an antiplatelet agent.^13,19

Intraocular steroid injection can be used in the management of some retinal disorders but has no value in nonarteritic central retinal artery occlusion.

Vision recovery in nonarteritic central retinal artery occlusion is variable, but the prognosis is generally poor. The visual acuity on presentation, the onset of the symptoms, and collateral vessels are major factors influencing long-term recovery. Most of the recovery occurs within 7 days and involves peripheral vision rather than central vision. Several studies report some recovery in peripheral vision in approximately 30% to 35% of affected eyes.^20–22

PROMPT ACTION MAY SAVE SIGHT

Vision loss is a common presenting symptom in the emergency setting. A meticulous history and systematic physical examination can narrow the differential diagnosis of this neuro-ophthalmologic emergency. Acute retinal ischemia from central retinal artery occlusion is the ocular equivalent of an ischemic stroke, and they share risk factors, diagnostic workup, and management approaches.

Both etiologic subtypes (ie, arteritic and nonarteritic) require prompt intervention by front-line physicians. If giant cell arteritis is suspected, corticosteroid therapy must be initiated to save the contralateral retina from ischemia. Suspicion of central retinal artery occlusion warrants immediate evaluation by a neurologist to consider thrombolysis. Prompt action and interdisciplinary care involving an ophthalmologist, neurologist, and emergency or internal medicine physician may save a patient from permanent visual disability.

KEY POINTS

• Monocular vision loss requires urgent evaluation with a multidisciplinary management approach.
• There are no consensus treatment guidelines for nonarteritic central retinal artery occlusion, but the workup includes a comprehensive stroke evaluation.
• Arteritic central retinal artery occlusion is most often due to giant cell arteritis, and when it is suspected, the patient should be empirically treated with steroids.

An 83-year-old man presented to the emergency department with acute, painless loss of vision in his left eye. His vision in that eye had been normal in the middle of the night when he woke to use the restroom, but on awakening 6 hours later he could perceive only light or darkness.

He denied headache, scalp tenderness, jaw claudication, fever, weight loss, myalgia, or other neurologic symptoms. He had not experienced any recent change in his vision before this presentation, including halos around lights, floaters, eye pain, or redness. However, 6 months ago he had undergone left cataract surgery (left phacoemulsification with intraocular implant) without complications. And he said that when he was 3 years old, he had sustained a serious injury to his right eye.

His medical history included ischemic heart disease and hypertension. His medications included losartan, furosemide, amlodi­pine, atorvastatin, and aspirin.

CAUSES OF ACUTE MONOCULAR VISION LOSS

1. Which of the following is the least likely cause of this patient’s acute monocular vision loss?

• Optic neuritis
• Retinal vein occlusion
• Retinal artery occlusion
• Pituitary apoplexy
• Retinal detachment

Acute vision loss is often so distressing to the patient that the emergency department may be the first step in evaluation. While its diagnosis and management often require an interdisciplinary effort, early evaluation and triage of this potential medical emergency is often done by clinicians without specialized training in ophthalmology.

The physiology of vision is complex and the list of possible causes of vision loss is long, but the differential diagnosis can be narrowed quickly by considering the time course of vision loss and the anatomic localization.¹

The time course (including onset and tempo) of vision loss can classified as:

• Transient (ie, vision returned to normal by the time seen by clinician)
• Acute (instantaneous onset, ie, within seconds to minutes)
• Subacute (progression over days to weeks)
• Chronic (insidious progression over months to years).

Although acute vision loss is usually dramatic, insidious vision loss may occasionally be unnoticed for a surprisingly long time until the normal eye is inadvertently shielded.

Anatomic localization. Lesions anterior to the optic chiasm cause monocular vision loss, whereas lesions at or posterior to the chiasm lead to bilateral visual field defects. Problems leading to monocular blindness can be broadly divided into 3 anatomic categories (Figure 1):

• Ocular medial (including the cornea, anterior chamber, and lens)
• Retinal
• Neurologic (including the optic nerve and chiasm).

