A 43-year-old, previously healthy woman was admitted to the hospital after 1 day of severe epigastric abdominal pain, nausea, and vomiting. She denied alcohol or tobacco use.

Her physical examination revealed normal vital signs and epigastric tenderness without rebound tenderness.

Notable laboratory results:

• Aspartate aminotransferase 149 U/L (reference range 10–35)
• Alanine aminotransferase 140 U/L (10–35)
• Alkaline phosphatase 178 IU/L (35–104)
• Total bilirubin 1.8 mg/dL (0.2–1.3)
• Amylase 1,244 U/L (28–100)
• Lipase 14,628 U/L (7–59).

Abdominal ultrasonography showed a dilated bile duct and gallstones.

The patient was diagnosed with biliary pancreatitis and was treated by placing her on nothing-by-mouth (NPO) status and giving intravenous fluids and analgesics. All symptoms had resolved by hospital day 3. She underwent laparoscopic cholecystectomy and was discharged the following day.

This is a typical case of biliary pancreatitis that was diagnosed and treated appropriately with a positive outcome. But was it necessary or beneficial to measure both the serum amylase and serum lipase to make the correct diagnosis and treat the patient appropriately?

IS MEASURING SERUM AMYLASE NECESSARY?

The American College of Gastroenterology practice guidelines suggest that measuring both serum amylase and serum lipase is not necessary.¹ Serum lipase alone is the preferred test for diagnosing acute pancreatitis, since it is more sensitive than serum amylase, just as specific, rises more quickly, and remains elevated longer.

In a retrospective study of 151 patients with acute pancreatitis,² the sensitivity of lipase was 96.6% and the specificity was 99.4%.² In contrast, the sensitivity of amylase was 78.6% and the specificity was 99.1%.

In another study,³ in 476 patients with acute pancreatitis, lipase had a sensitivity of 91% vs 62% for amylase. Again, specificity was similar between the two tests (92% for lipase and 93% for amylase). The authors concluded that lipase should replace amylase as the first-line laboratory investigation for suspected acute pancreatitis.

Smith et al⁴ reviewed 1,825 patients with acute pancreatitis and similarly concluded that pancreatic lipase is a more accurate biomarker of acute pancreatitis than serum amylase.

PRACTICE AT OUR HOSPITAL

Despite this guideline and evidence, concurrent ordering of serum amylase and lipase is common at many institutions.

We evaluated the practice of ordering both serum amylase and lipase for diagnosis of acute pancreatitis at our 300-bed academic medical hospital. From January 2011 through August 2014, our institution completed 26,254 orders for serum amylase and lipase measurement in 13,198 patients. In 9,938 (75%) of the patients, amylase and lipase were ordered concurrently. Of these, 482 patients (4.8%) had either amylase or lipase elevated above the diagnostic threshold, ie, 3 times the upper limit of normal, and 63 of the 482 patients had an elevation in serum amylase greater than 3 times the upper limit of normal without an elevation in serum lipase.

None of the patients had acute pancreatitis clinically (eg, typical abdominal pain, nausea, vomiting) or on imaging (pancreatic edema). The definitive cause of nonpancreatic hyperamylasemia could not be determined in these patients; they did not have evidence of salivary disorder, malignancy, or tubo-ovarian disease, and the hyperamylasemia was believed to be related to renal disease, diabetic ketoacidosis, infection, or medications, or to be idiopathic.

In 12 patients, the discrepancy between an elevated amylase and normal lipase resulted in additional imaging with computed tomography. Four patients were also unnecessarily kept NPO for 1 to 3 days, depriving them of nutrition and prolonging their hospital stay.

To minimize concurrent ordering of serum amylase and lipase, we introduced a best-practice alert in the computerized physician order entry systems. The alert mentioned that “ordering both serum amylase and lipase in cases of suspected pancreatitis is unnecessary. Serum lipase alone is sufficient.” However, ordering providers could still order both tests if they wanted to.

In the 3 months after the alert was implemented, serum lipase was ordered 1,780 times with 532 (30%) concurrent orders of amylase. Before the alert was instituted, amylase testing was ordered a mean of 450 times per month; afterward, this decreased by about 60%.

We are now considering eliminating serum amylase testing, as suggested by prior studies⁵ and the American Society of Clinical Pathology.⁶

ELIMINATING NEEDLESS EXPENSES

The relentless and unsustainable rise in healthcare costs has prompted physician-led groups such as the American Board of Internal Medicine Foundation and the American College of Physicians to focus on ways to cut waste and incorporate high-value, cost-conscious care into clinical practice.

In 2009 alone, waste in total healthcare expenditures was estimated at $765 billion. More than half of this astronomical figure was attributed to unnecessary and inefficiently delivered services, expenditures that physicians can directly avoid with changes to their practice.^7,8 Unnecessary laboratory tests such as serum amylase are just one of many wasteful practices.

Hospitals have much to lose when unnecessary tests are ordered. For inpatient hospital admissions in the United States, payment is based on the diagnosis-related group system, in which hospitals are paid a fixed amount per diagnosis. There is no additional reimbursement for laboratory tests. An unnecessary test such as serum amylase in suspected cases of acute pancreatitis thus becomes an expense with no corresponding benefit.

The cost of performing a serum amylase test for a typical laboratory is around $4 to $6. Serum amylase testing at our hospital resulted in unnecessary expense of about $35,000 annually. If we add the costs of additional imaging and prolonged hospitalization, the expenses are substantially more.

Despite this, most hospitals have been unwilling or unable to tackle the problem. This may be due to respect for physician autonomy, seemingly small financial loss, or organizational inertia. For the entire healthcare system, these seemingly minor costs add up. For example, from 2011 to 2014, Medicare Part B alone spent $19.4 million on serum amylase testing.

Ordering unnecessary laboratory tests is not a problem specific to our hospital, but rather a common problem encountered at many hospitals. Recognizing the widespread practice of ordering amylase, the Choosing Wisely initiative shared new recommendations from the American Society for Clinical Pathology supporting the use of lipase instead of amylase in suspected acute pancreatitis.⁷

Physicians who continue to order these tests show a disregard for evidence-based medicine, patient care, and healthcare costs.

CLINICAL BOTTOM LINE

Concurrent use of amylase and lipase testing to diagnose acute pancreatitis is an unnecessary expense for the hospital and can negatively affect patient care as it can lead to additional tests and prolonged hospitalization. Steps should be taken to minimize ordering of amylase by educating physicians and instituting best-practice alerts, or by eliminating the test altogether.

A 43-year-old, previously healthy woman was admitted to the hospital after 1 day of severe epigastric abdominal pain, nausea, and vomiting. She denied alcohol or tobacco use.

Her physical examination revealed normal vital signs and epigastric tenderness without rebound tenderness.

Notable laboratory results:

• Aspartate aminotransferase 149 U/L (reference range 10–35)
• Alanine aminotransferase 140 U/L (10–35)
• Alkaline phosphatase 178 IU/L (35–104)
• Total bilirubin 1.8 mg/dL (0.2–1.3)
• Amylase 1,244 U/L (28–100)
• Lipase 14,628 U/L (7–59).

Abdominal ultrasonography showed a dilated bile duct and gallstones.

The patient was diagnosed with biliary pancreatitis and was treated by placing her on nothing-by-mouth (NPO) status and giving intravenous fluids and analgesics. All symptoms had resolved by hospital day 3. She underwent laparoscopic cholecystectomy and was discharged the following day.

This is a typical case of biliary pancreatitis that was diagnosed and treated appropriately with a positive outcome. But was it necessary or beneficial to measure both the serum amylase and serum lipase to make the correct diagnosis and treat the patient appropriately?

IS MEASURING SERUM AMYLASE NECESSARY?

The American College of Gastroenterology practice guidelines suggest that measuring both serum amylase and serum lipase is not necessary.¹ Serum lipase alone is the preferred test for diagnosing acute pancreatitis, since it is more sensitive than serum amylase, just as specific, rises more quickly, and remains elevated longer.

In a retrospective study of 151 patients with acute pancreatitis,² the sensitivity of lipase was 96.6% and the specificity was 99.4%.² In contrast, the sensitivity of amylase was 78.6% and the specificity was 99.1%.

In another study,³ in 476 patients with acute pancreatitis, lipase had a sensitivity of 91% vs 62% for amylase. Again, specificity was similar between the two tests (92% for lipase and 93% for amylase). The authors concluded that lipase should replace amylase as the first-line laboratory investigation for suspected acute pancreatitis.

Smith et al⁴ reviewed 1,825 patients with acute pancreatitis and similarly concluded that pancreatic lipase is a more accurate biomarker of acute pancreatitis than serum amylase.

PRACTICE AT OUR HOSPITAL

Despite this guideline and evidence, concurrent ordering of serum amylase and lipase is common at many institutions.

We evaluated the practice of ordering both serum amylase and lipase for diagnosis of acute pancreatitis at our 300-bed academic medical hospital. From January 2011 through August 2014, our institution completed 26,254 orders for serum amylase and lipase measurement in 13,198 patients. In 9,938 (75%) of the patients, amylase and lipase were ordered concurrently. Of these, 482 patients (4.8%) had either amylase or lipase elevated above the diagnostic threshold, ie, 3 times the upper limit of normal, and 63 of the 482 patients had an elevation in serum amylase greater than 3 times the upper limit of normal without an elevation in serum lipase.

None of the patients had acute pancreatitis clinically (eg, typical abdominal pain, nausea, vomiting) or on imaging (pancreatic edema). The definitive cause of nonpancreatic hyperamylasemia could not be determined in these patients; they did not have evidence of salivary disorder, malignancy, or tubo-ovarian disease, and the hyperamylasemia was believed to be related to renal disease, diabetic ketoacidosis, infection, or medications, or to be idiopathic.

In 12 patients, the discrepancy between an elevated amylase and normal lipase resulted in additional imaging with computed tomography. Four patients were also unnecessarily kept NPO for 1 to 3 days, depriving them of nutrition and prolonging their hospital stay.

To minimize concurrent ordering of serum amylase and lipase, we introduced a best-practice alert in the computerized physician order entry systems. The alert mentioned that “ordering both serum amylase and lipase in cases of suspected pancreatitis is unnecessary. Serum lipase alone is sufficient.” However, ordering providers could still order both tests if they wanted to.

In the 3 months after the alert was implemented, serum lipase was ordered 1,780 times with 532 (30%) concurrent orders of amylase. Before the alert was instituted, amylase testing was ordered a mean of 450 times per month; afterward, this decreased by about 60%.

We are now considering eliminating serum amylase testing, as suggested by prior studies⁵ and the American Society of Clinical Pathology.⁶

ELIMINATING NEEDLESS EXPENSES

The relentless and unsustainable rise in healthcare costs has prompted physician-led groups such as the American Board of Internal Medicine Foundation and the American College of Physicians to focus on ways to cut waste and incorporate high-value, cost-conscious care into clinical practice.

In 2009 alone, waste in total healthcare expenditures was estimated at $765 billion. More than half of this astronomical figure was attributed to unnecessary and inefficiently delivered services, expenditures that physicians can directly avoid with changes to their practice.^7,8 Unnecessary laboratory tests such as serum amylase are just one of many wasteful practices.

Hospitals have much to lose when unnecessary tests are ordered. For inpatient hospital admissions in the United States, payment is based on the diagnosis-related group system, in which hospitals are paid a fixed amount per diagnosis. There is no additional reimbursement for laboratory tests. An unnecessary test such as serum amylase in suspected cases of acute pancreatitis thus becomes an expense with no corresponding benefit.

The cost of performing a serum amylase test for a typical laboratory is around $4 to $6. Serum amylase testing at our hospital resulted in unnecessary expense of about $35,000 annually. If we add the costs of additional imaging and prolonged hospitalization, the expenses are substantially more.

Despite this, most hospitals have been unwilling or unable to tackle the problem. This may be due to respect for physician autonomy, seemingly small financial loss, or organizational inertia. For the entire healthcare system, these seemingly minor costs add up. For example, from 2011 to 2014, Medicare Part B alone spent $19.4 million on serum amylase testing.

Ordering unnecessary laboratory tests is not a problem specific to our hospital, but rather a common problem encountered at many hospitals. Recognizing the widespread practice of ordering amylase, the Choosing Wisely initiative shared new recommendations from the American Society for Clinical Pathology supporting the use of lipase instead of amylase in suspected acute pancreatitis.⁷

Physicians who continue to order these tests show a disregard for evidence-based medicine, patient care, and healthcare costs.

CLINICAL BOTTOM LINE

Concurrent use of amylase and lipase testing to diagnose acute pancreatitis is an unnecessary expense for the hospital and can negatively affect patient care as it can lead to additional tests and prolonged hospitalization. Steps should be taken to minimize ordering of amylase by educating physicians and instituting best-practice alerts, or by eliminating the test altogether.

A 43-year-old, previously healthy woman was admitted to the hospital after 1 day of severe epigastric abdominal pain, nausea, and vomiting. She denied alcohol or tobacco use.

Her physical examination revealed normal vital signs and epigastric tenderness without rebound tenderness.

Notable laboratory results:

• Aspartate aminotransferase 149 U/L (reference range 10–35)
• Alanine aminotransferase 140 U/L (10–35)
• Alkaline phosphatase 178 IU/L (35–104)
• Total bilirubin 1.8 mg/dL (0.2–1.3)
• Amylase 1,244 U/L (28–100)
• Lipase 14,628 U/L (7–59).

Abdominal ultrasonography showed a dilated bile duct and gallstones.

The patient was diagnosed with biliary pancreatitis and was treated by placing her on nothing-by-mouth (NPO) status and giving intravenous fluids and analgesics. All symptoms had resolved by hospital day 3. She underwent laparoscopic cholecystectomy and was discharged the following day.

This is a typical case of biliary pancreatitis that was diagnosed and treated appropriately with a positive outcome. But was it necessary or beneficial to measure both the serum amylase and serum lipase to make the correct diagnosis and treat the patient appropriately?

IS MEASURING SERUM AMYLASE NECESSARY?

The American College of Gastroenterology practice guidelines suggest that measuring both serum amylase and serum lipase is not necessary.¹ Serum lipase alone is the preferred test for diagnosing acute pancreatitis, since it is more sensitive than serum amylase, just as specific, rises more quickly, and remains elevated longer.

In a retrospective study of 151 patients with acute pancreatitis,² the sensitivity of lipase was 96.6% and the specificity was 99.4%.² In contrast, the sensitivity of amylase was 78.6% and the specificity was 99.1%.

In another study,³ in 476 patients with acute pancreatitis, lipase had a sensitivity of 91% vs 62% for amylase. Again, specificity was similar between the two tests (92% for lipase and 93% for amylase). The authors concluded that lipase should replace amylase as the first-line laboratory investigation for suspected acute pancreatitis.

Smith et al⁴ reviewed 1,825 patients with acute pancreatitis and similarly concluded that pancreatic lipase is a more accurate biomarker of acute pancreatitis than serum amylase.

PRACTICE AT OUR HOSPITAL

Despite this guideline and evidence, concurrent ordering of serum amylase and lipase is common at many institutions.

We evaluated the practice of ordering both serum amylase and lipase for diagnosis of acute pancreatitis at our 300-bed academic medical hospital. From January 2011 through August 2014, our institution completed 26,254 orders for serum amylase and lipase measurement in 13,198 patients. In 9,938 (75%) of the patients, amylase and lipase were ordered concurrently. Of these, 482 patients (4.8%) had either amylase or lipase elevated above the diagnostic threshold, ie, 3 times the upper limit of normal, and 63 of the 482 patients had an elevation in serum amylase greater than 3 times the upper limit of normal without an elevation in serum lipase.

None of the patients had acute pancreatitis clinically (eg, typical abdominal pain, nausea, vomiting) or on imaging (pancreatic edema). The definitive cause of nonpancreatic hyperamylasemia could not be determined in these patients; they did not have evidence of salivary disorder, malignancy, or tubo-ovarian disease, and the hyperamylasemia was believed to be related to renal disease, diabetic ketoacidosis, infection, or medications, or to be idiopathic.

In 12 patients, the discrepancy between an elevated amylase and normal lipase resulted in additional imaging with computed tomography. Four patients were also unnecessarily kept NPO for 1 to 3 days, depriving them of nutrition and prolonging their hospital stay.

To minimize concurrent ordering of serum amylase and lipase, we introduced a best-practice alert in the computerized physician order entry systems. The alert mentioned that “ordering both serum amylase and lipase in cases of suspected pancreatitis is unnecessary. Serum lipase alone is sufficient.” However, ordering providers could still order both tests if they wanted to.

In the 3 months after the alert was implemented, serum lipase was ordered 1,780 times with 532 (30%) concurrent orders of amylase. Before the alert was instituted, amylase testing was ordered a mean of 450 times per month; afterward, this decreased by about 60%.

We are now considering eliminating serum amylase testing, as suggested by prior studies⁵ and the American Society of Clinical Pathology.⁶

ELIMINATING NEEDLESS EXPENSES

The relentless and unsustainable rise in healthcare costs has prompted physician-led groups such as the American Board of Internal Medicine Foundation and the American College of Physicians to focus on ways to cut waste and incorporate high-value, cost-conscious care into clinical practice.

In 2009 alone, waste in total healthcare expenditures was estimated at $765 billion. More than half of this astronomical figure was attributed to unnecessary and inefficiently delivered services, expenditures that physicians can directly avoid with changes to their practice.^7,8 Unnecessary laboratory tests such as serum amylase are just one of many wasteful practices.

Hospitals have much to lose when unnecessary tests are ordered. For inpatient hospital admissions in the United States, payment is based on the diagnosis-related group system, in which hospitals are paid a fixed amount per diagnosis. There is no additional reimbursement for laboratory tests. An unnecessary test such as serum amylase in suspected cases of acute pancreatitis thus becomes an expense with no corresponding benefit.

The cost of performing a serum amylase test for a typical laboratory is around $4 to $6. Serum amylase testing at our hospital resulted in unnecessary expense of about $35,000 annually. If we add the costs of additional imaging and prolonged hospitalization, the expenses are substantially more.

Despite this, most hospitals have been unwilling or unable to tackle the problem. This may be due to respect for physician autonomy, seemingly small financial loss, or organizational inertia. For the entire healthcare system, these seemingly minor costs add up. For example, from 2011 to 2014, Medicare Part B alone spent $19.4 million on serum amylase testing.

Ordering unnecessary laboratory tests is not a problem specific to our hospital, but rather a common problem encountered at many hospitals. Recognizing the widespread practice of ordering amylase, the Choosing Wisely initiative shared new recommendations from the American Society for Clinical Pathology supporting the use of lipase instead of amylase in suspected acute pancreatitis.⁷

Physicians who continue to order these tests show a disregard for evidence-based medicine, patient care, and healthcare costs.

CLINICAL BOTTOM LINE

Concurrent use of amylase and lipase testing to diagnose acute pancreatitis is an unnecessary expense for the hospital and can negatively affect patient care as it can lead to additional tests and prolonged hospitalization. Steps should be taken to minimize ordering of amylase by educating physicians and instituting best-practice alerts, or by eliminating the test altogether.

Antibiotic stewardship has always been a good idea. Now it is also required by the Joint Commission and the Center for Medicare and Medicaid Services (CMS). This article reviews the state of antibiotic use in the United States and efforts to improve antibiotic stewardship in practice. 

ANTIBIOTICS ARE DIFFERENT FROM OTHER DRUGS

Their efficacy wanes over time. Antibiotics are the only medications that become less useful over time even if used correctly. Although other types of drugs are continuously being improved, the old ones work as well today as they did when they first came out. But antibiotics that were in use 50 years ago are no longer as effective.

They are a shared resource. Antibiotics are regularly used by many specialties to deliver routine and advanced medical care. Surgeries, transplantation, and immunosuppressive therapy would be unsafe without antibiotics to treat infections. Some patients awaiting lung transplant are not considered good candidates if they have evidence of colonization by antibiotic-resistant organisms.

Individual use may harm others. Even people who are not exposed to an antibiotic can suffer the consequences of how others use them.

In a retrospective cohort study, Freedberg et al¹ analyzed the risk of hospitalized patients developing Clostridium difficile infection and found that the risk was higher if the previous occupant of the bed had received antibiotics. The putative mechanism is that a patient receiving antibiotics develops altered gut flora, leading to C difficile spores released into the environment and not eradicated by normal cleaning. The next patient using the bed is then exposed and infected.

ANTIBIOTIC USE IS HIGH

The US Centers for Disease Control (CDC) monitors antibiotic prescriptions throughout the United States. In the outpatient setting, enough antibiotics are prescribed nationwide for 5 out of every 6 people to get 1 course of antibiotics annually (835 prescriptions per 1,000 people). Rates vary widely among states, with the lowest rate in Alaska (501 prescriptions per 1,000 people) and the highest in West Virginia (1,285 prescriptions per 1,000 people).² In comparison, Scandinavian countries prescribe about 400 courses per 1,000 people, about 20% less than our lowest-prescribing state.³

Antibiotics are probably the most frequently prescribed drugs in US hospitals. Data from 2006 to 2012 showed that 55% of hospitalized patients received at least 1 dose of an antibiotic and that overall about 75% of all hospital days involved an antibiotic.⁴ Rates did not vary by hospital size, but nonteaching hospitals tended to use antibiotics more than teaching hospitals. Antibiotic use is much more common in intensive care units than in hospital wards (1,092 and 720 days of antibiotic treatment per 1,000 patient-days, respectively).

Although overall antibiotic use did not change significantly over the years of the survey, use patterns did: fluoroquinolone use dropped by 20%, possibly reflecting rising resistance or increased attention to associated side effects (although fluoroquinolones remain the most widely prescribed inpatient antibiotic class), and use of first-generation cephalosporins fell by 7%. A cause for concern is that the use of broad-spectrum and “last-resort” antibiotics increased: carbapenem use by 37%, vancomycin use by 32%, beta-lactam/beta-lactamase inhibitor use by 26%, and third- and fourth-generation cephalosporin use by 12%.⁴

About one-third of use is unnecessary

Many studies have tried to measure the extent of inappropriate or unnecessary antibiotic use. The results have been remarkably consistent at 20% to 40% for both inpatient and outpatient studies. One study of hospitalized patients not in the intensive care unit found that 30% of 1,941 days of prescribed antimicrobial therapy were unnecessary, mostly because patients received antibiotics for longer than needed or because antibiotics were used to treat noninfectious syndromes or colonizing microorganisms.⁵  

ANTIBIOTIC EXPOSURE HAS NEGATIVE CONSEQUENCES

Any exposure to a medication involves the potential for side effects; this is true for antibiotics whether or not their use is appropriate. An estimated 140,000 visits to emergency departments occur annually for adverse reactions to antibiotics.⁶ In hospitalized patients, these reactions can be severe, including renal and bone marrow toxicity. As with any medications, the risks and benefits of antibiotic therapy must be weighed patient by patient.

Disturbance of gut microbiome

Antibiotics’ disruptive effects on normal gut flora are becoming better understood and are even believed to increase the risk of obesity and asthma.^7,8 

Animal models provide evidence that altered flora is associated with sepsis, which is attributed to the gut microbiome’s role in containing dissemination of bacteria in the body.⁹ An ecological study provides further evidence. Baggs et al¹⁰ retrospectively studied more than 9 million patients discharged without sepsis from 473 US hospitals, of whom 0.6% were readmitted for sepsis within 90 days. Exposure to a broad-spectrum antibiotic was associated with a 50% increased risk of readmission within 90 days of discharge because of sepsis (odds ratio 1.50, 95% confidence interval 1.47–1.53).

Increase of C difficile infections

Antibiotics exert selective pressure, killing susceptible bacteria and allowing resistant bacteria to thrive.

The risk of C difficile infection is 7 to 10 times higher than at baseline for 1 month after antibiotic use and 3 times higher than baseline in the 2 months after that.¹¹ Multiple studies have found that stewardship efforts to reduce antibiotic use have resulted in fewer C difficile infections.

A nationwide effort in England over the past decade to reduce C difficile infections has resulted in 50% less use of fluoroquinolones and third-generation cephalosporins in patients over age 65. During that time, the incidence of C difficile infection in that age group fell by about 70%, with concomitant reductions in mortality and colectomy associated with infection. No increase in rates of hospital admissions, infection complications, or death were observed.^12–14

The primary goal of antibiotic stewardship is better patient care. The goal is not reduced antibiotic use or cost savings, although these could be viewed as favorable side effects. Sometimes, better patient care involves using more antibiotics: eg, a patient with presumed sepsis should be started quickly on broad-spectrum antibiotics, an action that also falls under antibiotic stewardship. The focus for stewardship efforts should be on optimizing appropriate use, ie, promoting the use of the right agent at the correct dosage and for the proper duration.

Stewardship improves clinical outcomes

Antibiotic stewardship is important not only to society but to individual patients.

Singh et al¹⁵ randomized patients suspected of having ventilator-associated pneumonia (but with a low likelihood of pneumonia) to either a 3-day course of ciprofloxacin or standard care (antibiotics for 10 to 21 days, with the drug and duration chosen by the treating physician). After 3 days, the patients in the experimental group were reevaluated, and antibiotics were stopped if the likelihood of pneumonia was still deemed low. In patients who received only the short course of antibiotics, mean length of stay in the intensive care unit was 9 days and the risk of acquiring an antibiotic-resistant superinfection during hospitalization was 14%, compared with a 15-day length of stay and 38% risk of antibiotic-resistant superinfection in patients in the standard treatment group.

Fishman¹⁶ reported a study at a single hospital that randomized patients to either receive standard care according to physician choice or be treated according to an antibiotic stewardship program. Patients in the antibiotic stewardship group were almost 3 times more likely than controls to receive appropriate therapy according to guidelines. More important, the antibiotic stewardship patients were almost twice as likely to be cured of their infection and were more than 80% less likely to have treatment failure.

DEVELOPING EFFECTIVE ANTIBIOTIC STEWARDSHIP PROGRAMS

A good model for improving antibiotic use is a recent nationwide program designed to reduce central line-associated bloodstream infections.¹⁷ Rates of these infections have dropped by about 50% over the past 5 years. The program included:

• Research to better understand the problem and how to fight it
• Well-defined programs and interventions
• Education to implement interventions, eg, deploying teams to teach better techniques of inserting and maintaining central lines
• A strong national measurement system (the CDC’s National Healthcare Safety Network) to track infections.

What constitutes an antibiotic stewardship program?

The CDC examined successful stewardship programs in a variety of hospital types, including large academic hospitals and smaller hospitals, and identified 7 common core elements that could serve as general principles that were common to successful antibiotic stewardship programs¹⁸:

• Leadership commitment from administration
• A single leader responsible for outcomes
• A single pharmacy leader
• Tracking of antibiotic use
• Regular reporting of antibiotic use and resistance
• Educating providers on use and resistance
• Specific improvement interventions.

Stewardship is harder in some settings

In reply to a CDC survey in 2014, 41% of more than 4,000 hospitals reported that they had antibiotic stewardship programs with all 7 core elements. The single element that predicted whether a complete program was in place was leadership support.¹⁹ The following year, 48% of respondents reported that they had a complete program in place. Percentages varied among states, with highs in Utah (77%) and California (70%) and lows in North Dakota (12%) and Vermont (7%). Large hospitals and major teaching hospitals were more likely to have a program with all 7 elements: 31% of hospitals with 50 or fewer beds had a complete program vs 66% of hospitals with at least 200 beds.²⁰

Short-stay, critical-access hospitals pose a special challenge, as only 26% reported having all core elements.^19,20 These facilities have fewer than 25 beds, and many patient stays are less than 3 days. Some do not employ full-time pharmacists or full-time clinicians. The CDC is collaborating with the American Hospital Association and the Pew Charitable Trusts to focus efforts on helping these hospitals, which requires a more flexible approach. About 100 critical-access hospitals nationwide have reported implementing all of the core elements and can serve as models for the others.

MEASURING IMPROVEMENT

The CDC has adopted a 3-pronged approach to measuring improvements in hospital antibiotic use:

• Estimate national aggregate antibiotic use described above
• Acquire information on antibiotic use at facility, practice, and provider levels
• Assess appropriate antibiotic use.

In hospitals, the CDC has concentrated on facility-level measurement. Hospitals need a system to track their own use and compare it with that of similar facilities. The CDC’s monitoring program, the Antibiotic Use Option of the National Healthcare Safety Network, captures electronic data on antibiotic use in a facility, enabling monitoring of use in each unit. Data can also be aggregated at regional, state, and national levels. This information can be used to develop benchmarks for antibiotic use, so that similar hospitals can be compared.

What is the ‘right’ amount of antibiotic use? Enter SAAR

Creating benchmarks for antibiotic use poses a number of challenges compared with most other areas in healthcare. Most public health measures are binary—eg, people either get an infection, a vaccination, or a smoking cessation intervention or not—and the direction of progress is clear. Antibiotics are different: not everybody needs them, but some people do. Usage should be reduced, but by exactly how much is unclear and varies between hospitals. In addition, being an outlier does not necessarily indicate a problem: a hospital unit for organ transplants will have high rates of antibiotic use, which is likely appropriate.

The CDC has taken initial steps to develop a risk-adjusted benchmark measure for hospital antibiotic use, the Standardized Antimicrobial Administration Ratio (SAAR). It compares a hospital’s observed antibiotic use with a calculation of predicted use based on its facility characteristics. Although still at an early stage, SAAR has been released and has been endorsed by the National Quality Forum. About 200 hospitals are submitting data to the CDC and collaborating with the CDC to evaluate the SAAR’s utility in driving improved antibiotic use.

Problems in measuring appropriate use

Measuring appropriate antibiotic use is easier in the outpatient setting, where detailed data have been collected for many years.

Fleming-Dutra et al²¹ compared medications prescribed during outpatient visits and the diagnoses coded for the visits. They found that about 13% of all outpatient visits resulted in an antibiotic prescription, 30% of which had no listed diagnosis that would justify an antibiotic (eg, viral upper respiratory infection). This kind of information provides a target for stewardship programs.

It is more difficult to conduct such a study in a hospital setting. Simply comparing discharge diagnoses to antibiotics prescribed is not useful: often antibiotics are started presumptively on admission for a patient with signs and symptoms of an infection, then stopped if the diagnosis does not warrant antibiotics, which is a reasonable strategy.

Also, many times, a patient with asymptomatic bacteriuria, which does not warrant antibiotics, is misdiagnosed as having a urinary tract infection, which does. So simply looking at the discharge code may not reveal whether therapy was appropriate.

Some studies have provided useful information. Fridkin et al²² studied 36 hospitals for the use of vancomycin, which is an especially good candidate drug for study because guidelines exist for appropriate use. Data were collected only from patients given vancomycin for more than 3 days, which should have eliminated empiric use of the drug and included only pathogen-driven therapy. Cases where therapy was for skin and soft-tissue infections were excluded because cultures are not usually obtained for these cases. Of patients given vancomycin, 9% had no diagnostic culture obtained at antibiotic initiation, 22% had diagnostic culture but results showed no gram-positive bacterial growth, and 5% had culture results revealing only oxacillin-susceptible Staphylococcus aureus. In 36% of cases, opportunities existed for improved prescribing.

Such data could be collected from the electronic medical record, and the CDC is focusing efforts in this direction.

NATIONAL ACTIVITIES IN ANTIBIOTIC STEWARDSHIP

In 2014, the White House launched a national strategy to combat antibiotic resistance,²³ followed by an action plan in 2015.²⁴ As a result, new investments have been made to improve antibiotic use, including funding for state health departments to begin stewardship efforts and to expand public awareness of the problems of antibiotic overuse. Research efforts are also being funded to improve implementation of existing stewardship practices and to develop new ones.

CMS is also exploring how to drive improved antibiotic use. In October 2016, it started requiring all US nursing homes to have antibiotic stewardship programs, and a similar requirement for hospitals has been proposed.

The Joint Commission issued a standard requiring that all their accredited facilities, starting with hospitals, have an antibiotic stewardship program by January 2017. This standard requires implementation of all the CDC’s core elements.

PROVEN INTERVENTIONS

Focusing on key interventions that are likely to be effective and well received by providers is a useful strategy for antibiotic stewardship efforts. A number of such interventions have been supported by research.

Postprescription antibiotic reviews or antibiotic ‘time-outs’

Antibiotics are often started empirically to treat hospitalized patients suspected of having an infection. The need for the antibiotic should be assessed a few days later, when culture results and more clinical information are available.  

Elligsen et al²⁵ evaluated the effects of providing a formal review and suggestions for antimicrobial optimization to critical care teams of 3 intensive care units in a single hospital after 3 and 10 days of antibiotic therapy. Mean monthly antibiotic use decreased from 644 days of therapy per 1,000 patient-days in the preintervention period to 503 days of therapy per 1,000 patient-days (P < .0001). C difficile infections were reduced from 11 cases to 6. Overall gram-negative susceptibility to meropenem increased in the critical care units. 

Targeting specific infections

Some infections are especially important to target with improvement efforts.

In 2011, Magill et al²⁶  conducted 1-day prevalence surveys in 183 hospitals in 10 states to examine patterns of antibiotic use. They found that lower respiratory tract infections and urinary tract infections accounted for more than half of all antibiotic use (35% and 22%, respectively), making them good candidates for improved use.

Community-acquired pneumonia can be targeted at multiple fronts.  One study showed that almost 30% of patients diagnosed with community-acquired pneumonia in the emergency department did not actually have pneumonia.²⁷  Duration of antibiotic therapy could also be targeted. Guidelines recommend that most patients with uncomplicated community-acquired pneumonia receive 5 to 7 days of antibiotic therapy. Avdic et al²⁸ performed a simple intervention involving education and feedback to teams in 1 hospital regarding antibiotic choice and duration. This resulted in reducing the duration of therapy for community-acquired pneumonia from a median of 10 to 7 days.

Asymptomatic bacteriuria is often misdiagnosed as a urinary tract infection and treated unnecessarily.^29–31

Trautner et al³² addressed this problem by targeting urine cultures rather than antibiotics, using a simple algorithm: if a patient did not have symptoms of urinary tract infection (fever, acute hematuria, delirium, rigors, flank pain, pelvic discomfort, urgency, frequency, dysuria, suprapubic pain), a urine culture was not recommended. If a patient did have symptoms but a problem other than urinary tract infection was deemed likely, evaluation of other sources of infection was recommended. Use of the algorithm resulted in fewer urine cultures and less antibiotic overtreatment of asymptomatic bacteriuria. Reductions persisted after the intervention ended. 

Antibiotic time-out at hospital discharge

Another study evaluated an intervention that required a pharmacist consultation for the critical care team when a patient was to be discharged with intravenous antibiotics (most often for pneumonia). In 28% of cases, chart review revealed that the infection had been completely treated at the time of discharge, so further antibiotic treatment was not indicated. No patients who avoided antibiotics at discharge were readmitted or subsequently visited the emergency department.³³

Targeting outpatient settings

A number of studies have evaluated simple interventions to improve outpatient antibiotic prescribing. Meeker et al³⁴ had providers place a poster in their examination rooms with a picture of the physician and a signed letter committing to the appropriate use of antibiotics. Inappropriate antibiotic use decreased 20% in the intervention group vs controls (P = .02). 

In a subsequent study,³⁵ the same group required providers to include a justification note in the electronic medical record every time an antibiotic was prescribed for an indication when guidelines do not recommend one. Inappropriate prescribing dropped from 23% to 5% (P < .001).

Another intervention in this study³⁵ provided physicians with periodic feedback according to whether their therapy was concordant with guidelines. They received an email with a subject line of either “You are a top performer” or “You are not a top performer.” The contents of the email provided data on how many antibiotic prescriptions they wrote for conditions that did not warrant them and how their prescribing habits compared with those of their top-performing peers. Mean inappropriate antibiotic prescribing fell from 20% to 4%.³⁵

This is a critical time for antibiotic stewardship efforts in the United States. The need has never been more urgent and, fortunately, the opportunities have never been more abundant. Requirements for stewardship programs will drive implementation, but hospitals will need support and guidance to help ensure that stewardship programs are as effective as possible. Ultimately, improving antibiotic use will require collaboration among all stakeholders. CDC is eager to partner with providers and others in their efforts to improve antibiotic use.

Antibiotic stewardship has always been a good idea. Now it is also required by the Joint Commission and the Center for Medicare and Medicaid Services (CMS). This article reviews the state of antibiotic use in the United States and efforts to improve antibiotic stewardship in practice. 

ANTIBIOTICS ARE DIFFERENT FROM OTHER DRUGS

Their efficacy wanes over time. Antibiotics are the only medications that become less useful over time even if used correctly. Although other types of drugs are continuously being improved, the old ones work as well today as they did when they first came out. But antibiotics that were in use 50 years ago are no longer as effective.

They are a shared resource. Antibiotics are regularly used by many specialties to deliver routine and advanced medical care. Surgeries, transplantation, and immunosuppressive therapy would be unsafe without antibiotics to treat infections. Some patients awaiting lung transplant are not considered good candidates if they have evidence of colonization by antibiotic-resistant organisms.

Individual use may harm others. Even people who are not exposed to an antibiotic can suffer the consequences of how others use them.

In a retrospective cohort study, Freedberg et al¹ analyzed the risk of hospitalized patients developing Clostridium difficile infection and found that the risk was higher if the previous occupant of the bed had received antibiotics. The putative mechanism is that a patient receiving antibiotics develops altered gut flora, leading to C difficile spores released into the environment and not eradicated by normal cleaning. The next patient using the bed is then exposed and infected.

ANTIBIOTIC USE IS HIGH

The US Centers for Disease Control (CDC) monitors antibiotic prescriptions throughout the United States. In the outpatient setting, enough antibiotics are prescribed nationwide for 5 out of every 6 people to get 1 course of antibiotics annually (835 prescriptions per 1,000 people). Rates vary widely among states, with the lowest rate in Alaska (501 prescriptions per 1,000 people) and the highest in West Virginia (1,285 prescriptions per 1,000 people).² In comparison, Scandinavian countries prescribe about 400 courses per 1,000 people, about 20% less than our lowest-prescribing state.³

Antibiotics are probably the most frequently prescribed drugs in US hospitals. Data from 2006 to 2012 showed that 55% of hospitalized patients received at least 1 dose of an antibiotic and that overall about 75% of all hospital days involved an antibiotic.⁴ Rates did not vary by hospital size, but nonteaching hospitals tended to use antibiotics more than teaching hospitals. Antibiotic use is much more common in intensive care units than in hospital wards (1,092 and 720 days of antibiotic treatment per 1,000 patient-days, respectively).

Although overall antibiotic use did not change significantly over the years of the survey, use patterns did: fluoroquinolone use dropped by 20%, possibly reflecting rising resistance or increased attention to associated side effects (although fluoroquinolones remain the most widely prescribed inpatient antibiotic class), and use of first-generation cephalosporins fell by 7%. A cause for concern is that the use of broad-spectrum and “last-resort” antibiotics increased: carbapenem use by 37%, vancomycin use by 32%, beta-lactam/beta-lactamase inhibitor use by 26%, and third- and fourth-generation cephalosporin use by 12%.⁴

About one-third of use is unnecessary

Many studies have tried to measure the extent of inappropriate or unnecessary antibiotic use. The results have been remarkably consistent at 20% to 40% for both inpatient and outpatient studies. One study of hospitalized patients not in the intensive care unit found that 30% of 1,941 days of prescribed antimicrobial therapy were unnecessary, mostly because patients received antibiotics for longer than needed or because antibiotics were used to treat noninfectious syndromes or colonizing microorganisms.⁵  

ANTIBIOTIC EXPOSURE HAS NEGATIVE CONSEQUENCES

Any exposure to a medication involves the potential for side effects; this is true for antibiotics whether or not their use is appropriate. An estimated 140,000 visits to emergency departments occur annually for adverse reactions to antibiotics.⁶ In hospitalized patients, these reactions can be severe, including renal and bone marrow toxicity. As with any medications, the risks and benefits of antibiotic therapy must be weighed patient by patient.

Disturbance of gut microbiome

Antibiotics’ disruptive effects on normal gut flora are becoming better understood and are even believed to increase the risk of obesity and asthma.^7,8 

Animal models provide evidence that altered flora is associated with sepsis, which is attributed to the gut microbiome’s role in containing dissemination of bacteria in the body.⁹ An ecological study provides further evidence. Baggs et al¹⁰ retrospectively studied more than 9 million patients discharged without sepsis from 473 US hospitals, of whom 0.6% were readmitted for sepsis within 90 days. Exposure to a broad-spectrum antibiotic was associated with a 50% increased risk of readmission within 90 days of discharge because of sepsis (odds ratio 1.50, 95% confidence interval 1.47–1.53).

Increase of C difficile infections

Antibiotics exert selective pressure, killing susceptible bacteria and allowing resistant bacteria to thrive.

The risk of C difficile infection is 7 to 10 times higher than at baseline for 1 month after antibiotic use and 3 times higher than baseline in the 2 months after that.¹¹ Multiple studies have found that stewardship efforts to reduce antibiotic use have resulted in fewer C difficile infections.

A nationwide effort in England over the past decade to reduce C difficile infections has resulted in 50% less use of fluoroquinolones and third-generation cephalosporins in patients over age 65. During that time, the incidence of C difficile infection in that age group fell by about 70%, with concomitant reductions in mortality and colectomy associated with infection. No increase in rates of hospital admissions, infection complications, or death were observed.^12–14

The primary goal of antibiotic stewardship is better patient care. The goal is not reduced antibiotic use or cost savings, although these could be viewed as favorable side effects. Sometimes, better patient care involves using more antibiotics: eg, a patient with presumed sepsis should be started quickly on broad-spectrum antibiotics, an action that also falls under antibiotic stewardship. The focus for stewardship efforts should be on optimizing appropriate use, ie, promoting the use of the right agent at the correct dosage and for the proper duration.

Stewardship improves clinical outcomes

Antibiotic stewardship is important not only to society but to individual patients.

Singh et al¹⁵ randomized patients suspected of having ventilator-associated pneumonia (but with a low likelihood of pneumonia) to either a 3-day course of ciprofloxacin or standard care (antibiotics for 10 to 21 days, with the drug and duration chosen by the treating physician). After 3 days, the patients in the experimental group were reevaluated, and antibiotics were stopped if the likelihood of pneumonia was still deemed low. In patients who received only the short course of antibiotics, mean length of stay in the intensive care unit was 9 days and the risk of acquiring an antibiotic-resistant superinfection during hospitalization was 14%, compared with a 15-day length of stay and 38% risk of antibiotic-resistant superinfection in patients in the standard treatment group.

Fishman¹⁶ reported a study at a single hospital that randomized patients to either receive standard care according to physician choice or be treated according to an antibiotic stewardship program. Patients in the antibiotic stewardship group were almost 3 times more likely than controls to receive appropriate therapy according to guidelines. More important, the antibiotic stewardship patients were almost twice as likely to be cured of their infection and were more than 80% less likely to have treatment failure.

DEVELOPING EFFECTIVE ANTIBIOTIC STEWARDSHIP PROGRAMS

A good model for improving antibiotic use is a recent nationwide program designed to reduce central line-associated bloodstream infections.¹⁷ Rates of these infections have dropped by about 50% over the past 5 years. The program included:

• Research to better understand the problem and how to fight it
• Well-defined programs and interventions
• Education to implement interventions, eg, deploying teams to teach better techniques of inserting and maintaining central lines
• A strong national measurement system (the CDC’s National Healthcare Safety Network) to track infections.

What constitutes an antibiotic stewardship program?

The CDC examined successful stewardship programs in a variety of hospital types, including large academic hospitals and smaller hospitals, and identified 7 common core elements that could serve as general principles that were common to successful antibiotic stewardship programs¹⁸:

• Leadership commitment from administration
• A single leader responsible for outcomes
• A single pharmacy leader
• Tracking of antibiotic use
• Regular reporting of antibiotic use and resistance
• Educating providers on use and resistance
• Specific improvement interventions.

Stewardship is harder in some settings

In reply to a CDC survey in 2014, 41% of more than 4,000 hospitals reported that they had antibiotic stewardship programs with all 7 core elements. The single element that predicted whether a complete program was in place was leadership support.¹⁹ The following year, 48% of respondents reported that they had a complete program in place. Percentages varied among states, with highs in Utah (77%) and California (70%) and lows in North Dakota (12%) and Vermont (7%). Large hospitals and major teaching hospitals were more likely to have a program with all 7 elements: 31% of hospitals with 50 or fewer beds had a complete program vs 66% of hospitals with at least 200 beds.²⁰

Short-stay, critical-access hospitals pose a special challenge, as only 26% reported having all core elements.^19,20 These facilities have fewer than 25 beds, and many patient stays are less than 3 days. Some do not employ full-time pharmacists or full-time clinicians. The CDC is collaborating with the American Hospital Association and the Pew Charitable Trusts to focus efforts on helping these hospitals, which requires a more flexible approach. About 100 critical-access hospitals nationwide have reported implementing all of the core elements and can serve as models for the others.

MEASURING IMPROVEMENT

The CDC has adopted a 3-pronged approach to measuring improvements in hospital antibiotic use:

• Estimate national aggregate antibiotic use described above
• Acquire information on antibiotic use at facility, practice, and provider levels
• Assess appropriate antibiotic use.

In hospitals, the CDC has concentrated on facility-level measurement. Hospitals need a system to track their own use and compare it with that of similar facilities. The CDC’s monitoring program, the Antibiotic Use Option of the National Healthcare Safety Network, captures electronic data on antibiotic use in a facility, enabling monitoring of use in each unit. Data can also be aggregated at regional, state, and national levels. This information can be used to develop benchmarks for antibiotic use, so that similar hospitals can be compared.

What is the ‘right’ amount of antibiotic use? Enter SAAR

Creating benchmarks for antibiotic use poses a number of challenges compared with most other areas in healthcare. Most public health measures are binary—eg, people either get an infection, a vaccination, or a smoking cessation intervention or not—and the direction of progress is clear. Antibiotics are different: not everybody needs them, but some people do. Usage should be reduced, but by exactly how much is unclear and varies between hospitals. In addition, being an outlier does not necessarily indicate a problem: a hospital unit for organ transplants will have high rates of antibiotic use, which is likely appropriate.

The CDC has taken initial steps to develop a risk-adjusted benchmark measure for hospital antibiotic use, the Standardized Antimicrobial Administration Ratio (SAAR). It compares a hospital’s observed antibiotic use with a calculation of predicted use based on its facility characteristics. Although still at an early stage, SAAR has been released and has been endorsed by the National Quality Forum. About 200 hospitals are submitting data to the CDC and collaborating with the CDC to evaluate the SAAR’s utility in driving improved antibiotic use.

Problems in measuring appropriate use

Measuring appropriate antibiotic use is easier in the outpatient setting, where detailed data have been collected for many years.

Fleming-Dutra et al²¹ compared medications prescribed during outpatient visits and the diagnoses coded for the visits. They found that about 13% of all outpatient visits resulted in an antibiotic prescription, 30% of which had no listed diagnosis that would justify an antibiotic (eg, viral upper respiratory infection). This kind of information provides a target for stewardship programs.