Clues from the history

A careful ophthalmic history is an essential initial step in the evaluation (Table 1). In addition, nonvisual symptoms can help narrow the differential diagnosis.

Nausea and vomiting often accompany acute elevation of intraocular pressure.

Focal neurologic deficits or other neurologic symptoms can point to a demyelinating disease such as multiple sclerosis.

Risk factors for vascular atherosclerotic disease such as diabetes, hypertension, and coronary artery disease raise concern for retinal, optic nerve, or cerebral ischemia.

Medications with anticholinergic and adrenergic properties can also precipitate monocular vision loss with acute angle-closure glaucoma.

Can we rule out anything yet?

Our patient presented with painless monocular vision loss. As discussed, causes of monocular vision loss can be localized to ocular abnormalities and prechiasmatic neurologic ones. Retinal detachment, occlusion of a retinal artery or vein, and optic neuritis are all important potential causes of acute monocular vision loss.

Pituitary apoplexy, on the other hand, is characterized by an acute increase in pituitary volume, often leading to compression of the optic chiasm resulting in a visual-field defect. It is most often characterized by binocular deficits (eg, bitemporal hemianopia) but is less likely to cause monocular vision loss.¹

CASE CONTINUED: EXAMINATION

On examination, the patient appeared comfortable. His temperature was 97.6°F (36.4°C), pulse 59 beats per minute, respiratory rate 18 per minute, and blood pressure 153/56 mm Hg.

Heart and lung examinations were notable for a grade 3 of 6 midsystolic, low-pitched murmur in the aortic area radiating to the neck, bilateral carotid bruits, and clear lungs. The cardiac impulse was normal in location and character. There was no evidence of aortic insufficiency (including auscultation during exhalation phase while sitting upright).

Eye examination. Visual acuity in the right eye was 20/200 with correction (owing to his eye injury at age 3). With the left eye, he could see only light or darkness. The conjunctiva and sclera were normal.

The right pupil was irregular and measured 3 mm (baseline from his previous eye injury). The left pupil was 3.5 mm. The direct pupillary response was preserved, but a relative afferent pupillary defect was present: on the swinging flashlight test, the left pupil dilated when the flashlight was passed from the right to the left pupil. Extraocular movements were full and intact bilaterally. The rest of the neurologic examination was normal.

An ophthalmologist was urgently consulted. A dilated funduscopic examination of the left eye revealed peripapillary atrophy, tortuous vessels, a cherry red macular spot, and flame hemorrhages, but no disc edema or pallor (Figure 2).

FURTHER WORKUP

2. Which of the following investigations would be least useful and not indicated at this point for this patient?

• Carotid ultrasonography
• Electrocardiography and echocardiography
• Magnetic resonance angiography of the brain
• Computed tomographic (CT) angiography of the head and neck
• Testing for the factor V Leiden and prothrombin gene mutations

A systematic ocular physical examination can offer important diagnostic information (Table 2). Ophthalmoscopy directly examines the optic disc, macula, and retinal vasculature. To interpret the funduscopic examination, we need a basic understanding of the vascular supply to the eye (Figure 3).

Information from references 4 and 5.

For example, the cherry red spot within the macula in our patient is characteristic of central retinal artery occlusion and highlights the relationship between anatomy and pathophysiology. The retina’s blood supply is compromised, leading to an ischemic, white background (secondary to edema of the inner third of the retina), but the macula continues to be nourished by the posterior ciliary arteries. This contrast in color is accentuated by the underlying structures composing the fovea, which lacks the nerve fiber layer and ganglion cell layer, making the vascular bed more visible.^2,3

Also in our patient, the marked reduction in visual acuity and relative afferent pupillary defect in the left eye point to unilateral optic nerve (or retinal ganglion cell) dysfunction. The findings on direct funduscopy were consistent with acute central retinal artery ischemia or occlusion. Central retinal artery occlusion can be either arteritic (due to inflammation, most often giant cell arteritis) or nonarteritic (due to atherosclerotic vascular disease).

Thus, carotid ultrasonography, electrocardiography, and transthoracic and transesophageal echocardiography are important components of the further workup. In addition, urgent brain imaging including either CT angiography or magnetic resonance angiography of the head and neck is indicated in all patients with central retinal artery occlusion.