It is more difficult to conduct such a study in a hospital setting. Simply comparing discharge diagnoses to antibiotics prescribed is not useful: often antibiotics are started presumptively on admission for a patient with signs and symptoms of an infection, then stopped if the diagnosis does not warrant antibiotics, which is a reasonable strategy.

Also, many times, a patient with asymptomatic bacteriuria, which does not warrant antibiotics, is misdiagnosed as having a urinary tract infection, which does. So simply looking at the discharge code may not reveal whether therapy was appropriate.

Some studies have provided useful information. Fridkin et al²² studied 36 hospitals for the use of vancomycin, which is an especially good candidate drug for study because guidelines exist for appropriate use. Data were collected only from patients given vancomycin for more than 3 days, which should have eliminated empiric use of the drug and included only pathogen-driven therapy. Cases where therapy was for skin and soft-tissue infections were excluded because cultures are not usually obtained for these cases. Of patients given vancomycin, 9% had no diagnostic culture obtained at antibiotic initiation, 22% had diagnostic culture but results showed no gram-positive bacterial growth, and 5% had culture results revealing only oxacillin-susceptible Staphylococcus aureus. In 36% of cases, opportunities existed for improved prescribing.

Such data could be collected from the electronic medical record, and the CDC is focusing efforts in this direction.

NATIONAL ACTIVITIES IN ANTIBIOTIC STEWARDSHIP

In 2014, the White House launched a national strategy to combat antibiotic resistance,²³ followed by an action plan in 2015.²⁴ As a result, new investments have been made to improve antibiotic use, including funding for state health departments to begin stewardship efforts and to expand public awareness of the problems of antibiotic overuse. Research efforts are also being funded to improve implementation of existing stewardship practices and to develop new ones.

CMS is also exploring how to drive improved antibiotic use. In October 2016, it started requiring all US nursing homes to have antibiotic stewardship programs, and a similar requirement for hospitals has been proposed.

The Joint Commission issued a standard requiring that all their accredited facilities, starting with hospitals, have an antibiotic stewardship program by January 2017. This standard requires implementation of all the CDC’s core elements.

PROVEN INTERVENTIONS

Focusing on key interventions that are likely to be effective and well received by providers is a useful strategy for antibiotic stewardship efforts. A number of such interventions have been supported by research.

Postprescription antibiotic reviews or antibiotic ‘time-outs’

Antibiotics are often started empirically to treat hospitalized patients suspected of having an infection. The need for the antibiotic should be assessed a few days later, when culture results and more clinical information are available.  

Elligsen et al²⁵ evaluated the effects of providing a formal review and suggestions for antimicrobial optimization to critical care teams of 3 intensive care units in a single hospital after 3 and 10 days of antibiotic therapy. Mean monthly antibiotic use decreased from 644 days of therapy per 1,000 patient-days in the preintervention period to 503 days of therapy per 1,000 patient-days (P < .0001). C difficile infections were reduced from 11 cases to 6. Overall gram-negative susceptibility to meropenem increased in the critical care units. 

Targeting specific infections

Some infections are especially important to target with improvement efforts.

In 2011, Magill et al²⁶  conducted 1-day prevalence surveys in 183 hospitals in 10 states to examine patterns of antibiotic use. They found that lower respiratory tract infections and urinary tract infections accounted for more than half of all antibiotic use (35% and 22%, respectively), making them good candidates for improved use.

Community-acquired pneumonia can be targeted at multiple fronts.  One study showed that almost 30% of patients diagnosed with community-acquired pneumonia in the emergency department did not actually have pneumonia.²⁷  Duration of antibiotic therapy could also be targeted. Guidelines recommend that most patients with uncomplicated community-acquired pneumonia receive 5 to 7 days of antibiotic therapy. Avdic et al²⁸ performed a simple intervention involving education and feedback to teams in 1 hospital regarding antibiotic choice and duration. This resulted in reducing the duration of therapy for community-acquired pneumonia from a median of 10 to 7 days.

Asymptomatic bacteriuria is often misdiagnosed as a urinary tract infection and treated unnecessarily.^29–31

Trautner et al³² addressed this problem by targeting urine cultures rather than antibiotics, using a simple algorithm: if a patient did not have symptoms of urinary tract infection (fever, acute hematuria, delirium, rigors, flank pain, pelvic discomfort, urgency, frequency, dysuria, suprapubic pain), a urine culture was not recommended. If a patient did have symptoms but a problem other than urinary tract infection was deemed likely, evaluation of other sources of infection was recommended. Use of the algorithm resulted in fewer urine cultures and less antibiotic overtreatment of asymptomatic bacteriuria. Reductions persisted after the intervention ended. 

Antibiotic time-out at hospital discharge

Another study evaluated an intervention that required a pharmacist consultation for the critical care team when a patient was to be discharged with intravenous antibiotics (most often for pneumonia). In 28% of cases, chart review revealed that the infection had been completely treated at the time of discharge, so further antibiotic treatment was not indicated. No patients who avoided antibiotics at discharge were readmitted or subsequently visited the emergency department.³³

Targeting outpatient settings

A number of studies have evaluated simple interventions to improve outpatient antibiotic prescribing. Meeker et al³⁴ had providers place a poster in their examination rooms with a picture of the physician and a signed letter committing to the appropriate use of antibiotics. Inappropriate antibiotic use decreased 20% in the intervention group vs controls (P = .02). 

In a subsequent study,³⁵ the same group required providers to include a justification note in the electronic medical record every time an antibiotic was prescribed for an indication when guidelines do not recommend one. Inappropriate prescribing dropped from 23% to 5% (P < .001).

Another intervention in this study³⁵ provided physicians with periodic feedback according to whether their therapy was concordant with guidelines. They received an email with a subject line of either “You are a top performer” or “You are not a top performer.” The contents of the email provided data on how many antibiotic prescriptions they wrote for conditions that did not warrant them and how their prescribing habits compared with those of their top-performing peers. Mean inappropriate antibiotic prescribing fell from 20% to 4%.³⁵

This is a critical time for antibiotic stewardship efforts in the United States. The need has never been more urgent and, fortunately, the opportunities have never been more abundant. Requirements for stewardship programs will drive implementation, but hospitals will need support and guidance to help ensure that stewardship programs are as effective as possible. Ultimately, improving antibiotic use will require collaboration among all stakeholders. CDC is eager to partner with providers and others in their efforts to improve antibiotic use.

Antibiotic stewardship has always been a good idea. Now it is also required by the Joint Commission and the Center for Medicare and Medicaid Services (CMS). This article reviews the state of antibiotic use in the United States and efforts to improve antibiotic stewardship in practice. 

ANTIBIOTICS ARE DIFFERENT FROM OTHER DRUGS

Their efficacy wanes over time. Antibiotics are the only medications that become less useful over time even if used correctly. Although other types of drugs are continuously being improved, the old ones work as well today as they did when they first came out. But antibiotics that were in use 50 years ago are no longer as effective.

They are a shared resource. Antibiotics are regularly used by many specialties to deliver routine and advanced medical care. Surgeries, transplantation, and immunosuppressive therapy would be unsafe without antibiotics to treat infections. Some patients awaiting lung transplant are not considered good candidates if they have evidence of colonization by antibiotic-resistant organisms.

Individual use may harm others. Even people who are not exposed to an antibiotic can suffer the consequences of how others use them.

In a retrospective cohort study, Freedberg et al¹ analyzed the risk of hospitalized patients developing Clostridium difficile infection and found that the risk was higher if the previous occupant of the bed had received antibiotics. The putative mechanism is that a patient receiving antibiotics develops altered gut flora, leading to C difficile spores released into the environment and not eradicated by normal cleaning. The next patient using the bed is then exposed and infected.

ANTIBIOTIC USE IS HIGH

The US Centers for Disease Control (CDC) monitors antibiotic prescriptions throughout the United States. In the outpatient setting, enough antibiotics are prescribed nationwide for 5 out of every 6 people to get 1 course of antibiotics annually (835 prescriptions per 1,000 people). Rates vary widely among states, with the lowest rate in Alaska (501 prescriptions per 1,000 people) and the highest in West Virginia (1,285 prescriptions per 1,000 people).² In comparison, Scandinavian countries prescribe about 400 courses per 1,000 people, about 20% less than our lowest-prescribing state.³

Antibiotics are probably the most frequently prescribed drugs in US hospitals. Data from 2006 to 2012 showed that 55% of hospitalized patients received at least 1 dose of an antibiotic and that overall about 75% of all hospital days involved an antibiotic.⁴ Rates did not vary by hospital size, but nonteaching hospitals tended to use antibiotics more than teaching hospitals. Antibiotic use is much more common in intensive care units than in hospital wards (1,092 and 720 days of antibiotic treatment per 1,000 patient-days, respectively).

Although overall antibiotic use did not change significantly over the years of the survey, use patterns did: fluoroquinolone use dropped by 20%, possibly reflecting rising resistance or increased attention to associated side effects (although fluoroquinolones remain the most widely prescribed inpatient antibiotic class), and use of first-generation cephalosporins fell by 7%. A cause for concern is that the use of broad-spectrum and “last-resort” antibiotics increased: carbapenem use by 37%, vancomycin use by 32%, beta-lactam/beta-lactamase inhibitor use by 26%, and third- and fourth-generation cephalosporin use by 12%.⁴

About one-third of use is unnecessary

Many studies have tried to measure the extent of inappropriate or unnecessary antibiotic use. The results have been remarkably consistent at 20% to 40% for both inpatient and outpatient studies. One study of hospitalized patients not in the intensive care unit found that 30% of 1,941 days of prescribed antimicrobial therapy were unnecessary, mostly because patients received antibiotics for longer than needed or because antibiotics were used to treat noninfectious syndromes or colonizing microorganisms.⁵  

ANTIBIOTIC EXPOSURE HAS NEGATIVE CONSEQUENCES

Any exposure to a medication involves the potential for side effects; this is true for antibiotics whether or not their use is appropriate. An estimated 140,000 visits to emergency departments occur annually for adverse reactions to antibiotics.⁶ In hospitalized patients, these reactions can be severe, including renal and bone marrow toxicity. As with any medications, the risks and benefits of antibiotic therapy must be weighed patient by patient.

Disturbance of gut microbiome

Antibiotics’ disruptive effects on normal gut flora are becoming better understood and are even believed to increase the risk of obesity and asthma.^7,8 

Animal models provide evidence that altered flora is associated with sepsis, which is attributed to the gut microbiome’s role in containing dissemination of bacteria in the body.⁹ An ecological study provides further evidence. Baggs et al¹⁰ retrospectively studied more than 9 million patients discharged without sepsis from 473 US hospitals, of whom 0.6% were readmitted for sepsis within 90 days. Exposure to a broad-spectrum antibiotic was associated with a 50% increased risk of readmission within 90 days of discharge because of sepsis (odds ratio 1.50, 95% confidence interval 1.47–1.53).

Increase of C difficile infections

Antibiotics exert selective pressure, killing susceptible bacteria and allowing resistant bacteria to thrive.

The risk of C difficile infection is 7 to 10 times higher than at baseline for 1 month after antibiotic use and 3 times higher than baseline in the 2 months after that.¹¹ Multiple studies have found that stewardship efforts to reduce antibiotic use have resulted in fewer C difficile infections.

A nationwide effort in England over the past decade to reduce C difficile infections has resulted in 50% less use of fluoroquinolones and third-generation cephalosporins in patients over age 65. During that time, the incidence of C difficile infection in that age group fell by about 70%, with concomitant reductions in mortality and colectomy associated with infection. No increase in rates of hospital admissions, infection complications, or death were observed.^12–14

The primary goal of antibiotic stewardship is better patient care. The goal is not reduced antibiotic use or cost savings, although these could be viewed as favorable side effects. Sometimes, better patient care involves using more antibiotics: eg, a patient with presumed sepsis should be started quickly on broad-spectrum antibiotics, an action that also falls under antibiotic stewardship. The focus for stewardship efforts should be on optimizing appropriate use, ie, promoting the use of the right agent at the correct dosage and for the proper duration.

Stewardship improves clinical outcomes

Antibiotic stewardship is important not only to society but to individual patients.

Singh et al¹⁵ randomized patients suspected of having ventilator-associated pneumonia (but with a low likelihood of pneumonia) to either a 3-day course of ciprofloxacin or standard care (antibiotics for 10 to 21 days, with the drug and duration chosen by the treating physician). After 3 days, the patients in the experimental group were reevaluated, and antibiotics were stopped if the likelihood of pneumonia was still deemed low. In patients who received only the short course of antibiotics, mean length of stay in the intensive care unit was 9 days and the risk of acquiring an antibiotic-resistant superinfection during hospitalization was 14%, compared with a 15-day length of stay and 38% risk of antibiotic-resistant superinfection in patients in the standard treatment group.

Fishman¹⁶ reported a study at a single hospital that randomized patients to either receive standard care according to physician choice or be treated according to an antibiotic stewardship program. Patients in the antibiotic stewardship group were almost 3 times more likely than controls to receive appropriate therapy according to guidelines. More important, the antibiotic stewardship patients were almost twice as likely to be cured of their infection and were more than 80% less likely to have treatment failure.

DEVELOPING EFFECTIVE ANTIBIOTIC STEWARDSHIP PROGRAMS

A good model for improving antibiotic use is a recent nationwide program designed to reduce central line-associated bloodstream infections.¹⁷ Rates of these infections have dropped by about 50% over the past 5 years. The program included:

• Research to better understand the problem and how to fight it
• Well-defined programs and interventions
• Education to implement interventions, eg, deploying teams to teach better techniques of inserting and maintaining central lines
• A strong national measurement system (the CDC’s National Healthcare Safety Network) to track infections.

What constitutes an antibiotic stewardship program?

The CDC examined successful stewardship programs in a variety of hospital types, including large academic hospitals and smaller hospitals, and identified 7 common core elements that could serve as general principles that were common to successful antibiotic stewardship programs¹⁸:

• Leadership commitment from administration
• A single leader responsible for outcomes
• A single pharmacy leader
• Tracking of antibiotic use
• Regular reporting of antibiotic use and resistance
• Educating providers on use and resistance
• Specific improvement interventions.

Stewardship is harder in some settings

In reply to a CDC survey in 2014, 41% of more than 4,000 hospitals reported that they had antibiotic stewardship programs with all 7 core elements. The single element that predicted whether a complete program was in place was leadership support.¹⁹ The following year, 48% of respondents reported that they had a complete program in place. Percentages varied among states, with highs in Utah (77%) and California (70%) and lows in North Dakota (12%) and Vermont (7%). Large hospitals and major teaching hospitals were more likely to have a program with all 7 elements: 31% of hospitals with 50 or fewer beds had a complete program vs 66% of hospitals with at least 200 beds.²⁰

Short-stay, critical-access hospitals pose a special challenge, as only 26% reported having all core elements.^19,20 These facilities have fewer than 25 beds, and many patient stays are less than 3 days. Some do not employ full-time pharmacists or full-time clinicians. The CDC is collaborating with the American Hospital Association and the Pew Charitable Trusts to focus efforts on helping these hospitals, which requires a more flexible approach. About 100 critical-access hospitals nationwide have reported implementing all of the core elements and can serve as models for the others.

MEASURING IMPROVEMENT

The CDC has adopted a 3-pronged approach to measuring improvements in hospital antibiotic use:

• Estimate national aggregate antibiotic use described above
• Acquire information on antibiotic use at facility, practice, and provider levels
• Assess appropriate antibiotic use.

In hospitals, the CDC has concentrated on facility-level measurement. Hospitals need a system to track their own use and compare it with that of similar facilities. The CDC’s monitoring program, the Antibiotic Use Option of the National Healthcare Safety Network, captures electronic data on antibiotic use in a facility, enabling monitoring of use in each unit. Data can also be aggregated at regional, state, and national levels. This information can be used to develop benchmarks for antibiotic use, so that similar hospitals can be compared.

What is the ‘right’ amount of antibiotic use? Enter SAAR

Creating benchmarks for antibiotic use poses a number of challenges compared with most other areas in healthcare. Most public health measures are binary—eg, people either get an infection, a vaccination, or a smoking cessation intervention or not—and the direction of progress is clear. Antibiotics are different: not everybody needs them, but some people do. Usage should be reduced, but by exactly how much is unclear and varies between hospitals. In addition, being an outlier does not necessarily indicate a problem: a hospital unit for organ transplants will have high rates of antibiotic use, which is likely appropriate.

The CDC has taken initial steps to develop a risk-adjusted benchmark measure for hospital antibiotic use, the Standardized Antimicrobial Administration Ratio (SAAR). It compares a hospital’s observed antibiotic use with a calculation of predicted use based on its facility characteristics. Although still at an early stage, SAAR has been released and has been endorsed by the National Quality Forum. About 200 hospitals are submitting data to the CDC and collaborating with the CDC to evaluate the SAAR’s utility in driving improved antibiotic use.

Problems in measuring appropriate use

Measuring appropriate antibiotic use is easier in the outpatient setting, where detailed data have been collected for many years.

Fleming-Dutra et al²¹ compared medications prescribed during outpatient visits and the diagnoses coded for the visits. They found that about 13% of all outpatient visits resulted in an antibiotic prescription, 30% of which had no listed diagnosis that would justify an antibiotic (eg, viral upper respiratory infection). This kind of information provides a target for stewardship programs.

It is more difficult to conduct such a study in a hospital setting. Simply comparing discharge diagnoses to antibiotics prescribed is not useful: often antibiotics are started presumptively on admission for a patient with signs and symptoms of an infection, then stopped if the diagnosis does not warrant antibiotics, which is a reasonable strategy.

Also, many times, a patient with asymptomatic bacteriuria, which does not warrant antibiotics, is misdiagnosed as having a urinary tract infection, which does. So simply looking at the discharge code may not reveal whether therapy was appropriate.

Some studies have provided useful information. Fridkin et al²² studied 36 hospitals for the use of vancomycin, which is an especially good candidate drug for study because guidelines exist for appropriate use. Data were collected only from patients given vancomycin for more than 3 days, which should have eliminated empiric use of the drug and included only pathogen-driven therapy. Cases where therapy was for skin and soft-tissue infections were excluded because cultures are not usually obtained for these cases. Of patients given vancomycin, 9% had no diagnostic culture obtained at antibiotic initiation, 22% had diagnostic culture but results showed no gram-positive bacterial growth, and 5% had culture results revealing only oxacillin-susceptible Staphylococcus aureus. In 36% of cases, opportunities existed for improved prescribing.

Such data could be collected from the electronic medical record, and the CDC is focusing efforts in this direction.

NATIONAL ACTIVITIES IN ANTIBIOTIC STEWARDSHIP

In 2014, the White House launched a national strategy to combat antibiotic resistance,²³ followed by an action plan in 2015.²⁴ As a result, new investments have been made to improve antibiotic use, including funding for state health departments to begin stewardship efforts and to expand public awareness of the problems of antibiotic overuse. Research efforts are also being funded to improve implementation of existing stewardship practices and to develop new ones.

CMS is also exploring how to drive improved antibiotic use. In October 2016, it started requiring all US nursing homes to have antibiotic stewardship programs, and a similar requirement for hospitals has been proposed.

The Joint Commission issued a standard requiring that all their accredited facilities, starting with hospitals, have an antibiotic stewardship program by January 2017. This standard requires implementation of all the CDC’s core elements.

PROVEN INTERVENTIONS

Focusing on key interventions that are likely to be effective and well received by providers is a useful strategy for antibiotic stewardship efforts. A number of such interventions have been supported by research.

Postprescription antibiotic reviews or antibiotic ‘time-outs’

Antibiotics are often started empirically to treat hospitalized patients suspected of having an infection. The need for the antibiotic should be assessed a few days later, when culture results and more clinical information are available.  

Elligsen et al²⁵ evaluated the effects of providing a formal review and suggestions for antimicrobial optimization to critical care teams of 3 intensive care units in a single hospital after 3 and 10 days of antibiotic therapy. Mean monthly antibiotic use decreased from 644 days of therapy per 1,000 patient-days in the preintervention period to 503 days of therapy per 1,000 patient-days (P < .0001). C difficile infections were reduced from 11 cases to 6. Overall gram-negative susceptibility to meropenem increased in the critical care units. 

Targeting specific infections

Some infections are especially important to target with improvement efforts.

In 2011, Magill et al²⁶  conducted 1-day prevalence surveys in 183 hospitals in 10 states to examine patterns of antibiotic use. They found that lower respiratory tract infections and urinary tract infections accounted for more than half of all antibiotic use (35% and 22%, respectively), making them good candidates for improved use.

Community-acquired pneumonia can be targeted at multiple fronts.  One study showed that almost 30% of patients diagnosed with community-acquired pneumonia in the emergency department did not actually have pneumonia.²⁷  Duration of antibiotic therapy could also be targeted. Guidelines recommend that most patients with uncomplicated community-acquired pneumonia receive 5 to 7 days of antibiotic therapy. Avdic et al²⁸ performed a simple intervention involving education and feedback to teams in 1 hospital regarding antibiotic choice and duration. This resulted in reducing the duration of therapy for community-acquired pneumonia from a median of 10 to 7 days.

Asymptomatic bacteriuria is often misdiagnosed as a urinary tract infection and treated unnecessarily.^29–31

Trautner et al³² addressed this problem by targeting urine cultures rather than antibiotics, using a simple algorithm: if a patient did not have symptoms of urinary tract infection (fever, acute hematuria, delirium, rigors, flank pain, pelvic discomfort, urgency, frequency, dysuria, suprapubic pain), a urine culture was not recommended. If a patient did have symptoms but a problem other than urinary tract infection was deemed likely, evaluation of other sources of infection was recommended. Use of the algorithm resulted in fewer urine cultures and less antibiotic overtreatment of asymptomatic bacteriuria. Reductions persisted after the intervention ended. 

Antibiotic time-out at hospital discharge

Another study evaluated an intervention that required a pharmacist consultation for the critical care team when a patient was to be discharged with intravenous antibiotics (most often for pneumonia). In 28% of cases, chart review revealed that the infection had been completely treated at the time of discharge, so further antibiotic treatment was not indicated. No patients who avoided antibiotics at discharge were readmitted or subsequently visited the emergency department.³³

Targeting outpatient settings

A number of studies have evaluated simple interventions to improve outpatient antibiotic prescribing. Meeker et al³⁴ had providers place a poster in their examination rooms with a picture of the physician and a signed letter committing to the appropriate use of antibiotics. Inappropriate antibiotic use decreased 20% in the intervention group vs controls (P = .02). 

In a subsequent study,³⁵ the same group required providers to include a justification note in the electronic medical record every time an antibiotic was prescribed for an indication when guidelines do not recommend one. Inappropriate prescribing dropped from 23% to 5% (P < .001).

Another intervention in this study³⁵ provided physicians with periodic feedback according to whether their therapy was concordant with guidelines. They received an email with a subject line of either “You are a top performer” or “You are not a top performer.” The contents of the email provided data on how many antibiotic prescriptions they wrote for conditions that did not warrant them and how their prescribing habits compared with those of their top-performing peers. Mean inappropriate antibiotic prescribing fell from 20% to 4%.³⁵

This is a critical time for antibiotic stewardship efforts in the United States. The need has never been more urgent and, fortunately, the opportunities have never been more abundant. Requirements for stewardship programs will drive implementation, but hospitals will need support and guidance to help ensure that stewardship programs are as effective as possible. Ultimately, improving antibiotic use will require collaboration among all stakeholders. CDC is eager to partner with providers and others in their efforts to improve antibiotic use.

An 83-year-old man presented with fatigue and anorexia. Two years earlier, a small lung nodule had been found that was suspected to be primary lung cancer; however, he had refused surgical treatment or chemotherapy because of his age.

Aminotransferase and alkaline phosphatase levels had been normal, and results of serologic testing for hepatitis viruses were negative, making chronic liver disease unlikely. He was not a habitual drinker and was not taking any medications.

Laboratory and imaging studies revealed lung cancer with hepatic metastasis complicated by severe hypercalcemia. The estradiol level was normal, but the serum vascular endothelial growth factor (VEGF) concentration was high.

PALMAR ERYTHEMA AND SYSTEMIC DISEASE

Palmar erythema syndrome is characterized by reddening of the palmar skin, especially in the thenar and hypothenar areas, the distal portion of the palm, and the fingertips; the dorsal surface of the hand is rarely affected.¹ The affected areas are typically not pruritic or painful.

Conditions in the differential diagnosis

The differential diagnosis of palmar erythema includes allergic drug eruptions, contact dermatitis, erythema multiforme, cellulitis, dermatomyositis, and palmoplantar pustulosis. Hand-foot syndrome and hand-foot skin reaction are other important conditions to consider in cancer patients undergoing chemotherapy.² Hand-foot syndrome and hand-foot skin reaction can present as palmoplantar erythema and are usually accompanied by dysesthesia and swelling.

Palmar erythema can develop in either primary or secondary forms as a result of an underlying systemic disease.² Although the pathogenesis is not fully understood, the impaired degradation or increased production of angiogenic factors appears to be essential. The hormone estrogen can induce vascularization³ and is known to cause palmar erythema in pregnant women and patients with cirrhosis. Because estradiol is metabolized in the liver, increased levels of estrogen are associated with hepatic decompensation in cirrhosis.⁴

Neoplasm can cause palmar erythema.^2,5 In a clinicopathologic study of brain tumors, palmar erythema was recognized in 27 (25%) of 107 patients.⁵ Histologic examination in that study demonstrated that the intensity of erythema correlated with both cutaneous vessel dilation and prominent vascularization in the patients’ brain tumors, suggesting the role of circulating angiogenic factors such as VEGF. VEGF is a potent mediator of angiogenesis, which is critical for tumor development and growth.⁶

Our patient had a metastatic hepatic tumor, a normal estradiol level, and an increased level of VEGF, suggesting that the VEGF produced by the neoplasm promoted the development of palmar erythema.

The presence of palmar erythema in cancer patients is likely underestimated² and may suggest the presence of malignancy when it develops in the elderly.

In our patient, intensive hydration and intravenous bisphosphonate administration rapidly corrected the malignancy-associated hypercalcemia. However, he was severely debilitated during the hospital stay and developed aspiration pneumonia repeatedly. Thereafter, he was transferred to hospice care. The palmar erythema remained after the electrolyte disorder was corrected.

An 83-year-old man presented with fatigue and anorexia. Two years earlier, a small lung nodule had been found that was suspected to be primary lung cancer; however, he had refused surgical treatment or chemotherapy because of his age.

Aminotransferase and alkaline phosphatase levels had been normal, and results of serologic testing for hepatitis viruses were negative, making chronic liver disease unlikely. He was not a habitual drinker and was not taking any medications.

Laboratory and imaging studies revealed lung cancer with hepatic metastasis complicated by severe hypercalcemia. The estradiol level was normal, but the serum vascular endothelial growth factor (VEGF) concentration was high.

PALMAR ERYTHEMA AND SYSTEMIC DISEASE

Palmar erythema syndrome is characterized by reddening of the palmar skin, especially in the thenar and hypothenar areas, the distal portion of the palm, and the fingertips; the dorsal surface of the hand is rarely affected.¹ The affected areas are typically not pruritic or painful.

Conditions in the differential diagnosis

The differential diagnosis of palmar erythema includes allergic drug eruptions, contact dermatitis, erythema multiforme, cellulitis, dermatomyositis, and palmoplantar pustulosis. Hand-foot syndrome and hand-foot skin reaction are other important conditions to consider in cancer patients undergoing chemotherapy.² Hand-foot syndrome and hand-foot skin reaction can present as palmoplantar erythema and are usually accompanied by dysesthesia and swelling.

Palmar erythema can develop in either primary or secondary forms as a result of an underlying systemic disease.² Although the pathogenesis is not fully understood, the impaired degradation or increased production of angiogenic factors appears to be essential. The hormone estrogen can induce vascularization³ and is known to cause palmar erythema in pregnant women and patients with cirrhosis. Because estradiol is metabolized in the liver, increased levels of estrogen are associated with hepatic decompensation in cirrhosis.⁴

Neoplasm can cause palmar erythema.^2,5 In a clinicopathologic study of brain tumors, palmar erythema was recognized in 27 (25%) of 107 patients.⁵ Histologic examination in that study demonstrated that the intensity of erythema correlated with both cutaneous vessel dilation and prominent vascularization in the patients’ brain tumors, suggesting the role of circulating angiogenic factors such as VEGF. VEGF is a potent mediator of angiogenesis, which is critical for tumor development and growth.⁶

Our patient had a metastatic hepatic tumor, a normal estradiol level, and an increased level of VEGF, suggesting that the VEGF produced by the neoplasm promoted the development of palmar erythema.

The presence of palmar erythema in cancer patients is likely underestimated² and may suggest the presence of malignancy when it develops in the elderly.

In our patient, intensive hydration and intravenous bisphosphonate administration rapidly corrected the malignancy-associated hypercalcemia. However, he was severely debilitated during the hospital stay and developed aspiration pneumonia repeatedly. Thereafter, he was transferred to hospice care. The palmar erythema remained after the electrolyte disorder was corrected.

An 83-year-old man presented with fatigue and anorexia. Two years earlier, a small lung nodule had been found that was suspected to be primary lung cancer; however, he had refused surgical treatment or chemotherapy because of his age.

Aminotransferase and alkaline phosphatase levels had been normal, and results of serologic testing for hepatitis viruses were negative, making chronic liver disease unlikely. He was not a habitual drinker and was not taking any medications.

Laboratory and imaging studies revealed lung cancer with hepatic metastasis complicated by severe hypercalcemia. The estradiol level was normal, but the serum vascular endothelial growth factor (VEGF) concentration was high.

PALMAR ERYTHEMA AND SYSTEMIC DISEASE

Palmar erythema syndrome is characterized by reddening of the palmar skin, especially in the thenar and hypothenar areas, the distal portion of the palm, and the fingertips; the dorsal surface of the hand is rarely affected.¹ The affected areas are typically not pruritic or painful.

Conditions in the differential diagnosis

The differential diagnosis of palmar erythema includes allergic drug eruptions, contact dermatitis, erythema multiforme, cellulitis, dermatomyositis, and palmoplantar pustulosis. Hand-foot syndrome and hand-foot skin reaction are other important conditions to consider in cancer patients undergoing chemotherapy.² Hand-foot syndrome and hand-foot skin reaction can present as palmoplantar erythema and are usually accompanied by dysesthesia and swelling.

Palmar erythema can develop in either primary or secondary forms as a result of an underlying systemic disease.² Although the pathogenesis is not fully understood, the impaired degradation or increased production of angiogenic factors appears to be essential. The hormone estrogen can induce vascularization³ and is known to cause palmar erythema in pregnant women and patients with cirrhosis. Because estradiol is metabolized in the liver, increased levels of estrogen are associated with hepatic decompensation in cirrhosis.⁴

Neoplasm can cause palmar erythema.^2,5 In a clinicopathologic study of brain tumors, palmar erythema was recognized in 27 (25%) of 107 patients.⁵ Histologic examination in that study demonstrated that the intensity of erythema correlated with both cutaneous vessel dilation and prominent vascularization in the patients’ brain tumors, suggesting the role of circulating angiogenic factors such as VEGF. VEGF is a potent mediator of angiogenesis, which is critical for tumor development and growth.⁶

Our patient had a metastatic hepatic tumor, a normal estradiol level, and an increased level of VEGF, suggesting that the VEGF produced by the neoplasm promoted the development of palmar erythema.

The presence of palmar erythema in cancer patients is likely underestimated² and may suggest the presence of malignancy when it develops in the elderly.

In our patient, intensive hydration and intravenous bisphosphonate administration rapidly corrected the malignancy-associated hypercalcemia. However, he was severely debilitated during the hospital stay and developed aspiration pneumonia repeatedly. Thereafter, he was transferred to hospice care. The palmar erythema remained after the electrolyte disorder was corrected.

Increasing numbers of women of childbearing age are receiving solid-organ transplants. All need counseling on how to prevent pregnancy while they are taking immunosuppressive agents. Some want to become pregnant after their transplant and thus require counseling and follow-up to maintain good health during pregnancy (Table 1).¹

Primary care physicians can assist with basic contraception counseling and pregnancy planning for their patients who have had solid-organ transplants. In this review, we describe contraceptive options and pregnancy planning for these women.

TRANSPLANTS IN WOMEN ARE INCREASING

Over the past 20 years, the number of solid-organ transplants in US women has increased steadily. Since 1988, 38% of the 634,000 transplants performed were in women, and 47% of these women were of childbearing age (ages 18 to 49).² Kidneys accounted for 60% of solid-organ transplants,² and kidney transplant is now commonly performed in women of childbearing age. In 2012, of 176,000 patients with a functioning renal graft, 40.5% were women, and recipients between ages 20 and 44 composed the second-largest age group.³

FERTILITY IN WOMEN WITH END-STAGE RENAL DISEASE

Women in their reproductive years who have end-stage renal disease have lower fertility rates than women in the general population. In women undergoing peritoneal dialysis or hemodialysis, conception rates decrease to around 0.5% per year.⁴ This lower rate is most likely related to hypothalamic-pituitary-gonadal dysfunction, leading to reduced or total impairment of ovulation, menstrual irregularities, and infertility.⁵

Fertility often returns within a few months after transplant,^1,6 and reported posttransplant pregnancy rates range from 3.3% to 18%,^7–9 with up to one-third of pregnancies being unintended.^6,10 These numbers are likely an underestimate because they do not reflect all pregnancies that are terminated, as many women do not voluntarily report having had an abortion.

Fertility is also severely diminished in women with end-stage liver disease. After liver transplant, sex hormone levels return to normal for many women, and menses soon resume.¹¹

In 2005, the National Transplantation Pregnancy Registry reported 1,418 pregnancies in 919 female recipients of solid-organ transplants. In 2010, this number had increased to 1,940 pregnancies in 1,185 recipients, of whom 75% were kidney transplant recipients.¹²

A successful pregnancy outcome is most likely when a minimum of 1 year intervenes between transplant and conception.^12,13

TERATOGENICITY OF IMMUNOSUPPRESSANTS

Immunosuppressant drugs commonly used for maintenance therapy after solid-organ transplant include the following:

• Calcineurin inhibitors (eg, cyclosporine,  tacrolimus)
• Antiproliferative and antimetabolite agents (eg, mycophenolate mofetil, azathioprine)
• Corticosteroids
• Mammalian target of rapamycin inhibitors (eg, sirolimus, everolimus)
• T-cell costimulation blockers (eg, belatacept).¹⁴

The US Food and Drug Administration (FDA) previously classified mycophenolate mofetil and azathioprine in pregnancy risk category D (positive evidence of human fetal risk). The teratogenic risk of mycophenolate mofetil is well established in studies documenting specific congenital malformations and fetal loss in the first trimester.^13,15 The teratogenic risk of azathioprine, on the other hand, is estimated to be minimal to small.¹⁶ Many of the associated fetal abnormalities may be related to the complexity of the underlying medical condition of the mother rather than to the medication.¹⁶

In June 2015, the FDA’s new Pregnancy and Lactation Labeling Rule went into effect, which removes the pregnancy letter categories A, B, C, D, and X from labeling.¹⁷ This rule was designed to help providers counsel their patients regarding the specific risks and benefits of a drug when used by pregnant or nursing women. However, the ABCDX categories are still commonly used. Table 2 shows information about the risks during pregnancy and lactation posed by the immunosuppressive drugs commonly used by posttransplant patients.¹⁸

To ensure a safe and successful pregnancy with the fewest fetal and maternal complications, women are generally advised to avoid pregnancy for at least 1 year after transplant.^19,20

In addition, women should meet certain clinical prerequisites after transplant before they conceive, as outlined by the American Society of Transplantation.^19,20 These include:

• No rejection within the previous year
• Adequate and stable graft function (eg, serum creatinine < 1.5 mg/dL and urinary protein excretion < 500 mg/24 hours)
• No acute infection that might affect the fetus
• Maintenance immunosuppression at stable dosages.

Other circumstances to consider include episodes of rejection in the first year after transplant (as evidenced by biopsy results or glomerular filtration rate), the woman’s age (advanced maternal age is unfavorable), or any history of noncompliance.

Every pregnancy in a transplant recipient must be carefully planned. Primary care providers should encourage patients to meet with their transplant team and obstetricians early and often to allow time for the care team to adjust the type and dosing of immunosuppressant drugs, to ensure stable graft function, and to optimize any current chronic medical conditions such as diabetes mellitus or hypertension before conception.

CONTRACEPTIVE COUNSELING AFTER TRANSPLANT

Pregnancy should be avoided while transplant patients are taking FDA category D immunosuppressant drugs and, as already mentioned, during the first year after transplant. Unintended pregnancy can have serious health consequences for the mother and the fetus, as well as poor pregnancy outcomes. The US Centers for Disease Control and Prevention (CDC) lists solid-organ transplant within the past 2 years as a condition that can lead to adverse events as a result of pregnancy.²¹ After a transplant, a woman’s risks from an unintended pregnancy are always greater than the risks from any contraceptive, and this is important to reinforce in counseling.

Two forms of reliable contraception should be used at all times, and consistent condom use should be encouraged as one of the methods. Condoms are not reliable when used as the sole contraceptive method because they have an 18% typical-use failure rate. However, they are an excellent adjunct to other contraceptive methods because they have the additional benefit of protecting against sexually transmitted disease.

Choosing the appropriate contraceptive method for recipients of solid-organ transplants can be challenging because of several factors, including the recipient’s preexisting medical problems and drug interactions of immunosuppressant medications.

CDC criteria and categories for contraceptive use

In 2010, the CDC released the US version of the Medical Eligibility Criteria (US MEC) for contraceptive use, which was based on the 2009 World Health Organization Medical Eligibility Criteria (WHO MEC); these criteria were revised in August 2016.²¹

• Category 1: A condition for which there is no restriction for the use of the contraceptive method
• Category 2: A condition for which the advantages of using the method generally outweigh the theoretical or proven risks
• Category 3: A condition for which the theoretical or proven risks usually outweigh the advantages of using the method
• Category 4: A condition that represents an unacceptable health risk if the contraceptive method is used.

These recommendations aimed to improve family planning options by clarifying the possible safe and effective contraceptive options available while considering the patient’s medical condition. The CDC added solid-organ transplant recipients to this document because of the prevalence of this group in the United States.

The CDC categorizes a patient’s medical condition after transplant as either complicated or uncomplicated. Complicated conditions include acute or chronic graft failure, graft rejection, and cardiac allograft vasculopathy.²¹

Effectiveness of contraceptive methods

Contraceptive methods can be divided into 4 categories based on estimated effectiveness, ie, the pregnancy rate with “typical use” of that particular method in 1 year^21–23:

• Very effective (0%–0.9%)
• Effective (1%–9%)
• Moderately effective (10%–25%)
• Less effective (26%–32%).

Typical use refers to failure rates for women and men whose use is not consistent nor always correct. Correct use, also described in the sections that follow, refers to failure rates for those whose use is consistent and always correct.

Women should be counseled regarding all available contraceptive options that are medically suitable for them, so they can choose the method that best fits their needs and lifestyle. They should receive counseling on emergency contraception, barrier protection against sexually transmitted disease, and the correct use of the contraceptive method they choose. They should be advised that if their chosen contraceptive method is unsatisfactory for any reason, they can switch to another method. Most importantly, providers need to impress on their patients that the risks associated with unintended pregnancy are far greater than the risks from any of the contraceptive methods.

This tier of contraception is the most effective regardless of the patient’s adherence; it includes long-acting, reversible contraceptives and permanent sterilization (both male and female) (Table 3).^21–23

Long-acting reversible contraceptives include intrauterine devices (IUDs) and the subdermal etonogestrel implant. Given their efficacy and favorable safety profile, long-acting reversible contraceptives are being promoted for use in women who have chronic medical conditions, such as transplants.²⁴

Intrauterine devices

IUDs are long-acting and reversible. They can be used by women who are nulliparous and those of all ages, including adolescents.²²

Two types of IUDs are available in the United States: nonhormonal (copper) and hormonal (levonorgestrel). The copper IUD is effective for at least 10 years, whereas the levonorgestrel IUDs last for 3 to 5 years.²²

Four levonorgestrel IUDs are currently available in the United States. Their sizes and doses vary: Mirena (52 µg), Skyla (13.5 µg), Liletta (52 µg), and Kyleena (19.5 µg).

Fewer than 1% of women become pregnant in the first year of IUD use.^22,23 IUDs are an ideal option for women with solid-organ transplants because they are so effective and because the patient does not have to do anything once the IUD is in.^22–24 The levonorgestrel IUD Mirena has the additional advantage of reducing heavy menstrual bleeding and is currently the only hormonal IUD with FDA approval for the management of menorrhagia.

About 12% of women in the general population use IUDs as their contraceptive method of choice,²⁵ whereas after solid-organ transplantation about 15% to 20% of women do.²⁶

Two historic concerns regarding IUDs may explain their low rate of use in transplant recipients.

First, IUDs were believed to be less effective in women on immunosuppressive drugs because IUDs act by inducing a local inflammatory reaction. However, IUDs involve macrophage activation, which is independent of the immune processes modified by immunosuppressants (primarily T-cell function).²⁷ A recent pilot study showed a strong inflammatory reaction in the endometrium of transplant recipients after levonorgestrel IUD insertion.²⁸

Second, there was concern about the increased risk of pelvic inflammatory disease with IUDs, but studies have shown levonorgestrel IUDs to be safe in transplant patients.^29,30

The CDC²¹ lists copper and levonorgestrel IUDs in MEC category 3 (the risks generally outweigh the advantages) for initiation in patients with complicated transplants and in category 2 (advantages generally outweigh the risks) in patients with uncomplicated organ transplants. The devices are in category 2 for both complicated and uncomplicated cases if the IUD is already in place.

Subdermal implant

A subdermal implant consisting of a single rod containing 68 mg of etonogestrel is commercially available in the United States. It is one of the most effective contraceptive methods, with the lowest rates of pregnancy—less than 1% per year, with protection lasting at least 3 years.^22,23 This low risk makes the subdermal implant a suitable method of contraception after transplant. Daily compliance is not required, and there are no hepatic first-pass effects, which results in higher bioavailability and less chance of drug interactions.

The main disadvantage of the subdermal implant and IUDs is unscheduled bleeding. An important benefit is prolonged amenorrhea, not only for patient convenience, but for reduction of endometrial cancer risk. Insertion and removal of the implant are considered minor office procedures. The implants are classified as US MEC category 2 in uncomplicated cases; initiation in complicated cases is considered category 3 but continuation is considered category 2.²¹

Permanent sterilization

Permanent sterilization is another option for women and men. In women, the fallopian tubes can be occluded with a coil system implanted vaginally through a hysteroscope, or they can be severed, tied, or clamped in a laparoscopic procedure or during cesarean delivery. Pregnancy rates after tubal ligation are less than 1%,^23,31 although concern exists for high failure rates with the hysteroscopic method.

Because younger patients are more likely than older patients to subsequently regret having the procedure done, all available contraceptive options should be discussed with them.³¹

For men, permanent sterilization is done by vasectomy, which has less associated risk and cost compared with sterilization for women.

EFFECTIVE CONTRACEPTIVE METHODS (UNINTENDED PREGNANCY RATE 1%–9%)

Effective contraceptive methods, the next tier down from very effective methods, include injectable contraceptives, combined hormonal contraceptives, and progestin-only contraceptives (Table 4).

Injectable contraceptives

Depot medroxyprogesterone acetate is an injectable progestin-only contraceptive that carries a pregnancy risk of 6% with typical use and less than 1% with correct use.²³ Thus, some failures are due to patients not returning for follow-up, but in some patients this method is not effective. Injections are given intramuscularly once every 3 months, avoiding the need for daily use.

A valid concern for transplant patients is that medroxyprogesterone acetate reduces bone mineral density. Although the bone effects are reversible in healthy adult women, caution is needed when prescribing this option to transplant patients who are already at increased risk of bone disease attributable to renal osteodystrophy and chronic corticosteroid use. ^32,33

Recently, a subcutaneous formulation of depot medroxyprogesterone acetate (104 mg)was added to the WHO MEC for contraceptive use.^34,35 The recommendations for the subcutaneous form are similar to those for the intramuscular form. In healthy women, the subcutaneous formulation is as safe and effective as the intramuscular form,³⁶ but its efficacy after solid-organ transplant has not been determined. Both forms of depot medroxyprogesterone acetate are category 2 in the US MEC for both complicated and uncomplicated transplant cases.²¹

Combined hormonal contraceptives contain both estrogen and progesterone and are available as pills, patches, or rings. Each product has an unintended pregnancy risk of 9% with typical use and less than 1% with correct use.²³ They require strict patient adherence to regular daily use, which likely explains their high failure rate with typical use.

Combined hormonal contraceptives reduce mortality risk in women in the general population,³⁷ but their effect on mortality  risk after transplant is unknown and needs further study. In women who received liver transplants, low-dose combined hormonal contraceptives have been found to be effective and well tolerated, but initiation should be delayed at least 6 months until postoperative organ stability is demonstrated.¹¹

Combined oral contraceptives are the most widely prescribed because they are convenient and familiar and have an acceptable safety profile in transplant patients,^11,33,37 despite their high failure rate with typical use. They regulate the menstrual cycle and reduce anemia associated with menstruation.

The transdermal contraceptive patch has a mechanism of action similar to that of the combined oral contraceptives, but it delivers estrogen and progesterone transdermally through the abdominal wall, thus avoiding first-pass metabolism in the liver and enzymatic degradation in the gut. It delivers 35 µg of ethinyl estradiol and 150 µg of norelgestromin (an active metabolite of norgestimate) daily.³⁸ It may cause higher circulating levels of estrogen than a combined oral contraceptive and may be associated with a higher risk of venous thromboembolism, but the evidence is conflicting.^39–42

The vaginal ring, made of Silastic, delivers ethinyl estradiol in a low dose (15 µg/day) and etonorgestrel 0.12 mg/day. Like the patch, it has the advantage of bypassing first-pass metabolism in the liver, making it a good option for transplant patients who are taking antirejection drugs, thus avoiding drug interactions.⁴¹

Both the transdermal patch and vaginal ring were studied in transplant patients and had favorable results.^24,43 The combined hormonal oral contraceptive pills, patch, and ring are in category 4 (unacceptable health risk) in the US MEC in patients with complicated cases, but they are in category 2 in uncomplicated cases.²¹

Combined hormonal contraceptives should not be considered first-line options by themselves for transplant patients because of their high failure rate with typical use.²⁴

Progestin-only pills

Although progestin-only pills have not been studied specifically in transplant patients, they can be considered for women who have contraindications to estrogen use. Estrogen use is contraindicated in women with a history of venous thromboembolism, thrombogenic mutations, estrogen-dependent neoplasia, hepatocellular adenoma, severe hypertension, vascular disease, and Budd-Chiari syndrome.