Thrombophilia testing, including tests for the factor V Leiden and prothrombin gene mutations, is indicated in specific cases when a hypercoagulable state is suggested by components of the history, physical examination, and laboratory and radiologic testing. Thrombophilia testing would be low-yield and should not be part of the first-line testing in elderly patients with several atherosclerotic risk factors, such as our patient.

CASE CONTINUED: LABORATORY AND IMAGING EVIDENCE

Initial laboratory work showed:

• Mild microcytic anemia
• Erythrocyte sedimentation rate 77 mm/hour (reference range 1–10)
• C-reactive protein 4.0 mg/dL (reference range < 0.9).

The rest of the complete blood cell count and metabolic profile were unremarkable. His hemoglobin A_1c value was 5.3% (reference range 4.8%–6.2%).

A neurologist was urgently consulted.

Magnetic resonance imaging of the brain without contrast revealed nonspecific white-matter disease with no evidence of ischemic stroke.

Magnetic resonance angiography of the head and neck with contrast demonstrated 20% to 40% stenosis in both carotid arteries with otherwise patent anterior and posterior circulation.

Continuous monitoring of the left carotid artery with transcranial Doppler ultrasonography was also ordered, and the study concluded there were no undetected microembolic events.

Transthoracic echocardiography showed aortic sclerosis with no other abnormalities.

Ophthalmic fluorescein angiography was performed and showed patchy choroidal hypoperfusion, severe delayed filling, and extensive pruning of the arterial circulation with no  involvement of the posterior ciliary arteries.

Given the elevated inflammatory markers, pulse-dose intravenous methylprednisolone was started, and a temporal artery biopsy was planned.

CENTRAL RETINAL ARTERY OCCLUSION: NONARTERITIC VS ARTERITIC CAUSES

3. Which of the following is least useful to differentiate arteritic from nonarteritic causes of central retinal artery occlusion?

• Finding emboli in the retinal vasculature on funduscopy
• Temporal artery biopsy
• Measuring the C-reactive protein level and the erythrocyte sedimentation rate
• Echocardiography
• Positron-emission tomography (PET)
• Retinal fluorescein angiography

In patients diagnosed with central retinal artery occlusion, the next step is to differentiate between nonarteritic and arteritic causes, since separating them has therapeutic relevance.

The carotid artery is the main culprit for embolic disease affecting the central retinal artery, leading to the nonarteritic subtype. Thus, evaluation of acute retinal ischemia secondary to nonarteritic central retinal artery occlusion is similar to the evaluation of patients with an acute cerebral stroke.⁴ Studies have shown that 25% of patients diagnosed with central retinal artery occlusion have an additional ischemic insult in the cerebrovascular system, and these patients are at high risk of recurrent ocular or cerebral infarction. Workup includes diffusion-weighted MRI, angiography, echocardiography, and telemetry.⁵

Arteritic central retinal artery occlusion is most often caused by giant cell arteritis. The American College of Rheumatology classification criteria for giant cell arteritis include 3 of the following 5:

• Age 50 or older
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• Erythrocyte sedimentation rate 50 mm/hour or greater
• Positive biopsy findings.⁶  

Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis and should be done whenever the disease is suspected.^7,8 However, the test is invasive and imperfect, as a negative result does not completely rule out giant cell arteritis.⁹

Although a unilateral temporal artery biopsy can be falsely negative, several studies evaluating the efficacy of bilateral biopsies did not show significant improvement in the diagnostic yield.^10,11

Ophthalmic fluorescein angiography is another helpful test for distinguishing nonarteritic from arteritic central retinal artery occlusion.¹² Involvement of the posterior ciliary arteries usually occurs in giant cell arteritis, and this leads to choroidal malperfusion with or without retinal involvement. The optic nerve may also be infarcted by closure of the paraoptic vessels fed by the posterior ciliary vessels.^12,13 Such involvement of multiple vessels would not be typical with nonarteritic central retinal artery occlusion. Thus, this finding is helpful in making the final diagnosis along with supplying possible prognostic information.¹³

PET-CT is emerging as a test for early inflammation in extracranial disease, but its utility for diagnosing intracranial disease is limited by high uptake of the tracer fluoro­deoxyglucose by the brain and low resolution.¹⁴ Currently, it has no established role in the evaluation of patients with central retinal artery occlusion and would have no utility in differentiating arteritic vs nonarteritic causes of central retinal artery occlusion.