Progestin-only pills inhibit ovulation in only about half of a woman’s cycles, but they prevent conception by other mechanisms as well, such as causing thickening of the cervical mucus. They also alter the endometrium to make it unfavorable for implantation and reduce the ciliary activity of the fallopian tube.

Strict adherence is important for effectiveness because progestin-only pills have a shorter half-life than combined hormonal contraceptives and also suppress ovulation less effectively.²² Failure rates are similar or somewhat higher than with combined hormonal contraceptives; with typical use, about 9 in 100 women can become pregnant in the first year.²³ According to the US MEC,²¹ progestin-only pills are classified as category 2 for patients after both complicated and uncomplicated transplants.

MODERATELY EFFECTIVE METHODS (PREGNANCY RATE 10%–25%)

This tier of contraceptives includes all barrier methods, ie, male and female condoms, vaginal diaphragms, cervical caps, and sponges (Table 5).

Condoms (male and female)

When male condoms are used as the only birth control method, pregnancy occurs less often (18% with typical use and 2% with correct use) than with female condoms (21% with typical use and 5% with correct use).²³ Male and female condoms are the only contraceptive methods that also prevent transmission of sexually transmitted disease.²⁴

Caps, sponges, diaphragms

Cervical caps, vaginal sponges, and vaginal diaphragms are other forms of barrier contraceptives. All barrier methods should be combined with another contraceptive method to provide reliable protection against pregnancy. These methods are considered category 1 according to the US MEC.

LESS-EFFECTIVE METHODS

Fertility awareness-based methods such as the rhythm method have an associated pregnancy rate of about 25% with typical use and 3% to 5% with correct use²³ and cannot be relied on for use by transplant recipients.²⁴

Withdrawal and spermicides are considered least effective and unreliable for pregnancy prevention.

KNOW YOUR OPTIONS

With the growing number of women in their reproductive years receiving solid-organ transplants in the United States, it is increasingly important for healthcare providers to be aware of contraceptive options and reproductive life planning for this high-risk population.

Safe and effective forms of contraception are available, and additional information to guide the choice can be found in the Summary Chart of US MEC for Contraceptive Use, which is also available in a free smart phone app through the CDC.⁴⁴

Pregnancy after transplant carries high risks, requiring these patients to have special counseling and monitoring. Fortunately, planned pregnancy at least 1 year after transplant can lead to successful outcomes in these women.

Increasing numbers of women of childbearing age are receiving solid-organ transplants. All need counseling on how to prevent pregnancy while they are taking immunosuppressive agents. Some want to become pregnant after their transplant and thus require counseling and follow-up to maintain good health during pregnancy (Table 1).¹

Primary care physicians can assist with basic contraception counseling and pregnancy planning for their patients who have had solid-organ transplants. In this review, we describe contraceptive options and pregnancy planning for these women.

TRANSPLANTS IN WOMEN ARE INCREASING

Over the past 20 years, the number of solid-organ transplants in US women has increased steadily. Since 1988, 38% of the 634,000 transplants performed were in women, and 47% of these women were of childbearing age (ages 18 to 49).² Kidneys accounted for 60% of solid-organ transplants,² and kidney transplant is now commonly performed in women of childbearing age. In 2012, of 176,000 patients with a functioning renal graft, 40.5% were women, and recipients between ages 20 and 44 composed the second-largest age group.³

FERTILITY IN WOMEN WITH END-STAGE RENAL DISEASE

Women in their reproductive years who have end-stage renal disease have lower fertility rates than women in the general population. In women undergoing peritoneal dialysis or hemodialysis, conception rates decrease to around 0.5% per year.⁴ This lower rate is most likely related to hypothalamic-pituitary-gonadal dysfunction, leading to reduced or total impairment of ovulation, menstrual irregularities, and infertility.⁵

Fertility often returns within a few months after transplant,^1,6 and reported posttransplant pregnancy rates range from 3.3% to 18%,^7–9 with up to one-third of pregnancies being unintended.^6,10 These numbers are likely an underestimate because they do not reflect all pregnancies that are terminated, as many women do not voluntarily report having had an abortion.

Fertility is also severely diminished in women with end-stage liver disease. After liver transplant, sex hormone levels return to normal for many women, and menses soon resume.¹¹

In 2005, the National Transplantation Pregnancy Registry reported 1,418 pregnancies in 919 female recipients of solid-organ transplants. In 2010, this number had increased to 1,940 pregnancies in 1,185 recipients, of whom 75% were kidney transplant recipients.¹²

A successful pregnancy outcome is most likely when a minimum of 1 year intervenes between transplant and conception.^12,13

TERATOGENICITY OF IMMUNOSUPPRESSANTS

Immunosuppressant drugs commonly used for maintenance therapy after solid-organ transplant include the following:

• Calcineurin inhibitors (eg, cyclosporine,  tacrolimus)
• Antiproliferative and antimetabolite agents (eg, mycophenolate mofetil, azathioprine)
• Corticosteroids
• Mammalian target of rapamycin inhibitors (eg, sirolimus, everolimus)
• T-cell costimulation blockers (eg, belatacept).¹⁴

The US Food and Drug Administration (FDA) previously classified mycophenolate mofetil and azathioprine in pregnancy risk category D (positive evidence of human fetal risk). The teratogenic risk of mycophenolate mofetil is well established in studies documenting specific congenital malformations and fetal loss in the first trimester.^13,15 The teratogenic risk of azathioprine, on the other hand, is estimated to be minimal to small.¹⁶ Many of the associated fetal abnormalities may be related to the complexity of the underlying medical condition of the mother rather than to the medication.¹⁶

In June 2015, the FDA’s new Pregnancy and Lactation Labeling Rule went into effect, which removes the pregnancy letter categories A, B, C, D, and X from labeling.¹⁷ This rule was designed to help providers counsel their patients regarding the specific risks and benefits of a drug when used by pregnant or nursing women. However, the ABCDX categories are still commonly used. Table 2 shows information about the risks during pregnancy and lactation posed by the immunosuppressive drugs commonly used by posttransplant patients.¹⁸

To ensure a safe and successful pregnancy with the fewest fetal and maternal complications, women are generally advised to avoid pregnancy for at least 1 year after transplant.^19,20

In addition, women should meet certain clinical prerequisites after transplant before they conceive, as outlined by the American Society of Transplantation.^19,20 These include:

• No rejection within the previous year
• Adequate and stable graft function (eg, serum creatinine < 1.5 mg/dL and urinary protein excretion < 500 mg/24 hours)
• No acute infection that might affect the fetus
• Maintenance immunosuppression at stable dosages.

Other circumstances to consider include episodes of rejection in the first year after transplant (as evidenced by biopsy results or glomerular filtration rate), the woman’s age (advanced maternal age is unfavorable), or any history of noncompliance.

Every pregnancy in a transplant recipient must be carefully planned. Primary care providers should encourage patients to meet with their transplant team and obstetricians early and often to allow time for the care team to adjust the type and dosing of immunosuppressant drugs, to ensure stable graft function, and to optimize any current chronic medical conditions such as diabetes mellitus or hypertension before conception.

CONTRACEPTIVE COUNSELING AFTER TRANSPLANT

Pregnancy should be avoided while transplant patients are taking FDA category D immunosuppressant drugs and, as already mentioned, during the first year after transplant. Unintended pregnancy can have serious health consequences for the mother and the fetus, as well as poor pregnancy outcomes. The US Centers for Disease Control and Prevention (CDC) lists solid-organ transplant within the past 2 years as a condition that can lead to adverse events as a result of pregnancy.²¹ After a transplant, a woman’s risks from an unintended pregnancy are always greater than the risks from any contraceptive, and this is important to reinforce in counseling.

Two forms of reliable contraception should be used at all times, and consistent condom use should be encouraged as one of the methods. Condoms are not reliable when used as the sole contraceptive method because they have an 18% typical-use failure rate. However, they are an excellent adjunct to other contraceptive methods because they have the additional benefit of protecting against sexually transmitted disease.

Choosing the appropriate contraceptive method for recipients of solid-organ transplants can be challenging because of several factors, including the recipient’s preexisting medical problems and drug interactions of immunosuppressant medications.

CDC criteria and categories for contraceptive use

In 2010, the CDC released the US version of the Medical Eligibility Criteria (US MEC) for contraceptive use, which was based on the 2009 World Health Organization Medical Eligibility Criteria (WHO MEC); these criteria were revised in August 2016.²¹

• Category 1: A condition for which there is no restriction for the use of the contraceptive method
• Category 2: A condition for which the advantages of using the method generally outweigh the theoretical or proven risks
• Category 3: A condition for which the theoretical or proven risks usually outweigh the advantages of using the method
• Category 4: A condition that represents an unacceptable health risk if the contraceptive method is used.

These recommendations aimed to improve family planning options by clarifying the possible safe and effective contraceptive options available while considering the patient’s medical condition. The CDC added solid-organ transplant recipients to this document because of the prevalence of this group in the United States.

The CDC categorizes a patient’s medical condition after transplant as either complicated or uncomplicated. Complicated conditions include acute or chronic graft failure, graft rejection, and cardiac allograft vasculopathy.²¹

Effectiveness of contraceptive methods

Contraceptive methods can be divided into 4 categories based on estimated effectiveness, ie, the pregnancy rate with “typical use” of that particular method in 1 year^21–23:

• Very effective (0%–0.9%)
• Effective (1%–9%)
• Moderately effective (10%–25%)
• Less effective (26%–32%).

Typical use refers to failure rates for women and men whose use is not consistent nor always correct. Correct use, also described in the sections that follow, refers to failure rates for those whose use is consistent and always correct.

Women should be counseled regarding all available contraceptive options that are medically suitable for them, so they can choose the method that best fits their needs and lifestyle. They should receive counseling on emergency contraception, barrier protection against sexually transmitted disease, and the correct use of the contraceptive method they choose. They should be advised that if their chosen contraceptive method is unsatisfactory for any reason, they can switch to another method. Most importantly, providers need to impress on their patients that the risks associated with unintended pregnancy are far greater than the risks from any of the contraceptive methods.

This tier of contraception is the most effective regardless of the patient’s adherence; it includes long-acting, reversible contraceptives and permanent sterilization (both male and female) (Table 3).^21–23

Long-acting reversible contraceptives include intrauterine devices (IUDs) and the subdermal etonogestrel implant. Given their efficacy and favorable safety profile, long-acting reversible contraceptives are being promoted for use in women who have chronic medical conditions, such as transplants.²⁴

Intrauterine devices

IUDs are long-acting and reversible. They can be used by women who are nulliparous and those of all ages, including adolescents.²²

Two types of IUDs are available in the United States: nonhormonal (copper) and hormonal (levonorgestrel). The copper IUD is effective for at least 10 years, whereas the levonorgestrel IUDs last for 3 to 5 years.²²

Four levonorgestrel IUDs are currently available in the United States. Their sizes and doses vary: Mirena (52 µg), Skyla (13.5 µg), Liletta (52 µg), and Kyleena (19.5 µg).

Fewer than 1% of women become pregnant in the first year of IUD use.^22,23 IUDs are an ideal option for women with solid-organ transplants because they are so effective and because the patient does not have to do anything once the IUD is in.^22–24 The levonorgestrel IUD Mirena has the additional advantage of reducing heavy menstrual bleeding and is currently the only hormonal IUD with FDA approval for the management of menorrhagia.

About 12% of women in the general population use IUDs as their contraceptive method of choice,²⁵ whereas after solid-organ transplantation about 15% to 20% of women do.²⁶

Two historic concerns regarding IUDs may explain their low rate of use in transplant recipients.

First, IUDs were believed to be less effective in women on immunosuppressive drugs because IUDs act by inducing a local inflammatory reaction. However, IUDs involve macrophage activation, which is independent of the immune processes modified by immunosuppressants (primarily T-cell function).²⁷ A recent pilot study showed a strong inflammatory reaction in the endometrium of transplant recipients after levonorgestrel IUD insertion.²⁸

Second, there was concern about the increased risk of pelvic inflammatory disease with IUDs, but studies have shown levonorgestrel IUDs to be safe in transplant patients.^29,30

The CDC²¹ lists copper and levonorgestrel IUDs in MEC category 3 (the risks generally outweigh the advantages) for initiation in patients with complicated transplants and in category 2 (advantages generally outweigh the risks) in patients with uncomplicated organ transplants. The devices are in category 2 for both complicated and uncomplicated cases if the IUD is already in place.

Subdermal implant

A subdermal implant consisting of a single rod containing 68 mg of etonogestrel is commercially available in the United States. It is one of the most effective contraceptive methods, with the lowest rates of pregnancy—less than 1% per year, with protection lasting at least 3 years.^22,23 This low risk makes the subdermal implant a suitable method of contraception after transplant. Daily compliance is not required, and there are no hepatic first-pass effects, which results in higher bioavailability and less chance of drug interactions.

The main disadvantage of the subdermal implant and IUDs is unscheduled bleeding. An important benefit is prolonged amenorrhea, not only for patient convenience, but for reduction of endometrial cancer risk. Insertion and removal of the implant are considered minor office procedures. The implants are classified as US MEC category 2 in uncomplicated cases; initiation in complicated cases is considered category 3 but continuation is considered category 2.²¹

Permanent sterilization

Permanent sterilization is another option for women and men. In women, the fallopian tubes can be occluded with a coil system implanted vaginally through a hysteroscope, or they can be severed, tied, or clamped in a laparoscopic procedure or during cesarean delivery. Pregnancy rates after tubal ligation are less than 1%,^23,31 although concern exists for high failure rates with the hysteroscopic method.

Because younger patients are more likely than older patients to subsequently regret having the procedure done, all available contraceptive options should be discussed with them.³¹

For men, permanent sterilization is done by vasectomy, which has less associated risk and cost compared with sterilization for women.

EFFECTIVE CONTRACEPTIVE METHODS (UNINTENDED PREGNANCY RATE 1%–9%)

Effective contraceptive methods, the next tier down from very effective methods, include injectable contraceptives, combined hormonal contraceptives, and progestin-only contraceptives (Table 4).

Injectable contraceptives

Depot medroxyprogesterone acetate is an injectable progestin-only contraceptive that carries a pregnancy risk of 6% with typical use and less than 1% with correct use.²³ Thus, some failures are due to patients not returning for follow-up, but in some patients this method is not effective. Injections are given intramuscularly once every 3 months, avoiding the need for daily use.

A valid concern for transplant patients is that medroxyprogesterone acetate reduces bone mineral density. Although the bone effects are reversible in healthy adult women, caution is needed when prescribing this option to transplant patients who are already at increased risk of bone disease attributable to renal osteodystrophy and chronic corticosteroid use. ^32,33

Recently, a subcutaneous formulation of depot medroxyprogesterone acetate (104 mg)was added to the WHO MEC for contraceptive use.^34,35 The recommendations for the subcutaneous form are similar to those for the intramuscular form. In healthy women, the subcutaneous formulation is as safe and effective as the intramuscular form,³⁶ but its efficacy after solid-organ transplant has not been determined. Both forms of depot medroxyprogesterone acetate are category 2 in the US MEC for both complicated and uncomplicated transplant cases.²¹

Combined hormonal contraceptives contain both estrogen and progesterone and are available as pills, patches, or rings. Each product has an unintended pregnancy risk of 9% with typical use and less than 1% with correct use.²³ They require strict patient adherence to regular daily use, which likely explains their high failure rate with typical use.

Combined hormonal contraceptives reduce mortality risk in women in the general population,³⁷ but their effect on mortality  risk after transplant is unknown and needs further study. In women who received liver transplants, low-dose combined hormonal contraceptives have been found to be effective and well tolerated, but initiation should be delayed at least 6 months until postoperative organ stability is demonstrated.¹¹

Combined oral contraceptives are the most widely prescribed because they are convenient and familiar and have an acceptable safety profile in transplant patients,^11,33,37 despite their high failure rate with typical use. They regulate the menstrual cycle and reduce anemia associated with menstruation.

The transdermal contraceptive patch has a mechanism of action similar to that of the combined oral contraceptives, but it delivers estrogen and progesterone transdermally through the abdominal wall, thus avoiding first-pass metabolism in the liver and enzymatic degradation in the gut. It delivers 35 µg of ethinyl estradiol and 150 µg of norelgestromin (an active metabolite of norgestimate) daily.³⁸ It may cause higher circulating levels of estrogen than a combined oral contraceptive and may be associated with a higher risk of venous thromboembolism, but the evidence is conflicting.^39–42

The vaginal ring, made of Silastic, delivers ethinyl estradiol in a low dose (15 µg/day) and etonorgestrel 0.12 mg/day. Like the patch, it has the advantage of bypassing first-pass metabolism in the liver, making it a good option for transplant patients who are taking antirejection drugs, thus avoiding drug interactions.⁴¹

Both the transdermal patch and vaginal ring were studied in transplant patients and had favorable results.^24,43 The combined hormonal oral contraceptive pills, patch, and ring are in category 4 (unacceptable health risk) in the US MEC in patients with complicated cases, but they are in category 2 in uncomplicated cases.²¹

Combined hormonal contraceptives should not be considered first-line options by themselves for transplant patients because of their high failure rate with typical use.²⁴

Progestin-only pills

Although progestin-only pills have not been studied specifically in transplant patients, they can be considered for women who have contraindications to estrogen use. Estrogen use is contraindicated in women with a history of venous thromboembolism, thrombogenic mutations, estrogen-dependent neoplasia, hepatocellular adenoma, severe hypertension, vascular disease, and Budd-Chiari syndrome.

Progestin-only pills inhibit ovulation in only about half of a woman’s cycles, but they prevent conception by other mechanisms as well, such as causing thickening of the cervical mucus. They also alter the endometrium to make it unfavorable for implantation and reduce the ciliary activity of the fallopian tube.

Strict adherence is important for effectiveness because progestin-only pills have a shorter half-life than combined hormonal contraceptives and also suppress ovulation less effectively.²² Failure rates are similar or somewhat higher than with combined hormonal contraceptives; with typical use, about 9 in 100 women can become pregnant in the first year.²³ According to the US MEC,²¹ progestin-only pills are classified as category 2 for patients after both complicated and uncomplicated transplants.

MODERATELY EFFECTIVE METHODS (PREGNANCY RATE 10%–25%)

This tier of contraceptives includes all barrier methods, ie, male and female condoms, vaginal diaphragms, cervical caps, and sponges (Table 5).

Condoms (male and female)

When male condoms are used as the only birth control method, pregnancy occurs less often (18% with typical use and 2% with correct use) than with female condoms (21% with typical use and 5% with correct use).²³ Male and female condoms are the only contraceptive methods that also prevent transmission of sexually transmitted disease.²⁴

Caps, sponges, diaphragms

Cervical caps, vaginal sponges, and vaginal diaphragms are other forms of barrier contraceptives. All barrier methods should be combined with another contraceptive method to provide reliable protection against pregnancy. These methods are considered category 1 according to the US MEC.

LESS-EFFECTIVE METHODS

Fertility awareness-based methods such as the rhythm method have an associated pregnancy rate of about 25% with typical use and 3% to 5% with correct use²³ and cannot be relied on for use by transplant recipients.²⁴

Withdrawal and spermicides are considered least effective and unreliable for pregnancy prevention.

KNOW YOUR OPTIONS

With the growing number of women in their reproductive years receiving solid-organ transplants in the United States, it is increasingly important for healthcare providers to be aware of contraceptive options and reproductive life planning for this high-risk population.

Safe and effective forms of contraception are available, and additional information to guide the choice can be found in the Summary Chart of US MEC for Contraceptive Use, which is also available in a free smart phone app through the CDC.⁴⁴

Pregnancy after transplant carries high risks, requiring these patients to have special counseling and monitoring. Fortunately, planned pregnancy at least 1 year after transplant can lead to successful outcomes in these women.

Increasing numbers of women of childbearing age are receiving solid-organ transplants. All need counseling on how to prevent pregnancy while they are taking immunosuppressive agents. Some want to become pregnant after their transplant and thus require counseling and follow-up to maintain good health during pregnancy (Table 1).¹

Primary care physicians can assist with basic contraception counseling and pregnancy planning for their patients who have had solid-organ transplants. In this review, we describe contraceptive options and pregnancy planning for these women.

TRANSPLANTS IN WOMEN ARE INCREASING

Over the past 20 years, the number of solid-organ transplants in US women has increased steadily. Since 1988, 38% of the 634,000 transplants performed were in women, and 47% of these women were of childbearing age (ages 18 to 49).² Kidneys accounted for 60% of solid-organ transplants,² and kidney transplant is now commonly performed in women of childbearing age. In 2012, of 176,000 patients with a functioning renal graft, 40.5% were women, and recipients between ages 20 and 44 composed the second-largest age group.³

FERTILITY IN WOMEN WITH END-STAGE RENAL DISEASE

Women in their reproductive years who have end-stage renal disease have lower fertility rates than women in the general population. In women undergoing peritoneal dialysis or hemodialysis, conception rates decrease to around 0.5% per year.⁴ This lower rate is most likely related to hypothalamic-pituitary-gonadal dysfunction, leading to reduced or total impairment of ovulation, menstrual irregularities, and infertility.⁵

Fertility often returns within a few months after transplant,^1,6 and reported posttransplant pregnancy rates range from 3.3% to 18%,^7–9 with up to one-third of pregnancies being unintended.^6,10 These numbers are likely an underestimate because they do not reflect all pregnancies that are terminated, as many women do not voluntarily report having had an abortion.

Fertility is also severely diminished in women with end-stage liver disease. After liver transplant, sex hormone levels return to normal for many women, and menses soon resume.¹¹

In 2005, the National Transplantation Pregnancy Registry reported 1,418 pregnancies in 919 female recipients of solid-organ transplants. In 2010, this number had increased to 1,940 pregnancies in 1,185 recipients, of whom 75% were kidney transplant recipients.¹²

A successful pregnancy outcome is most likely when a minimum of 1 year intervenes between transplant and conception.^12,13

TERATOGENICITY OF IMMUNOSUPPRESSANTS

Immunosuppressant drugs commonly used for maintenance therapy after solid-organ transplant include the following:

• Calcineurin inhibitors (eg, cyclosporine,  tacrolimus)
• Antiproliferative and antimetabolite agents (eg, mycophenolate mofetil, azathioprine)
• Corticosteroids
• Mammalian target of rapamycin inhibitors (eg, sirolimus, everolimus)
• T-cell costimulation blockers (eg, belatacept).¹⁴

The US Food and Drug Administration (FDA) previously classified mycophenolate mofetil and azathioprine in pregnancy risk category D (positive evidence of human fetal risk). The teratogenic risk of mycophenolate mofetil is well established in studies documenting specific congenital malformations and fetal loss in the first trimester.^13,15 The teratogenic risk of azathioprine, on the other hand, is estimated to be minimal to small.¹⁶ Many of the associated fetal abnormalities may be related to the complexity of the underlying medical condition of the mother rather than to the medication.¹⁶

In June 2015, the FDA’s new Pregnancy and Lactation Labeling Rule went into effect, which removes the pregnancy letter categories A, B, C, D, and X from labeling.¹⁷ This rule was designed to help providers counsel their patients regarding the specific risks and benefits of a drug when used by pregnant or nursing women. However, the ABCDX categories are still commonly used. Table 2 shows information about the risks during pregnancy and lactation posed by the immunosuppressive drugs commonly used by posttransplant patients.¹⁸

To ensure a safe and successful pregnancy with the fewest fetal and maternal complications, women are generally advised to avoid pregnancy for at least 1 year after transplant.^19,20

In addition, women should meet certain clinical prerequisites after transplant before they conceive, as outlined by the American Society of Transplantation.^19,20 These include:

• No rejection within the previous year
• Adequate and stable graft function (eg, serum creatinine < 1.5 mg/dL and urinary protein excretion < 500 mg/24 hours)
• No acute infection that might affect the fetus
• Maintenance immunosuppression at stable dosages.