If giant cell arteritis is suspected, it is essential to start intravenous pulse-dose methyl­prednisolone early to prevent further vision loss in the contralateral eye. Treatment should not be delayed for invasive testing or temporal artery biopsy. Improvement in headache, jaw claudication, or scalp tenderness once steroids are initiated also helps support the diagnosis of giant cell arteritis.⁷

Unfortunately, visual symptoms may be irreversible despite treatment.

Our patient’s central retinal artery occlusion

This case highlights how difficult it is in practice to distinguish nonarteritic from arteritic central retinal artery occlusion.

Our patient had numerous cardiovascular risk factors, including known carotid and coronary artery disease, favoring a nonarteritic diagnosis.

On the other hand, his elevated inflammatory markers suggested an underlying inflammatory response. He lacked the characteristic headache and other systemic signs of giant cell arteritis, but this has been described in about 25% of patients.¹⁵ If emboli are seen on funduscopy, further workup for arteritic central retinal artery occlusion is not warranted, but emboli are not always present. Then again, absence of posterior ciliary artery involvement on fluorescein angiography pointed away from giant cell arteritis.

CASE CONTINUED: FINAL DIAGNOSIS

Biopsy of the left temporal artery showed intimal thickening with focal destruction of the internal elastic lamina by dystrophic calcification with no evidence of inflammatory infiltrates, giant cells, or granulomata in the adventitia, media, or intima. Based on the results of biopsy study and fluorescein angiography, we concluded that this was nonarteritic central retinal artery occlusion related to atherosclerotic disease.

Methylprednisolone was discontinued. The patient was discharged on aspirin, losartan, furosemide, amlodipine, and high-dose atorvastatin for standard stroke prevention. He was followed by the medical team and the ophthalmology department. At 6 weeks, there was only marginal improvement in the visual acuity of the left eye.

4. Management of nonarteritic central retinal artery occlusion could include all of the following except which one?

• Ocular massage
• Intravenous thrombolysis
• Intra-arterial thrombolysis
• Risk-factor modification
• Intraocular steroid injection

In patients with acute vision loss from nonarteritic central retinal artery occlusion, acute strategies to restore retinal perfusion include noninvasive “standard” therapies and thrombolysis (intravenous or intra-arterial). Unfortunately, consensus and guidelines are lacking.

Traditional therapies include sublingual isosorbide dinitrate, systemic pentoxifylline, inhalation of a carbogen, hyperbaric oxygen, ocular massage, intravenous acetazolamide and mannitol, anterior chamber paracentesis, and systemic steroids. However, none of these have been shown to be more effective than placebo.¹⁶

Thrombolytic therapy, analogous to the treatment of patients with ischemic stroke or myocardial infarction, is more controversial in acute central retinal artery occlusion.¹³ Data from small case-series suggested that intra-arterial or intravenous thrombolysis might improve visual acuity with reasonable safety.¹⁷ On the other hand, a randomized study from the United Kingdom that compared intra-arterial thrombolysis within a 24-hour window and conservative measures concluded that thrombolysis should not be used.¹⁸

Thrombolysis is thus used only in selected patients on a case-specific basis with involvement of a multispecialty team including stroke neurologists, especially if patients present within hours of onset and have concomitant neurologic symptoms.

Treatment beyond the acute phase focuses on preventing complications of the eye ischemia and aggressively managing systemic atherosclerotic risk factors to decrease the incidence of further ischemic events. Other interventions  include endarterectomy for significant carotid stenosis and anticoagulation to prevent cardioembolic embolization (such as atrial fibrillation). Most experts agree on the addition of an antiplatelet agent.^13,19

Intraocular steroid injection can be used in the management of some retinal disorders but has no value in nonarteritic central retinal artery occlusion.