Other circumstances to consider include episodes of rejection in the first year after transplant (as evidenced by biopsy results or glomerular filtration rate), the woman’s age (advanced maternal age is unfavorable), or any history of noncompliance.

Every pregnancy in a transplant recipient must be carefully planned. Primary care providers should encourage patients to meet with their transplant team and obstetricians early and often to allow time for the care team to adjust the type and dosing of immunosuppressant drugs, to ensure stable graft function, and to optimize any current chronic medical conditions such as diabetes mellitus or hypertension before conception.

CONTRACEPTIVE COUNSELING AFTER TRANSPLANT

Pregnancy should be avoided while transplant patients are taking FDA category D immunosuppressant drugs and, as already mentioned, during the first year after transplant. Unintended pregnancy can have serious health consequences for the mother and the fetus, as well as poor pregnancy outcomes. The US Centers for Disease Control and Prevention (CDC) lists solid-organ transplant within the past 2 years as a condition that can lead to adverse events as a result of pregnancy.²¹ After a transplant, a woman’s risks from an unintended pregnancy are always greater than the risks from any contraceptive, and this is important to reinforce in counseling.

Two forms of reliable contraception should be used at all times, and consistent condom use should be encouraged as one of the methods. Condoms are not reliable when used as the sole contraceptive method because they have an 18% typical-use failure rate. However, they are an excellent adjunct to other contraceptive methods because they have the additional benefit of protecting against sexually transmitted disease.

Choosing the appropriate contraceptive method for recipients of solid-organ transplants can be challenging because of several factors, including the recipient’s preexisting medical problems and drug interactions of immunosuppressant medications.

CDC criteria and categories for contraceptive use

In 2010, the CDC released the US version of the Medical Eligibility Criteria (US MEC) for contraceptive use, which was based on the 2009 World Health Organization Medical Eligibility Criteria (WHO MEC); these criteria were revised in August 2016.²¹

• Category 1: A condition for which there is no restriction for the use of the contraceptive method
• Category 2: A condition for which the advantages of using the method generally outweigh the theoretical or proven risks
• Category 3: A condition for which the theoretical or proven risks usually outweigh the advantages of using the method
• Category 4: A condition that represents an unacceptable health risk if the contraceptive method is used.

These recommendations aimed to improve family planning options by clarifying the possible safe and effective contraceptive options available while considering the patient’s medical condition. The CDC added solid-organ transplant recipients to this document because of the prevalence of this group in the United States.

The CDC categorizes a patient’s medical condition after transplant as either complicated or uncomplicated. Complicated conditions include acute or chronic graft failure, graft rejection, and cardiac allograft vasculopathy.²¹

Effectiveness of contraceptive methods

Contraceptive methods can be divided into 4 categories based on estimated effectiveness, ie, the pregnancy rate with “typical use” of that particular method in 1 year^21–23:

• Very effective (0%–0.9%)
• Effective (1%–9%)
• Moderately effective (10%–25%)
• Less effective (26%–32%).

Typical use refers to failure rates for women and men whose use is not consistent nor always correct. Correct use, also described in the sections that follow, refers to failure rates for those whose use is consistent and always correct.

Women should be counseled regarding all available contraceptive options that are medically suitable for them, so they can choose the method that best fits their needs and lifestyle. They should receive counseling on emergency contraception, barrier protection against sexually transmitted disease, and the correct use of the contraceptive method they choose. They should be advised that if their chosen contraceptive method is unsatisfactory for any reason, they can switch to another method. Most importantly, providers need to impress on their patients that the risks associated with unintended pregnancy are far greater than the risks from any of the contraceptive methods.

This tier of contraception is the most effective regardless of the patient’s adherence; it includes long-acting, reversible contraceptives and permanent sterilization (both male and female) (Table 3).^21–23

Long-acting reversible contraceptives include intrauterine devices (IUDs) and the subdermal etonogestrel implant. Given their efficacy and favorable safety profile, long-acting reversible contraceptives are being promoted for use in women who have chronic medical conditions, such as transplants.²⁴

Intrauterine devices

IUDs are long-acting and reversible. They can be used by women who are nulliparous and those of all ages, including adolescents.²²

Two types of IUDs are available in the United States: nonhormonal (copper) and hormonal (levonorgestrel). The copper IUD is effective for at least 10 years, whereas the levonorgestrel IUDs last for 3 to 5 years.²²

Four levonorgestrel IUDs are currently available in the United States. Their sizes and doses vary: Mirena (52 µg), Skyla (13.5 µg), Liletta (52 µg), and Kyleena (19.5 µg).

Fewer than 1% of women become pregnant in the first year of IUD use.^22,23 IUDs are an ideal option for women with solid-organ transplants because they are so effective and because the patient does not have to do anything once the IUD is in.^22–24 The levonorgestrel IUD Mirena has the additional advantage of reducing heavy menstrual bleeding and is currently the only hormonal IUD with FDA approval for the management of menorrhagia.

About 12% of women in the general population use IUDs as their contraceptive method of choice,²⁵ whereas after solid-organ transplantation about 15% to 20% of women do.²⁶

Two historic concerns regarding IUDs may explain their low rate of use in transplant recipients.

First, IUDs were believed to be less effective in women on immunosuppressive drugs because IUDs act by inducing a local inflammatory reaction. However, IUDs involve macrophage activation, which is independent of the immune processes modified by immunosuppressants (primarily T-cell function).²⁷ A recent pilot study showed a strong inflammatory reaction in the endometrium of transplant recipients after levonorgestrel IUD insertion.²⁸

Second, there was concern about the increased risk of pelvic inflammatory disease with IUDs, but studies have shown levonorgestrel IUDs to be safe in transplant patients.^29,30

The CDC²¹ lists copper and levonorgestrel IUDs in MEC category 3 (the risks generally outweigh the advantages) for initiation in patients with complicated transplants and in category 2 (advantages generally outweigh the risks) in patients with uncomplicated organ transplants. The devices are in category 2 for both complicated and uncomplicated cases if the IUD is already in place.

Subdermal implant

A subdermal implant consisting of a single rod containing 68 mg of etonogestrel is commercially available in the United States. It is one of the most effective contraceptive methods, with the lowest rates of pregnancy—less than 1% per year, with protection lasting at least 3 years.^22,23 This low risk makes the subdermal implant a suitable method of contraception after transplant. Daily compliance is not required, and there are no hepatic first-pass effects, which results in higher bioavailability and less chance of drug interactions.

The main disadvantage of the subdermal implant and IUDs is unscheduled bleeding. An important benefit is prolonged amenorrhea, not only for patient convenience, but for reduction of endometrial cancer risk. Insertion and removal of the implant are considered minor office procedures. The implants are classified as US MEC category 2 in uncomplicated cases; initiation in complicated cases is considered category 3 but continuation is considered category 2.²¹

Permanent sterilization

Permanent sterilization is another option for women and men. In women, the fallopian tubes can be occluded with a coil system implanted vaginally through a hysteroscope, or they can be severed, tied, or clamped in a laparoscopic procedure or during cesarean delivery. Pregnancy rates after tubal ligation are less than 1%,^23,31 although concern exists for high failure rates with the hysteroscopic method.

Because younger patients are more likely than older patients to subsequently regret having the procedure done, all available contraceptive options should be discussed with them.³¹

For men, permanent sterilization is done by vasectomy, which has less associated risk and cost compared with sterilization for women.

EFFECTIVE CONTRACEPTIVE METHODS (UNINTENDED PREGNANCY RATE 1%–9%)

Effective contraceptive methods, the next tier down from very effective methods, include injectable contraceptives, combined hormonal contraceptives, and progestin-only contraceptives (Table 4).

Injectable contraceptives

Depot medroxyprogesterone acetate is an injectable progestin-only contraceptive that carries a pregnancy risk of 6% with typical use and less than 1% with correct use.²³ Thus, some failures are due to patients not returning for follow-up, but in some patients this method is not effective. Injections are given intramuscularly once every 3 months, avoiding the need for daily use.

A valid concern for transplant patients is that medroxyprogesterone acetate reduces bone mineral density. Although the bone effects are reversible in healthy adult women, caution is needed when prescribing this option to transplant patients who are already at increased risk of bone disease attributable to renal osteodystrophy and chronic corticosteroid use. ^32,33

Recently, a subcutaneous formulation of depot medroxyprogesterone acetate (104 mg)was added to the WHO MEC for contraceptive use.^34,35 The recommendations for the subcutaneous form are similar to those for the intramuscular form. In healthy women, the subcutaneous formulation is as safe and effective as the intramuscular form,³⁶ but its efficacy after solid-organ transplant has not been determined. Both forms of depot medroxyprogesterone acetate are category 2 in the US MEC for both complicated and uncomplicated transplant cases.²¹

Combined hormonal contraceptives contain both estrogen and progesterone and are available as pills, patches, or rings. Each product has an unintended pregnancy risk of 9% with typical use and less than 1% with correct use.²³ They require strict patient adherence to regular daily use, which likely explains their high failure rate with typical use.

Combined hormonal contraceptives reduce mortality risk in women in the general population,³⁷ but their effect on mortality  risk after transplant is unknown and needs further study. In women who received liver transplants, low-dose combined hormonal contraceptives have been found to be effective and well tolerated, but initiation should be delayed at least 6 months until postoperative organ stability is demonstrated.¹¹

Combined oral contraceptives are the most widely prescribed because they are convenient and familiar and have an acceptable safety profile in transplant patients,^11,33,37 despite their high failure rate with typical use. They regulate the menstrual cycle and reduce anemia associated with menstruation.

The transdermal contraceptive patch has a mechanism of action similar to that of the combined oral contraceptives, but it delivers estrogen and progesterone transdermally through the abdominal wall, thus avoiding first-pass metabolism in the liver and enzymatic degradation in the gut. It delivers 35 µg of ethinyl estradiol and 150 µg of norelgestromin (an active metabolite of norgestimate) daily.³⁸ It may cause higher circulating levels of estrogen than a combined oral contraceptive and may be associated with a higher risk of venous thromboembolism, but the evidence is conflicting.^39–42

The vaginal ring, made of Silastic, delivers ethinyl estradiol in a low dose (15 µg/day) and etonorgestrel 0.12 mg/day. Like the patch, it has the advantage of bypassing first-pass metabolism in the liver, making it a good option for transplant patients who are taking antirejection drugs, thus avoiding drug interactions.⁴¹

Both the transdermal patch and vaginal ring were studied in transplant patients and had favorable results.^24,43 The combined hormonal oral contraceptive pills, patch, and ring are in category 4 (unacceptable health risk) in the US MEC in patients with complicated cases, but they are in category 2 in uncomplicated cases.²¹

Combined hormonal contraceptives should not be considered first-line options by themselves for transplant patients because of their high failure rate with typical use.²⁴

Progestin-only pills

Although progestin-only pills have not been studied specifically in transplant patients, they can be considered for women who have contraindications to estrogen use. Estrogen use is contraindicated in women with a history of venous thromboembolism, thrombogenic mutations, estrogen-dependent neoplasia, hepatocellular adenoma, severe hypertension, vascular disease, and Budd-Chiari syndrome.

Progestin-only pills inhibit ovulation in only about half of a woman’s cycles, but they prevent conception by other mechanisms as well, such as causing thickening of the cervical mucus. They also alter the endometrium to make it unfavorable for implantation and reduce the ciliary activity of the fallopian tube.

Strict adherence is important for effectiveness because progestin-only pills have a shorter half-life than combined hormonal contraceptives and also suppress ovulation less effectively.²² Failure rates are similar or somewhat higher than with combined hormonal contraceptives; with typical use, about 9 in 100 women can become pregnant in the first year.²³ According to the US MEC,²¹ progestin-only pills are classified as category 2 for patients after both complicated and uncomplicated transplants.

MODERATELY EFFECTIVE METHODS (PREGNANCY RATE 10%–25%)

This tier of contraceptives includes all barrier methods, ie, male and female condoms, vaginal diaphragms, cervical caps, and sponges (Table 5).

Condoms (male and female)

When male condoms are used as the only birth control method, pregnancy occurs less often (18% with typical use and 2% with correct use) than with female condoms (21% with typical use and 5% with correct use).²³ Male and female condoms are the only contraceptive methods that also prevent transmission of sexually transmitted disease.²⁴

Caps, sponges, diaphragms

Cervical caps, vaginal sponges, and vaginal diaphragms are other forms of barrier contraceptives. All barrier methods should be combined with another contraceptive method to provide reliable protection against pregnancy. These methods are considered category 1 according to the US MEC.

LESS-EFFECTIVE METHODS

Fertility awareness-based methods such as the rhythm method have an associated pregnancy rate of about 25% with typical use and 3% to 5% with correct use²³ and cannot be relied on for use by transplant recipients.²⁴

Withdrawal and spermicides are considered least effective and unreliable for pregnancy prevention.

KNOW YOUR OPTIONS

With the growing number of women in their reproductive years receiving solid-organ transplants in the United States, it is increasingly important for healthcare providers to be aware of contraceptive options and reproductive life planning for this high-risk population.

Safe and effective forms of contraception are available, and additional information to guide the choice can be found in the Summary Chart of US MEC for Contraceptive Use, which is also available in a free smart phone app through the CDC.⁴⁴

Pregnancy after transplant carries high risks, requiring these patients to have special counseling and monitoring. Fortunately, planned pregnancy at least 1 year after transplant can lead to successful outcomes in these women.

A 64-year-old woman undergoes elective T10-S1 nerve decompression with fusion for chronic idiopathic scoliosis. Soon afterward, she develops acute urinary retention attributed to an Escherichia coli urinary tract infection and narcotic medications. She is treated with antibiotics, an indwelling catheter is inserted, and her symptoms resolve. She is transferred to the inpatient physical rehabilitation unit.

See related editorial

On postoperative day 9, she develops an acute change in mental status, suddenly becoming extremely anxious and falsely believing she has a “terminal illness.” A psychiatrist suggests that these symptoms are a manifestation of delirium, given the patient’s recent surgery and exposure to benzodiazepine and narcotic medications. On postoperative day 10, she is awake but is now mute and uncooperative. An internist is consulted for an evaluation for encephalopathy and delirium.

MEDICAL HISTORY

Her medical history, obtained by chart review and interviewing her husband, includes well-controlled bipolar disorder over the last 4 years, with no episodes of frank psychosis or mania. She had a “bout of delirium” 4 years earlier attributed to a catastrophic life event, but the symptoms resolved after adjustment of her anxiolytic and mood-stabilizing drugs. She also has well-controlled hypertension, hypothyroidism, and gastroesophageal reflux. Her only surgery was her recent elective procedure.

She has a family history of dementia (Pick disease in her mother).

She is married, lives with her husband, and has an adult son. She is employed as a media specialist and also teaches English as a second language. Before this hospital admission, she was described as happy and content, though her primary psychiatrist had noted intermittent anxiety. Her husband does not suspect illicit drug use and denies significant alcohol or tobacco abuse.

A thorough review of systems is not possible, given her encephalopathy. But before her acute decline, she had complained of “choking on blood” and a subjective inability to swallow.

Her home medications include dextroamphetamine extended-release, alprazolam as needed for sleep, venlafaxine extended-release, lamotrigine, lisinopril, propranolol, amlodipine, atorvastatin, levothyroxine, omep­razole, iron, and vitamin B₁₂. At the time of the evaluation, she is on her home medications with the addition of olanzapine, vitamin D, polyethylene glycol, and an intravenous infusion of dextrose 5% with 0.45% saline at a rate of 100 mL/hour. She has allergies to latex, penicillin, peanuts, and shellfish.

PHYSICAL EXAMINATION

On physical examination, the patient seems healthy and appears normal for her stated age. She is wearing a spinal brace and is in no apparent distress. She is afebrile, pulse 104 beats per minute, respirations 16 breaths per minute and unlabored, and oxygen saturation good on room air. The skin is normal. No thyromegaly, bruits, or lymphadenopathy is noted. Cardiovascular, respiratory, and abdominal examinations, though limited by the spinal brace, are unremarkable. She has no evidence of peripheral edema or vascular insufficiency. Muscle bulk and tone are adequate and symmetric.

She is awake and alert and able to follow simple commands with some prompting. She does not initiate movements spontaneously. She makes some eye contact but does not track or acknowledge the interviewer consistently and does not respond verbally to questions. Her sclera are nonicteric, the pupils are equally round and reactive to light, and the external ocular muscles are intact. There is no facial asymmetry, and the tongue protrudes at midline. She blinks appropriately to threat bilaterally. Strength is at least 3/5 in the upper extremities and 2/5 in the lower extremities, though the examination is limited by lack of patient cooperation. She shows minimal grimace on noxious stimulation but does not withdraw extremities. Reflexes are present and mildly depressed symmetrically. Plantar reflexes are downgoing bilaterally.

INITIAL LABORATORY EVALUATION

On initial laboratory testing, the serum sodium is 132 mmol/L (reference range 136–144), stable since admission. Point-of-care glucose is 98 mg/dL. Aspartate aminotransferase and alanine aminotransferase levels are mildly elevated at 59 U/L (13–35) and 51 U/L (7–38), respectively, but serum ammonia is undetectable. Vitamin B₁₂, folate, thyroid-stimulating hormone, and free thyroxine are within the normal ranges. Leukocytosis is noted, with 14 × 10⁹ cells/L (3.7–11.0), 86% neutrophils, and a mild left shift. Urinalysis is negative for leukocyte esterase, nitrites, and white blood cells.

1. Which of the following risk factors predisposes this patient to postoperative delirium?

• Hyponatremia
• Polypharmacy
• Family history of dementia
• Depression

Altered mental status, or encephalopathy, is one of the most common yet challenging conditions in medicine. When a consult is placed for altered mental status, it is important to determine the affected domain that has changed from the patient’s normal state. Changes can include alterations in consciousness, attention, behavior, cognition, language, speech, and praxis and can reflect varying degrees of cerebral dysfunction.

Electrolyte abnormalities

Disorders of sodium homeostasis are common in hospitalized patients and may contribute to the onset of delirium. Hyponatremia is especially frequent and often iatrogenic, with a prevalence significantly higher in women (2.1% vs 1.3%, P = .0044) and in the elderly.²

Neurologic manifestations are often the result of cerebral edema due to osmolar volume shifts.^3–6 Acute hyponatremic encephalopathy is most likely to occur when sodium shifts are rapid, usually within 24 hours, and is often seen in postoperative patients requiring significant volume resuscitation with hypotonic fluids.⁶ Young premenopausal women appear to be at especially high risk of permanent brain damage secondary to hyponatremic encephalopathy,⁷ a finding that may reflect the limited compliance within the intracranial vault and lack of significant involutional parenchymal changes that occur with aging.^8–11

Aging also has important effects on fluid balance, as restoration of body fluid homeostasis is slower in older patients.¹²

Hormonal effects of estrogen appear to play a synergistic role in the expression of arginine vasopressin in postmenopausal women, further contributing to hyponatremia.

Although our patient has mild hyponatremia, there has been no acute change in her sodium balance since admission to the hospital, and so it is unlikely to be the cause of her acute delirium. Her mild hyponatremia may in part be from hypo-osmolar maintenance fluids with dextrose 5% and 0.45% normal saline.

Mild chronic hyponatremia may affect balance and has been associated with increased mortality risk in certain chronic disease states, but this is unlikely to be the main cause of acute delirium.

Polypharmacy

Patients admitted to the hospital with polypharmacy are at high risk of drug-induced delirium. In approaching delirium, a patient’s medications should be evaluated for interactions, as well as for possible effects of newly prescribed drugs. New medications that affect cytochrome P450 enzymes warrant investigation, as do drugs with narrow therapeutic windows that the patient has been using long-term.

Consultation with a clinical pharmacist is often helpful. Macrolides, protease inhibitors, and nondihydropyridine calcium channel blockers are common P450 inhibitors, while many anticonvulsants are known inducers of the P450 system. Selective serotonin reuptake inhibitors and diuretics can lead to electrolyte imbalances such as hyponatremia, which may further predispose to bouts of delirium, as described above.

The patient’s extensive list of psychoactive medications makes polypharmacy a significant risk factor for delirium. Quetiapine and venlafaxine both cause sedation and increase the risk of serotonin syndrome. However, in this case, the patient does not have marked fever, rigidity, or hyperreflexia to corroborate that diagnosis.

Dementia

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines dementia as a disorder involving cognitive impairment in at least 1 cognitive domain, with a significant decline from a previous level of functioning.¹ These impairments need not necessarily occur separately from bouts of delirium, but the time course for most forms of dementia tends to be progressive over a subacute to chronic duration.

Dementia increases the risk for acute confusion and delirium in hospitalized patients.¹³ This is partly reflected by pathophysiologic changes that leave elderly patients susceptible to the effects of anticholinergic drugs.¹⁴ Structural changes due to small-vessel ischemia may also predispose patients to seizures in the setting of metabolic derangement or critical illness. Diagnosing dementia thus remains a challenge, as dementia must be clearly distinguished from other disorders such as delirium and depression.

The acute change in this patient’s case makes the isolated diagnosis of dementia much less likely than other causes of altered mental status. Also, her previous level of function does not suggest a clinically significant personal history of impairment.

Mental illness

Several studies have examined the link between preoperative mental health disorders and postoperative delirium.^15–17 Depression appears to be a risk factor for postoperative delirium in patients undergoing elective orthopedic surgery,¹⁵ and this includes elderly patients.¹⁶ While a clear etiologic link has yet to be determined, disruption of circadian rhythm and abnormal cerebral response to stress may play a role. Studies have also suggested an association between schizophrenia and delirium, though this may be related to perioperative suspension of medications.¹⁷

Bipolar disorder has not been well studied with regard to postoperative complications. However, this patient has had a previous episode of decompensated mania, therefore making bipolar disorder a plausible condition in the differential diagnosis.

CASE CONTINUED: ACUTE DETERIORATION

Without a clearly identifiable cause for our patient’s acute confusional state, neurology and medical consultants recommend neuroimaging.

Computed tomography (CT) and magnetic resonance imaging (MRI) without contrast are ordered and performed on postoperative day 11 and demonstrate chronic small-vessel ischemic disease, consistent with our patient’s age, as well as frontotemporal atrophy. There is no evidence of mass effect, bleeding, or acute ischemia.

Overnight, she becomes obtunded, and the rapid response team is called. Her vital signs appear stable, and she is afebrile. Basic laboratory studies, imaging, and electrocardiography are repeated, and the results are unchanged from recent tests. She is transferred to the intensive care unit (ICU) for closer monitoring.

2. What is most likely cause of the patient’s declining mental status, and what is the next appropriate step?

• Acute stroke: repeat MRI with contrast
• Urinary tract infection: order blood and urine cultures, and start empiric antibiotics
• Neuroleptic malignant syndrome: start dantrolene
• Seizures: order electroencephalography (EEG)

Acute stroke

Acute stroke can affect mental status and consciousness through several pathways. Stroke syndromes can vary in presentation depending on the level of cortical and subcortical involvement, with clinical manifestations including confusion, aphasia, neglect, and inattention. Wakefulness and the ability to maintain consciousness is impaired, with disruption of the ascending reticular activating system, often seen in injuries to the brainstem. Large territorial or hemispheric infarcts, with subsequent cerebral edema, can also disrupt this system and lead to cerebral herniation and coma.

MRI without contrast is extremely sensitive for ischemia and can typically detect ischemia in acute stroke within 3 to 30 minutes.^18–20 Repeating the study with contrast is unlikely to provide additional benefit.