Vision recovery in nonarteritic central retinal artery occlusion is variable, but the prognosis is generally poor. The visual acuity on presentation, the onset of the symptoms, and collateral vessels are major factors influencing long-term recovery. Most of the recovery occurs within 7 days and involves peripheral vision rather than central vision. Several studies report some recovery in peripheral vision in approximately 30% to 35% of affected eyes.^20–22

PROMPT ACTION MAY SAVE SIGHT

Vision loss is a common presenting symptom in the emergency setting. A meticulous history and systematic physical examination can narrow the differential diagnosis of this neuro-ophthalmologic emergency. Acute retinal ischemia from central retinal artery occlusion is the ocular equivalent of an ischemic stroke, and they share risk factors, diagnostic workup, and management approaches.

Both etiologic subtypes (ie, arteritic and nonarteritic) require prompt intervention by front-line physicians. If giant cell arteritis is suspected, corticosteroid therapy must be initiated to save the contralateral retina from ischemia. Suspicion of central retinal artery occlusion warrants immediate evaluation by a neurologist to consider thrombolysis. Prompt action and interdisciplinary care involving an ophthalmologist, neurologist, and emergency or internal medicine physician may save a patient from permanent visual disability.

KEY POINTS

• Monocular vision loss requires urgent evaluation with a multidisciplinary management approach.
• There are no consensus treatment guidelines for nonarteritic central retinal artery occlusion, but the workup includes a comprehensive stroke evaluation.
• Arteritic central retinal artery occlusion is most often due to giant cell arteritis, and when it is suspected, the patient should be empirically treated with steroids.

A 40-year-old man was brought to the emergency department with altered mental status. His roommate had found him lying unconscious in snow on the lawn outside his residence. When the emergency medical services team arrived, they recorded a core body temperature of 28.3°C (82.9°F) and instituted advanced cardiac life support.

During transit to the hospital, the patient’s heart rhythm changed from asystole to ventricular fibrillation, and defibrillation was performed twice.

Upon his arrival at the emergency room, advanced life support was continued, resulting in return of spontaneous circulation, with slow, wide-complex QRS rhythm noted on electrocardiography (ECG).

On examination, the patient’s pupils were fixed and dilated. The extremities were cold to palpation. The core body temperature dropped to 27.7°C (81.9°F).

Laboratory test results showed severe acidemia (arterial pH 6.8), elevated aspartate aminotransferase and alanine aminotransferase levels, and elevated creatinine and troponin. The troponin was measured 3 times and rose from 0.8 ng/mL to 0.9 ng/mL. A urine toxicology screen was positive for cannabinoids and cocaine.

ECG revealed J-point elevation (Osborn waves) in the precordial leads (Figure 1). A baseline electrocardiogram in the medical record from a previous admission had been normal.

An aggressive hypothermia protocol was initiated, but the patient died despite resuscitation efforts.

HYPOTHERMIA AND HEART RHYTHMS

Hypothermia—a core body temperature below 35°C (95°F)—causes generalized slowing of impulse conduction through cardiac tissues, shown on ECG as a prolongation of the PR, RR, QRS, and QT intervals.¹

A characteristic feature is elevation of the J point, also called the J wave or Osborn wave, most prominent in precordial leads V₂ to V₅ and caused by abnormal membrane repolarization in the early phase. The degree of hypothermia correlates linearly with the amplitude of the Osborn wave.^2,3

Laboratory tests can identify complications such as rhabdomyolysis, spontaneous bleeding, and lactic acidosis. Moderate to severe hypothermia may cause prolongation of all ECG intervals. Management requires resuscitation and rewarming.

Conditions to consider in the differential diagnosis are Brugada syndrome, hypercalcemia, and early repolarization syndrome.

A 40-year-old man was brought to the emergency department with altered mental status. His roommate had found him lying unconscious in snow on the lawn outside his residence. When the emergency medical services team arrived, they recorded a core body temperature of 28.3°C (82.9°F) and instituted advanced cardiac life support.

During transit to the hospital, the patient’s heart rhythm changed from asystole to ventricular fibrillation, and defibrillation was performed twice.

Upon his arrival at the emergency room, advanced life support was continued, resulting in return of spontaneous circulation, with slow, wide-complex QRS rhythm noted on electrocardiography (ECG).

On examination, the patient’s pupils were fixed and dilated. The extremities were cold to palpation. The core body temperature dropped to 27.7°C (81.9°F).

Laboratory test results showed severe acidemia (arterial pH 6.8), elevated aspartate aminotransferase and alanine aminotransferase levels, and elevated creatinine and troponin. The troponin was measured 3 times and rose from 0.8 ng/mL to 0.9 ng/mL. A urine toxicology screen was positive for cannabinoids and cocaine.

ECG revealed J-point elevation (Osborn waves) in the precordial leads (Figure 1). A baseline electrocardiogram in the medical record from a previous admission had been normal.

An aggressive hypothermia protocol was initiated, but the patient died despite resuscitation efforts.

HYPOTHERMIA AND HEART RHYTHMS

Hypothermia—a core body temperature below 35°C (95°F)—causes generalized slowing of impulse conduction through cardiac tissues, shown on ECG as a prolongation of the PR, RR, QRS, and QT intervals.¹

A characteristic feature is elevation of the J point, also called the J wave or Osborn wave, most prominent in precordial leads V₂ to V₅ and caused by abnormal membrane repolarization in the early phase. The degree of hypothermia correlates linearly with the amplitude of the Osborn wave.^2,3

Laboratory tests can identify complications such as rhabdomyolysis, spontaneous bleeding, and lactic acidosis. Moderate to severe hypothermia may cause prolongation of all ECG intervals. Management requires resuscitation and rewarming.

Conditions to consider in the differential diagnosis are Brugada syndrome, hypercalcemia, and early repolarization syndrome.

A 40-year-old man was brought to the emergency department with altered mental status. His roommate had found him lying unconscious in snow on the lawn outside his residence. When the emergency medical services team arrived, they recorded a core body temperature of 28.3°C (82.9°F) and instituted advanced cardiac life support.

During transit to the hospital, the patient’s heart rhythm changed from asystole to ventricular fibrillation, and defibrillation was performed twice.

Upon his arrival at the emergency room, advanced life support was continued, resulting in return of spontaneous circulation, with slow, wide-complex QRS rhythm noted on electrocardiography (ECG).

On examination, the patient’s pupils were fixed and dilated. The extremities were cold to palpation. The core body temperature dropped to 27.7°C (81.9°F).

Laboratory test results showed severe acidemia (arterial pH 6.8), elevated aspartate aminotransferase and alanine aminotransferase levels, and elevated creatinine and troponin. The troponin was measured 3 times and rose from 0.8 ng/mL to 0.9 ng/mL. A urine toxicology screen was positive for cannabinoids and cocaine.

ECG revealed J-point elevation (Osborn waves) in the precordial leads (Figure 1). A baseline electrocardiogram in the medical record from a previous admission had been normal.

An aggressive hypothermia protocol was initiated, but the patient died despite resuscitation efforts.

HYPOTHERMIA AND HEART RHYTHMS

Hypothermia—a core body temperature below 35°C (95°F)—causes generalized slowing of impulse conduction through cardiac tissues, shown on ECG as a prolongation of the PR, RR, QRS, and QT intervals.¹

A characteristic feature is elevation of the J point, also called the J wave or Osborn wave, most prominent in precordial leads V₂ to V₅ and caused by abnormal membrane repolarization in the early phase. The degree of hypothermia correlates linearly with the amplitude of the Osborn wave.^2,3

Laboratory tests can identify complications such as rhabdomyolysis, spontaneous bleeding, and lactic acidosis. Moderate to severe hypothermia may cause prolongation of all ECG intervals. Management requires resuscitation and rewarming.

Conditions to consider in the differential diagnosis are Brugada syndrome, hypercalcemia, and early repolarization syndrome.