In our patient’s case, the lack of localizing neurologic symptoms, in addition to her recent negative neuroimaging workup, makes the diagnosis of acute stroke unlikely.

Infection

The role of severe infection in patients with altered mental status is well documented and likely relates to diffuse cerebral dysfunction caused by an inflammatory cascade. Less well understood is the role of occult infection, especially urinary tract infection, in otherwise immunocompetent patients. Urinary tract infection has long been thought to cause delirium in otherwise asymptomatic elderly patients, but few studies have examined this relationship, and those studies have been shown to have significant methodologic errors.²¹ In the absence of better data, urinary tract infection as the cause of frank delirium in an otherwise well patient should be viewed with skepticism, and alternative causes should be sought.

Although the patient has a nonspecific leukocytosis, her benign urinalysis and lack of corroborating evidence makes urinary tract infection an unlikely cause of her frank delirium.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is defined as fever, rigidity, mental status changes, and autonomic instability after exposure to antidopaminergic drugs. It is classically seen after administration of typical antipsychotics, though atypical antipsychotics and antiemetic drugs may be implicated as well.

Patients often exhibit agitation and confusion, which when severe may progress to mutism and catatonia. Likewise, psychotropic drugs such as quetiapine and venlafaxine, used in combination, have the additional risk of serotonin syndrome.

Additional symptoms include hyperreflexia, ataxia, and myoclonus. Withdrawal of the causative agent and supportive care are the mainstays of therapy. Targeted therapies with agents such as dantrolene, bromocriptine, and amantadine have also been reported anecdotally, but their efficacy is unclear, with variable results.²²

As noted earlier, the addition of quetiapine to the patient’s already lengthy medication list could conceivably cause neuroleptic malignant syndrome or serotonin syndrome and should be considered. However, additional neurologic findings to confirm this diagnosis are lacking.

Seizures

Nonconvulsive seizure, particularly nonconvulsive status epilepticus (NCSE), is not well recognized and is particularly challenging to diagnose without EEG. In several case series of patients presenting to the emergency room with altered mental status, NCSE was found in 16% to 28% of patients in whom EEG was performed after an initial evaluation failed to show an obvious cause for the delirium.^23,24 Historical features are unreliable for ruling out NCSE as a cause of delirium, as up to 41% of patients in whom the condition is ultimately diagnosed have only confusion as the presenting clinical symptom.²⁵

Likewise, alternating ictal and postictal periods may mimic the typical waxing and waning course classically associated with delirium of other causes. Physical findings such as nystagmus, anisocoria, and hippus may be helpful but are often overlooked or absent. EEG is thus an essential requirement for the diagnosis.²⁶

Given the lack of a clear diagnosis, a workup with EEG should be considered in this patient.

CASE CONTINUED: ADDITIONAL SIGNS

In the ICU, our patient is evaluated by the intensivist team. Her vital signs are stable, and while she is now awakening, she is unable to follow commands and remains mute. She does not initiate movement spontaneously but offers slight resistance to passive movements, holding and maintaining postures her extremities are placed in. She keeps her eyes closed, but when opened by the examining physician, dysconjugate gaze and anisocoria are noted.

3. What clinical entity is most consistent with these physical findings, and what is the next step in management?

• Catatonia secondary to bipolar disorder type I: challenge with intravenous lorazepam 2 mg
• Oculomotor nerve palsy due to enlarging intracranial aneurysm: aggressive blood pressure lowering, elevation of the head of the bed
• Toxic leukoencephalopathy: supportive care and withdrawal of the causative agent
• NCSE: challenge with intravenous lorazepam 2 mg and order EEG

Catatonia

The DSM-5 defines catatonia as a behavioral syndrome complicating an underlying psychiatric or medical condition, as opposed to a distinct diagnosis. It is most commonly encountered in psychiatric illnesses including bipolar disorder, major depression, and schizophrenia. Akinesis, stupor, mutism, and “waxy” flexibility often dominate the clinical picture.

The pathophysiology is poorly defined, but likely involves neurotransmitter imbalances particularly with an increase in N-methyl-d-aspartate (NMDA) activity and suppression of gamma-aminobutyric acid (GABA) activity. This hypothesis is supported by the finding that benzodiazepines, electroconvulsive therapy, and NMDA antagonists such as amantadine are all effective in treating catatonia.^27,28 Findings of focal neurologic abnormalities warrant further investigation. EEG may be necessary to differentiate catatonia from NCSE, as both may respond to a benzodiazepine challenge.

As pure catatonia is a diagnosis of exclusion, further workup, including EEG, is necessary to confirm the diagnosis.

Oculomotor nerve palsy

Anisocoria together with dysconjugate gaze should prompt consideration of a lesion involving the oculomotor nerve. Loss of tonic muscle activity from the lateral rectus and superior oblique cause a downward and outward gaze. Furthermore, loss of parasympathetic tone occurs with compressive palsies of the oculomotor nerve, clinically manifesting as a mydriatic and unreactive pupil with ptosis. Given its anatomic course and proximity to other vascular and parenchymal structures, the oculomotor nerve is vulnerable to compression from many sources, including aneurysmal dilation (especially of the posterior cerebral artery), uncal herniation, and inflammation of the cavernous sinus.

Noncontrast CT and lumbar puncture are very sensitive for making the diagnosis of sentinel bleeding within the first 24 hours,²⁹ whereas computed tomographic angiography and magnetic resonance angiography can reliably detect unruptured aneurysms as small as 3 mm.³⁰

Conditions that can lead to oculomotor palsy are unlikely to cause an acute gain in appendicular muscle tone, as noted by the catatonia this patient is demonstrating. Also, mass lesions or bleeding associated with oculomotor palsy is likely to cause acute loss of tone. Chronic upper-motor neuron lesions lead to spasticity rather than the waxy flexibility seen in this patient. In our patient, the findings of isolated anisocoria without further clinical evidence of oculomotor nerve compression make this diagnosis unlikely.

Toxic leukoencephalopathy

Toxic leukoencephalopathy—widespread destruction of myelin, particularly in the white matter tracts that support higher cortical functions—can be caused by antineoplastic agents, immunosuppressant agents, and industrial solvents, as well as by abuse of vaporized drugs such as heroin (“chasing the dragon”). In its mild forms it may cause behavioral disturbances or inattention. In severe forms, a neurobehavioral syndrome of akinetic mutism may be present and can mimic catatonia.³¹

The diagnosis is often based on the clinical history and neuroimaging, particularly MRI, which demonstrates hyperintensity of the white matter tracts in T2-weighted images.³²

This patient does not have a clear history of exposure to an agent typically associated with toxic leukoencephalopathy and does not have the corroborating MRI findings to support this diagnosis.

Because recent neuroimaging revealed no structural brain lesions and no cause for brain herniation, the patient receives a challenge of 2 mg of intravenous lorazepam to treat potential NCSE. Subsequent improvement is noted in her anisocoria, gaze deviation, and encephalopathy. EEG reveals frequent focal seizures arising from mesial frontal regions with bilateral hemisphere propagation, consistent with bifrontal focal NCSE.

As our patient is being transferred to a room for continuous EEG monitoring, her condition begins to deteriorate, and she again becomes more encephalopathic, with anisocoria and dysconjugate gaze. Additional doses of lorazepam are given (to complete a 0.1-mg/kg load), and additional therapy with intravenous fos­phenytoin (20-mg/kg load) is given. Intubation is done for airway protection.

Continuous EEG monitoring reveals multiple frequent electrographic seizures arising from the bifrontal territories, concerning for persistent focal NCSE. A midazolam drip is initiated for EEG burst suppression of cerebral activity. Over 24 hours, EEG shows resolution of seizure activity. As the patient is weaned from sedation, she awakens and follows commands consistently, tolerating extubation without complications. Her neurologic status remains stable over the next 48 hours, having returned to her neurologic baseline level of functioning. She is able to be transferred out of the ICU in stable condition while continuing on scheduled antiepileptic therapy with phenytoin.

ALTERED MENTAL STATUS IN INPATIENTS

Altered mental status is one of the most frequently encountered reasons for medical consultation from nonmedical services. The workup and management of metabolic, toxic, psychiatric, and neurologic causes requires a deep appreciation for the broad differential diagnosis and a multidisciplinary approach. Physicians caring for these patients should avoid prematurely drawing conclusions when the patient’s clinical condition fails to respond to typical measures.

Delirium is a challenging adverse event in older patients during hospitalization, with a significant national financial burden of $164 billion per year.³³ The prevalence of delirium in adults on hospital admission is estimated as 14% to 24%, with an inpatient hospitalization incidence ranging from 6% to 56% in general hospital patients.³⁴ In addition, postoperative delirium has been reported in 15% to 53% of older patients.³⁵

While delirium is preventable in 30% to 40% of cases,^36,37 it remains an important independent prognostic determinant of hospital outcomes.^38–40

Delirium in hospitalized patients requires a thorough, individualized workup. In our patient’s case, the clinical findings of hypoactive delirium were found to be manifestations of NCSE, a rare life-threatening and potentially reversible neurologic disease.

While establishing seizures as a diagnosis, careful attention must first be directed towards investigating environmental or metabolic triggers that may be inciting the disease. This often involves a similar workup for metabolic derangements, as seen in the approach to delirium.

The diagnosis of NCSE, while made in this patient’s case, remains challenging. Careful physical examination should assess for automatisms, “negative” symptoms (staring, aphasia, weakness), and “positive” symptoms (hallucinations, psychosis). Cataplexy, mutism, and other acute psychiatric features have been associated with NCSE,⁴⁴ highlighting the importance of EEG. A trial of a benzodiazepine in conjunction with clinical and EEG monitoring may help guide clinical decision- making.

As there is no current universally accepted definition for NCSE nor an accepted agreement on required EEG diagnostic features at this time,⁴¹ accurate diagnosis is most likely to be obtained in facilities with both subspecialty neurologic consultation and EEG capabilities.

Our patient’s family history of Pick disease is interesting, as this is a progressive form of frontotemporal dementia with both sporadic and genetically linked cases. Recent studies have shown evidence that patients with neurodegenerative disease have increased seizure frequency early in the disease course,³¹ and efforts are under way to establish the incidence of first unprovoked seizure in patients with frontotemporal dementia. In our patient’s case, resolution of seizure activity yielded a return to her baseline level of neurologic function.

Early use of selective serotonin reuptake inhibitors has been shown to help with the behavioral symptoms of frontotemporal dementia,⁴⁵ but increasing requirements over time may indicate progression of neurodegeneration and should warrant further appropriate investigation.

In our patient’s case, escalating dose requirements may have reflected worsening frontotemporal atrophy. However, the diagnosis of a neurodegenerative disease such as frontotemporal dementia in a patient such as ours is not definitively established at this time and is being investigated on an outpatient basis.

Given the frequency of delirium and its many risk factors in the inpatient setting, verifying a causative diagnosis can be difficult. Detailed consideration of the patient’s individual clinical circumstances, often in concert with appropriate subspecialty consultations, is essential to the evaluation. Although it is time-intensive, multidisciplinary intervention can lead to safer outcomes and shorter hospital stays.

A 64-year-old woman undergoes elective T10-S1 nerve decompression with fusion for chronic idiopathic scoliosis. Soon afterward, she develops acute urinary retention attributed to an Escherichia coli urinary tract infection and narcotic medications. She is treated with antibiotics, an indwelling catheter is inserted, and her symptoms resolve. She is transferred to the inpatient physical rehabilitation unit.

See related editorial

On postoperative day 9, she develops an acute change in mental status, suddenly becoming extremely anxious and falsely believing she has a “terminal illness.” A psychiatrist suggests that these symptoms are a manifestation of delirium, given the patient’s recent surgery and exposure to benzodiazepine and narcotic medications. On postoperative day 10, she is awake but is now mute and uncooperative. An internist is consulted for an evaluation for encephalopathy and delirium.

MEDICAL HISTORY

Her medical history, obtained by chart review and interviewing her husband, includes well-controlled bipolar disorder over the last 4 years, with no episodes of frank psychosis or mania. She had a “bout of delirium” 4 years earlier attributed to a catastrophic life event, but the symptoms resolved after adjustment of her anxiolytic and mood-stabilizing drugs. She also has well-controlled hypertension, hypothyroidism, and gastroesophageal reflux. Her only surgery was her recent elective procedure.

She has a family history of dementia (Pick disease in her mother).

She is married, lives with her husband, and has an adult son. She is employed as a media specialist and also teaches English as a second language. Before this hospital admission, she was described as happy and content, though her primary psychiatrist had noted intermittent anxiety. Her husband does not suspect illicit drug use and denies significant alcohol or tobacco abuse.

A thorough review of systems is not possible, given her encephalopathy. But before her acute decline, she had complained of “choking on blood” and a subjective inability to swallow.

Her home medications include dextroamphetamine extended-release, alprazolam as needed for sleep, venlafaxine extended-release, lamotrigine, lisinopril, propranolol, amlodipine, atorvastatin, levothyroxine, omep­razole, iron, and vitamin B₁₂. At the time of the evaluation, she is on her home medications with the addition of olanzapine, vitamin D, polyethylene glycol, and an intravenous infusion of dextrose 5% with 0.45% saline at a rate of 100 mL/hour. She has allergies to latex, penicillin, peanuts, and shellfish.

PHYSICAL EXAMINATION

On physical examination, the patient seems healthy and appears normal for her stated age. She is wearing a spinal brace and is in no apparent distress. She is afebrile, pulse 104 beats per minute, respirations 16 breaths per minute and unlabored, and oxygen saturation good on room air. The skin is normal. No thyromegaly, bruits, or lymphadenopathy is noted. Cardiovascular, respiratory, and abdominal examinations, though limited by the spinal brace, are unremarkable. She has no evidence of peripheral edema or vascular insufficiency. Muscle bulk and tone are adequate and symmetric.

She is awake and alert and able to follow simple commands with some prompting. She does not initiate movements spontaneously. She makes some eye contact but does not track or acknowledge the interviewer consistently and does not respond verbally to questions. Her sclera are nonicteric, the pupils are equally round and reactive to light, and the external ocular muscles are intact. There is no facial asymmetry, and the tongue protrudes at midline. She blinks appropriately to threat bilaterally. Strength is at least 3/5 in the upper extremities and 2/5 in the lower extremities, though the examination is limited by lack of patient cooperation. She shows minimal grimace on noxious stimulation but does not withdraw extremities. Reflexes are present and mildly depressed symmetrically. Plantar reflexes are downgoing bilaterally.

INITIAL LABORATORY EVALUATION

On initial laboratory testing, the serum sodium is 132 mmol/L (reference range 136–144), stable since admission. Point-of-care glucose is 98 mg/dL. Aspartate aminotransferase and alanine aminotransferase levels are mildly elevated at 59 U/L (13–35) and 51 U/L (7–38), respectively, but serum ammonia is undetectable. Vitamin B₁₂, folate, thyroid-stimulating hormone, and free thyroxine are within the normal ranges. Leukocytosis is noted, with 14 × 10⁹ cells/L (3.7–11.0), 86% neutrophils, and a mild left shift. Urinalysis is negative for leukocyte esterase, nitrites, and white blood cells.

1. Which of the following risk factors predisposes this patient to postoperative delirium?

• Hyponatremia
• Polypharmacy
• Family history of dementia
• Depression

Altered mental status, or encephalopathy, is one of the most common yet challenging conditions in medicine. When a consult is placed for altered mental status, it is important to determine the affected domain that has changed from the patient’s normal state. Changes can include alterations in consciousness, attention, behavior, cognition, language, speech, and praxis and can reflect varying degrees of cerebral dysfunction.

Electrolyte abnormalities

Disorders of sodium homeostasis are common in hospitalized patients and may contribute to the onset of delirium. Hyponatremia is especially frequent and often iatrogenic, with a prevalence significantly higher in women (2.1% vs 1.3%, P = .0044) and in the elderly.²

Neurologic manifestations are often the result of cerebral edema due to osmolar volume shifts.^3–6 Acute hyponatremic encephalopathy is most likely to occur when sodium shifts are rapid, usually within 24 hours, and is often seen in postoperative patients requiring significant volume resuscitation with hypotonic fluids.⁶ Young premenopausal women appear to be at especially high risk of permanent brain damage secondary to hyponatremic encephalopathy,⁷ a finding that may reflect the limited compliance within the intracranial vault and lack of significant involutional parenchymal changes that occur with aging.^8–11

Aging also has important effects on fluid balance, as restoration of body fluid homeostasis is slower in older patients.¹²

Hormonal effects of estrogen appear to play a synergistic role in the expression of arginine vasopressin in postmenopausal women, further contributing to hyponatremia.

Although our patient has mild hyponatremia, there has been no acute change in her sodium balance since admission to the hospital, and so it is unlikely to be the cause of her acute delirium. Her mild hyponatremia may in part be from hypo-osmolar maintenance fluids with dextrose 5% and 0.45% normal saline.

Mild chronic hyponatremia may affect balance and has been associated with increased mortality risk in certain chronic disease states, but this is unlikely to be the main cause of acute delirium.

Polypharmacy

Patients admitted to the hospital with polypharmacy are at high risk of drug-induced delirium. In approaching delirium, a patient’s medications should be evaluated for interactions, as well as for possible effects of newly prescribed drugs. New medications that affect cytochrome P450 enzymes warrant investigation, as do drugs with narrow therapeutic windows that the patient has been using long-term.

Consultation with a clinical pharmacist is often helpful. Macrolides, protease inhibitors, and nondihydropyridine calcium channel blockers are common P450 inhibitors, while many anticonvulsants are known inducers of the P450 system. Selective serotonin reuptake inhibitors and diuretics can lead to electrolyte imbalances such as hyponatremia, which may further predispose to bouts of delirium, as described above.

The patient’s extensive list of psychoactive medications makes polypharmacy a significant risk factor for delirium. Quetiapine and venlafaxine both cause sedation and increase the risk of serotonin syndrome. However, in this case, the patient does not have marked fever, rigidity, or hyperreflexia to corroborate that diagnosis.

Dementia

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines dementia as a disorder involving cognitive impairment in at least 1 cognitive domain, with a significant decline from a previous level of functioning.¹ These impairments need not necessarily occur separately from bouts of delirium, but the time course for most forms of dementia tends to be progressive over a subacute to chronic duration.

Dementia increases the risk for acute confusion and delirium in hospitalized patients.¹³ This is partly reflected by pathophysiologic changes that leave elderly patients susceptible to the effects of anticholinergic drugs.¹⁴ Structural changes due to small-vessel ischemia may also predispose patients to seizures in the setting of metabolic derangement or critical illness. Diagnosing dementia thus remains a challenge, as dementia must be clearly distinguished from other disorders such as delirium and depression.

The acute change in this patient’s case makes the isolated diagnosis of dementia much less likely than other causes of altered mental status. Also, her previous level of function does not suggest a clinically significant personal history of impairment.

Mental illness

Several studies have examined the link between preoperative mental health disorders and postoperative delirium.^15–17 Depression appears to be a risk factor for postoperative delirium in patients undergoing elective orthopedic surgery,¹⁵ and this includes elderly patients.¹⁶ While a clear etiologic link has yet to be determined, disruption of circadian rhythm and abnormal cerebral response to stress may play a role. Studies have also suggested an association between schizophrenia and delirium, though this may be related to perioperative suspension of medications.¹⁷

Bipolar disorder has not been well studied with regard to postoperative complications. However, this patient has had a previous episode of decompensated mania, therefore making bipolar disorder a plausible condition in the differential diagnosis.

CASE CONTINUED: ACUTE DETERIORATION

Without a clearly identifiable cause for our patient’s acute confusional state, neurology and medical consultants recommend neuroimaging.

Computed tomography (CT) and magnetic resonance imaging (MRI) without contrast are ordered and performed on postoperative day 11 and demonstrate chronic small-vessel ischemic disease, consistent with our patient’s age, as well as frontotemporal atrophy. There is no evidence of mass effect, bleeding, or acute ischemia.

Overnight, she becomes obtunded, and the rapid response team is called. Her vital signs appear stable, and she is afebrile. Basic laboratory studies, imaging, and electrocardiography are repeated, and the results are unchanged from recent tests. She is transferred to the intensive care unit (ICU) for closer monitoring.

2. What is most likely cause of the patient’s declining mental status, and what is the next appropriate step?

• Acute stroke: repeat MRI with contrast
• Urinary tract infection: order blood and urine cultures, and start empiric antibiotics
• Neuroleptic malignant syndrome: start dantrolene
• Seizures: order electroencephalography (EEG)

Acute stroke

Acute stroke can affect mental status and consciousness through several pathways. Stroke syndromes can vary in presentation depending on the level of cortical and subcortical involvement, with clinical manifestations including confusion, aphasia, neglect, and inattention. Wakefulness and the ability to maintain consciousness is impaired, with disruption of the ascending reticular activating system, often seen in injuries to the brainstem. Large territorial or hemispheric infarcts, with subsequent cerebral edema, can also disrupt this system and lead to cerebral herniation and coma.

MRI without contrast is extremely sensitive for ischemia and can typically detect ischemia in acute stroke within 3 to 30 minutes.^18–20 Repeating the study with contrast is unlikely to provide additional benefit.

In our patient’s case, the lack of localizing neurologic symptoms, in addition to her recent negative neuroimaging workup, makes the diagnosis of acute stroke unlikely.

Infection

The role of severe infection in patients with altered mental status is well documented and likely relates to diffuse cerebral dysfunction caused by an inflammatory cascade. Less well understood is the role of occult infection, especially urinary tract infection, in otherwise immunocompetent patients. Urinary tract infection has long been thought to cause delirium in otherwise asymptomatic elderly patients, but few studies have examined this relationship, and those studies have been shown to have significant methodologic errors.²¹ In the absence of better data, urinary tract infection as the cause of frank delirium in an otherwise well patient should be viewed with skepticism, and alternative causes should be sought.

Although the patient has a nonspecific leukocytosis, her benign urinalysis and lack of corroborating evidence makes urinary tract infection an unlikely cause of her frank delirium.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is defined as fever, rigidity, mental status changes, and autonomic instability after exposure to antidopaminergic drugs. It is classically seen after administration of typical antipsychotics, though atypical antipsychotics and antiemetic drugs may be implicated as well.

Patients often exhibit agitation and confusion, which when severe may progress to mutism and catatonia. Likewise, psychotropic drugs such as quetiapine and venlafaxine, used in combination, have the additional risk of serotonin syndrome.

Additional symptoms include hyperreflexia, ataxia, and myoclonus. Withdrawal of the causative agent and supportive care are the mainstays of therapy. Targeted therapies with agents such as dantrolene, bromocriptine, and amantadine have also been reported anecdotally, but their efficacy is unclear, with variable results.²²

As noted earlier, the addition of quetiapine to the patient’s already lengthy medication list could conceivably cause neuroleptic malignant syndrome or serotonin syndrome and should be considered. However, additional neurologic findings to confirm this diagnosis are lacking.

Seizures

Nonconvulsive seizure, particularly nonconvulsive status epilepticus (NCSE), is not well recognized and is particularly challenging to diagnose without EEG. In several case series of patients presenting to the emergency room with altered mental status, NCSE was found in 16% to 28% of patients in whom EEG was performed after an initial evaluation failed to show an obvious cause for the delirium.^23,24 Historical features are unreliable for ruling out NCSE as a cause of delirium, as up to 41% of patients in whom the condition is ultimately diagnosed have only confusion as the presenting clinical symptom.²⁵

Likewise, alternating ictal and postictal periods may mimic the typical waxing and waning course classically associated with delirium of other causes. Physical findings such as nystagmus, anisocoria, and hippus may be helpful but are often overlooked or absent. EEG is thus an essential requirement for the diagnosis.²⁶

Given the lack of a clear diagnosis, a workup with EEG should be considered in this patient.

CASE CONTINUED: ADDITIONAL SIGNS

In the ICU, our patient is evaluated by the intensivist team. Her vital signs are stable, and while she is now awakening, she is unable to follow commands and remains mute. She does not initiate movement spontaneously but offers slight resistance to passive movements, holding and maintaining postures her extremities are placed in. She keeps her eyes closed, but when opened by the examining physician, dysconjugate gaze and anisocoria are noted.

3. What clinical entity is most consistent with these physical findings, and what is the next step in management?

• Catatonia secondary to bipolar disorder type I: challenge with intravenous lorazepam 2 mg
• Oculomotor nerve palsy due to enlarging intracranial aneurysm: aggressive blood pressure lowering, elevation of the head of the bed
• Toxic leukoencephalopathy: supportive care and withdrawal of the causative agent
• NCSE: challenge with intravenous lorazepam 2 mg and order EEG

Catatonia

The DSM-5 defines catatonia as a behavioral syndrome complicating an underlying psychiatric or medical condition, as opposed to a distinct diagnosis. It is most commonly encountered in psychiatric illnesses including bipolar disorder, major depression, and schizophrenia. Akinesis, stupor, mutism, and “waxy” flexibility often dominate the clinical picture.

The pathophysiology is poorly defined, but likely involves neurotransmitter imbalances particularly with an increase in N-methyl-d-aspartate (NMDA) activity and suppression of gamma-aminobutyric acid (GABA) activity. This hypothesis is supported by the finding that benzodiazepines, electroconvulsive therapy, and NMDA antagonists such as amantadine are all effective in treating catatonia.^27,28 Findings of focal neurologic abnormalities warrant further investigation. EEG may be necessary to differentiate catatonia from NCSE, as both may respond to a benzodiazepine challenge.

As pure catatonia is a diagnosis of exclusion, further workup, including EEG, is necessary to confirm the diagnosis.

Oculomotor nerve palsy

Anisocoria together with dysconjugate gaze should prompt consideration of a lesion involving the oculomotor nerve. Loss of tonic muscle activity from the lateral rectus and superior oblique cause a downward and outward gaze. Furthermore, loss of parasympathetic tone occurs with compressive palsies of the oculomotor nerve, clinically manifesting as a mydriatic and unreactive pupil with ptosis. Given its anatomic course and proximity to other vascular and parenchymal structures, the oculomotor nerve is vulnerable to compression from many sources, including aneurysmal dilation (especially of the posterior cerebral artery), uncal herniation, and inflammation of the cavernous sinus.

Noncontrast CT and lumbar puncture are very sensitive for making the diagnosis of sentinel bleeding within the first 24 hours,²⁹ whereas computed tomographic angiography and magnetic resonance angiography can reliably detect unruptured aneurysms as small as 3 mm.³⁰

Conditions that can lead to oculomotor palsy are unlikely to cause an acute gain in appendicular muscle tone, as noted by the catatonia this patient is demonstrating. Also, mass lesions or bleeding associated with oculomotor palsy is likely to cause acute loss of tone. Chronic upper-motor neuron lesions lead to spasticity rather than the waxy flexibility seen in this patient. In our patient, the findings of isolated anisocoria without further clinical evidence of oculomotor nerve compression make this diagnosis unlikely.

Toxic leukoencephalopathy

Toxic leukoencephalopathy—widespread destruction of myelin, particularly in the white matter tracts that support higher cortical functions—can be caused by antineoplastic agents, immunosuppressant agents, and industrial solvents, as well as by abuse of vaporized drugs such as heroin (“chasing the dragon”). In its mild forms it may cause behavioral disturbances or inattention. In severe forms, a neurobehavioral syndrome of akinetic mutism may be present and can mimic catatonia.³¹

The diagnosis is often based on the clinical history and neuroimaging, particularly MRI, which demonstrates hyperintensity of the white matter tracts in T2-weighted images.³²

This patient does not have a clear history of exposure to an agent typically associated with toxic leukoencephalopathy and does not have the corroborating MRI findings to support this diagnosis.

Because recent neuroimaging revealed no structural brain lesions and no cause for brain herniation, the patient receives a challenge of 2 mg of intravenous lorazepam to treat potential NCSE. Subsequent improvement is noted in her anisocoria, gaze deviation, and encephalopathy. EEG reveals frequent focal seizures arising from mesial frontal regions with bilateral hemisphere propagation, consistent with bifrontal focal NCSE.

As our patient is being transferred to a room for continuous EEG monitoring, her condition begins to deteriorate, and she again becomes more encephalopathic, with anisocoria and dysconjugate gaze. Additional doses of lorazepam are given (to complete a 0.1-mg/kg load), and additional therapy with intravenous fos­phenytoin (20-mg/kg load) is given. Intubation is done for airway protection.

Continuous EEG monitoring reveals multiple frequent electrographic seizures arising from the bifrontal territories, concerning for persistent focal NCSE. A midazolam drip is initiated for EEG burst suppression of cerebral activity. Over 24 hours, EEG shows resolution of seizure activity. As the patient is weaned from sedation, she awakens and follows commands consistently, tolerating extubation without complications. Her neurologic status remains stable over the next 48 hours, having returned to her neurologic baseline level of functioning. She is able to be transferred out of the ICU in stable condition while continuing on scheduled antiepileptic therapy with phenytoin.

ALTERED MENTAL STATUS IN INPATIENTS

Altered mental status is one of the most frequently encountered reasons for medical consultation from nonmedical services. The workup and management of metabolic, toxic, psychiatric, and neurologic causes requires a deep appreciation for the broad differential diagnosis and a multidisciplinary approach. Physicians caring for these patients should avoid prematurely drawing conclusions when the patient’s clinical condition fails to respond to typical measures.

Delirium is a challenging adverse event in older patients during hospitalization, with a significant national financial burden of $164 billion per year.³³ The prevalence of delirium in adults on hospital admission is estimated as 14% to 24%, with an inpatient hospitalization incidence ranging from 6% to 56% in general hospital patients.³⁴ In addition, postoperative delirium has been reported in 15% to 53% of older patients.³⁵

While delirium is preventable in 30% to 40% of cases,^36,37 it remains an important independent prognostic determinant of hospital outcomes.^38–40

Delirium in hospitalized patients requires a thorough, individualized workup. In our patient’s case, the clinical findings of hypoactive delirium were found to be manifestations of NCSE, a rare life-threatening and potentially reversible neurologic disease.

While establishing seizures as a diagnosis, careful attention must first be directed towards investigating environmental or metabolic triggers that may be inciting the disease. This often involves a similar workup for metabolic derangements, as seen in the approach to delirium.

The diagnosis of NCSE, while made in this patient’s case, remains challenging. Careful physical examination should assess for automatisms, “negative” symptoms (staring, aphasia, weakness), and “positive” symptoms (hallucinations, psychosis). Cataplexy, mutism, and other acute psychiatric features have been associated with NCSE,⁴⁴ highlighting the importance of EEG. A trial of a benzodiazepine in conjunction with clinical and EEG monitoring may help guide clinical decision- making.

As there is no current universally accepted definition for NCSE nor an accepted agreement on required EEG diagnostic features at this time,⁴¹ accurate diagnosis is most likely to be obtained in facilities with both subspecialty neurologic consultation and EEG capabilities.

Our patient’s family history of Pick disease is interesting, as this is a progressive form of frontotemporal dementia with both sporadic and genetically linked cases. Recent studies have shown evidence that patients with neurodegenerative disease have increased seizure frequency early in the disease course,³¹ and efforts are under way to establish the incidence of first unprovoked seizure in patients with frontotemporal dementia. In our patient’s case, resolution of seizure activity yielded a return to her baseline level of neurologic function.

Early use of selective serotonin reuptake inhibitors has been shown to help with the behavioral symptoms of frontotemporal dementia,⁴⁵ but increasing requirements over time may indicate progression of neurodegeneration and should warrant further appropriate investigation.

In our patient’s case, escalating dose requirements may have reflected worsening frontotemporal atrophy. However, the diagnosis of a neurodegenerative disease such as frontotemporal dementia in a patient such as ours is not definitively established at this time and is being investigated on an outpatient basis.

Given the frequency of delirium and its many risk factors in the inpatient setting, verifying a causative diagnosis can be difficult. Detailed consideration of the patient’s individual clinical circumstances, often in concert with appropriate subspecialty consultations, is essential to the evaluation. Although it is time-intensive, multidisciplinary intervention can lead to safer outcomes and shorter hospital stays.

A 64-year-old woman undergoes elective T10-S1 nerve decompression with fusion for chronic idiopathic scoliosis. Soon afterward, she develops acute urinary retention attributed to an Escherichia coli urinary tract infection and narcotic medications. She is treated with antibiotics, an indwelling catheter is inserted, and her symptoms resolve. She is transferred to the inpatient physical rehabilitation unit.

See related editorial

On postoperative day 9, she develops an acute change in mental status, suddenly becoming extremely anxious and falsely believing she has a “terminal illness.” A psychiatrist suggests that these symptoms are a manifestation of delirium, given the patient’s recent surgery and exposure to benzodiazepine and narcotic medications. On postoperative day 10, she is awake but is now mute and uncooperative. An internist is consulted for an evaluation for encephalopathy and delirium.

MEDICAL HISTORY

Her medical history, obtained by chart review and interviewing her husband, includes well-controlled bipolar disorder over the last 4 years, with no episodes of frank psychosis or mania. She had a “bout of delirium” 4 years earlier attributed to a catastrophic life event, but the symptoms resolved after adjustment of her anxiolytic and mood-stabilizing drugs. She also has well-controlled hypertension, hypothyroidism, and gastroesophageal reflux. Her only surgery was her recent elective procedure.

She has a family history of dementia (Pick disease in her mother).

She is married, lives with her husband, and has an adult son. She is employed as a media specialist and also teaches English as a second language. Before this hospital admission, she was described as happy and content, though her primary psychiatrist had noted intermittent anxiety. Her husband does not suspect illicit drug use and denies significant alcohol or tobacco abuse.

A thorough review of systems is not possible, given her encephalopathy. But before her acute decline, she had complained of “choking on blood” and a subjective inability to swallow.

Her home medications include dextroamphetamine extended-release, alprazolam as needed for sleep, venlafaxine extended-release, lamotrigine, lisinopril, propranolol, amlodipine, atorvastatin, levothyroxine, omep­razole, iron, and vitamin B₁₂. At the time of the evaluation, she is on her home medications with the addition of olanzapine, vitamin D, polyethylene glycol, and an intravenous infusion of dextrose 5% with 0.45% saline at a rate of 100 mL/hour. She has allergies to latex, penicillin, peanuts, and shellfish.

PHYSICAL EXAMINATION

On physical examination, the patient seems healthy and appears normal for her stated age. She is wearing a spinal brace and is in no apparent distress. She is afebrile, pulse 104 beats per minute, respirations 16 breaths per minute and unlabored, and oxygen saturation good on room air. The skin is normal. No thyromegaly, bruits, or lymphadenopathy is noted. Cardiovascular, respiratory, and abdominal examinations, though limited by the spinal brace, are unremarkable. She has no evidence of peripheral edema or vascular insufficiency. Muscle bulk and tone are adequate and symmetric.

She is awake and alert and able to follow simple commands with some prompting. She does not initiate movements spontaneously. She makes some eye contact but does not track or acknowledge the interviewer consistently and does not respond verbally to questions. Her sclera are nonicteric, the pupils are equally round and reactive to light, and the external ocular muscles are intact. There is no facial asymmetry, and the tongue protrudes at midline. She blinks appropriately to threat bilaterally. Strength is at least 3/5 in the upper extremities and 2/5 in the lower extremities, though the examination is limited by lack of patient cooperation. She shows minimal grimace on noxious stimulation but does not withdraw extremities. Reflexes are present and mildly depressed symmetrically. Plantar reflexes are downgoing bilaterally.

INITIAL LABORATORY EVALUATION

On initial laboratory testing, the serum sodium is 132 mmol/L (reference range 136–144), stable since admission. Point-of-care glucose is 98 mg/dL. Aspartate aminotransferase and alanine aminotransferase levels are mildly elevated at 59 U/L (13–35) and 51 U/L (7–38), respectively, but serum ammonia is undetectable. Vitamin B₁₂, folate, thyroid-stimulating hormone, and free thyroxine are within the normal ranges. Leukocytosis is noted, with 14 × 10⁹ cells/L (3.7–11.0), 86% neutrophils, and a mild left shift. Urinalysis is negative for leukocyte esterase, nitrites, and white blood cells.

1. Which of the following risk factors predisposes this patient to postoperative delirium?

• Hyponatremia
• Polypharmacy
• Family history of dementia
• Depression

Altered mental status, or encephalopathy, is one of the most common yet challenging conditions in medicine. When a consult is placed for altered mental status, it is important to determine the affected domain that has changed from the patient’s normal state. Changes can include alterations in consciousness, attention, behavior, cognition, language, speech, and praxis and can reflect varying degrees of cerebral dysfunction.

Electrolyte abnormalities

Disorders of sodium homeostasis are common in hospitalized patients and may contribute to the onset of delirium. Hyponatremia is especially frequent and often iatrogenic, with a prevalence significantly higher in women (2.1% vs 1.3%, P = .0044) and in the elderly.²

Neurologic manifestations are often the result of cerebral edema due to osmolar volume shifts.^3–6 Acute hyponatremic encephalopathy is most likely to occur when sodium shifts are rapid, usually within 24 hours, and is often seen in postoperative patients requiring significant volume resuscitation with hypotonic fluids.⁶ Young premenopausal women appear to be at especially high risk of permanent brain damage secondary to hyponatremic encephalopathy,⁷ a finding that may reflect the limited compliance within the intracranial vault and lack of significant involutional parenchymal changes that occur with aging.^8–11

Aging also has important effects on fluid balance, as restoration of body fluid homeostasis is slower in older patients.¹²

Hormonal effects of estrogen appear to play a synergistic role in the expression of arginine vasopressin in postmenopausal women, further contributing to hyponatremia.

Although our patient has mild hyponatremia, there has been no acute change in her sodium balance since admission to the hospital, and so it is unlikely to be the cause of her acute delirium. Her mild hyponatremia may in part be from hypo-osmolar maintenance fluids with dextrose 5% and 0.45% normal saline.

Mild chronic hyponatremia may affect balance and has been associated with increased mortality risk in certain chronic disease states, but this is unlikely to be the main cause of acute delirium.

Polypharmacy

Patients admitted to the hospital with polypharmacy are at high risk of drug-induced delirium. In approaching delirium, a patient’s medications should be evaluated for interactions, as well as for possible effects of newly prescribed drugs. New medications that affect cytochrome P450 enzymes warrant investigation, as do drugs with narrow therapeutic windows that the patient has been using long-term.

Consultation with a clinical pharmacist is often helpful. Macrolides, protease inhibitors, and nondihydropyridine calcium channel blockers are common P450 inhibitors, while many anticonvulsants are known inducers of the P450 system. Selective serotonin reuptake inhibitors and diuretics can lead to electrolyte imbalances such as hyponatremia, which may further predispose to bouts of delirium, as described above.

The patient’s extensive list of psychoactive medications makes polypharmacy a significant risk factor for delirium. Quetiapine and venlafaxine both cause sedation and increase the risk of serotonin syndrome. However, in this case, the patient does not have marked fever, rigidity, or hyperreflexia to corroborate that diagnosis.

Dementia

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), defines dementia as a disorder involving cognitive impairment in at least 1 cognitive domain, with a significant decline from a previous level of functioning.¹ These impairments need not necessarily occur separately from bouts of delirium, but the time course for most forms of dementia tends to be progressive over a subacute to chronic duration.

Dementia increases the risk for acute confusion and delirium in hospitalized patients.¹³ This is partly reflected by pathophysiologic changes that leave elderly patients susceptible to the effects of anticholinergic drugs.¹⁴ Structural changes due to small-vessel ischemia may also predispose patients to seizures in the setting of metabolic derangement or critical illness. Diagnosing dementia thus remains a challenge, as dementia must be clearly distinguished from other disorders such as delirium and depression.

The acute change in this patient’s case makes the isolated diagnosis of dementia much less likely than other causes of altered mental status. Also, her previous level of function does not suggest a clinically significant personal history of impairment.

Mental illness

Several studies have examined the link between preoperative mental health disorders and postoperative delirium.^15–17 Depression appears to be a risk factor for postoperative delirium in patients undergoing elective orthopedic surgery,¹⁵ and this includes elderly patients.¹⁶ While a clear etiologic link has yet to be determined, disruption of circadian rhythm and abnormal cerebral response to stress may play a role. Studies have also suggested an association between schizophrenia and delirium, though this may be related to perioperative suspension of medications.¹⁷

Bipolar disorder has not been well studied with regard to postoperative complications. However, this patient has had a previous episode of decompensated mania, therefore making bipolar disorder a plausible condition in the differential diagnosis.

CASE CONTINUED: ACUTE DETERIORATION

Without a clearly identifiable cause for our patient’s acute confusional state, neurology and medical consultants recommend neuroimaging.

Computed tomography (CT) and magnetic resonance imaging (MRI) without contrast are ordered and performed on postoperative day 11 and demonstrate chronic small-vessel ischemic disease, consistent with our patient’s age, as well as frontotemporal atrophy. There is no evidence of mass effect, bleeding, or acute ischemia.

Overnight, she becomes obtunded, and the rapid response team is called. Her vital signs appear stable, and she is afebrile. Basic laboratory studies, imaging, and electrocardiography are repeated, and the results are unchanged from recent tests. She is transferred to the intensive care unit (ICU) for closer monitoring.

2. What is most likely cause of the patient’s declining mental status, and what is the next appropriate step?

• Acute stroke: repeat MRI with contrast
• Urinary tract infection: order blood and urine cultures, and start empiric antibiotics
• Neuroleptic malignant syndrome: start dantrolene
• Seizures: order electroencephalography (EEG)

Acute stroke

Acute stroke can affect mental status and consciousness through several pathways. Stroke syndromes can vary in presentation depending on the level of cortical and subcortical involvement, with clinical manifestations including confusion, aphasia, neglect, and inattention. Wakefulness and the ability to maintain consciousness is impaired, with disruption of the ascending reticular activating system, often seen in injuries to the brainstem. Large territorial or hemispheric infarcts, with subsequent cerebral edema, can also disrupt this system and lead to cerebral herniation and coma.

MRI without contrast is extremely sensitive for ischemia and can typically detect ischemia in acute stroke within 3 to 30 minutes.^18–20 Repeating the study with contrast is unlikely to provide additional benefit.

In our patient’s case, the lack of localizing neurologic symptoms, in addition to her recent negative neuroimaging workup, makes the diagnosis of acute stroke unlikely.

Infection

The role of severe infection in patients with altered mental status is well documented and likely relates to diffuse cerebral dysfunction caused by an inflammatory cascade. Less well understood is the role of occult infection, especially urinary tract infection, in otherwise immunocompetent patients. Urinary tract infection has long been thought to cause delirium in otherwise asymptomatic elderly patients, but few studies have examined this relationship, and those studies have been shown to have significant methodologic errors.²¹ In the absence of better data, urinary tract infection as the cause of frank delirium in an otherwise well patient should be viewed with skepticism, and alternative causes should be sought.

Although the patient has a nonspecific leukocytosis, her benign urinalysis and lack of corroborating evidence makes urinary tract infection an unlikely cause of her frank delirium.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is defined as fever, rigidity, mental status changes, and autonomic instability after exposure to antidopaminergic drugs. It is classically seen after administration of typical antipsychotics, though atypical antipsychotics and antiemetic drugs may be implicated as well.

Patients often exhibit agitation and confusion, which when severe may progress to mutism and catatonia. Likewise, psychotropic drugs such as quetiapine and venlafaxine, used in combination, have the additional risk of serotonin syndrome.

Additional symptoms include hyperreflexia, ataxia, and myoclonus. Withdrawal of the causative agent and supportive care are the mainstays of therapy. Targeted therapies with agents such as dantrolene, bromocriptine, and amantadine have also been reported anecdotally, but their efficacy is unclear, with variable results.²²

As noted earlier, the addition of quetiapine to the patient’s already lengthy medication list could conceivably cause neuroleptic malignant syndrome or serotonin syndrome and should be considered. However, additional neurologic findings to confirm this diagnosis are lacking.

Seizures

Nonconvulsive seizure, particularly nonconvulsive status epilepticus (NCSE), is not well recognized and is particularly challenging to diagnose without EEG. In several case series of patients presenting to the emergency room with altered mental status, NCSE was found in 16% to 28% of patients in whom EEG was performed after an initial evaluation failed to show an obvious cause for the delirium.^23,24 Historical features are unreliable for ruling out NCSE as a cause of delirium, as up to 41% of patients in whom the condition is ultimately diagnosed have only confusion as the presenting clinical symptom.²⁵

Likewise, alternating ictal and postictal periods may mimic the typical waxing and waning course classically associated with delirium of other causes. Physical findings such as nystagmus, anisocoria, and hippus may be helpful but are often overlooked or absent. EEG is thus an essential requirement for the diagnosis.²⁶

Given the lack of a clear diagnosis, a workup with EEG should be considered in this patient.

CASE CONTINUED: ADDITIONAL SIGNS

In the ICU, our patient is evaluated by the intensivist team. Her vital signs are stable, and while she is now awakening, she is unable to follow commands and remains mute. She does not initiate movement spontaneously but offers slight resistance to passive movements, holding and maintaining postures her extremities are placed in. She keeps her eyes closed, but when opened by the examining physician, dysconjugate gaze and anisocoria are noted.

3. What clinical entity is most consistent with these physical findings, and what is the next step in management?

• Catatonia secondary to bipolar disorder type I: challenge with intravenous lorazepam 2 mg
• Oculomotor nerve palsy due to enlarging intracranial aneurysm: aggressive blood pressure lowering, elevation of the head of the bed
• Toxic leukoencephalopathy: supportive care and withdrawal of the causative agent
• NCSE: challenge with intravenous lorazepam 2 mg and order EEG

Catatonia

The DSM-5 defines catatonia as a behavioral syndrome complicating an underlying psychiatric or medical condition, as opposed to a distinct diagnosis. It is most commonly encountered in psychiatric illnesses including bipolar disorder, major depression, and schizophrenia. Akinesis, stupor, mutism, and “waxy” flexibility often dominate the clinical picture.

The pathophysiology is poorly defined, but likely involves neurotransmitter imbalances particularly with an increase in N-methyl-d-aspartate (NMDA) activity and suppression of gamma-aminobutyric acid (GABA) activity. This hypothesis is supported by the finding that benzodiazepines, electroconvulsive therapy, and NMDA antagonists such as amantadine are all effective in treating catatonia.^27,28 Findings of focal neurologic abnormalities warrant further investigation. EEG may be necessary to differentiate catatonia from NCSE, as both may respond to a benzodiazepine challenge.

As pure catatonia is a diagnosis of exclusion, further workup, including EEG, is necessary to confirm the diagnosis.

Oculomotor nerve palsy

Anisocoria together with dysconjugate gaze should prompt consideration of a lesion involving the oculomotor nerve. Loss of tonic muscle activity from the lateral rectus and superior oblique cause a downward and outward gaze. Furthermore, loss of parasympathetic tone occurs with compressive palsies of the oculomotor nerve, clinically manifesting as a mydriatic and unreactive pupil with ptosis. Given its anatomic course and proximity to other vascular and parenchymal structures, the oculomotor nerve is vulnerable to compression from many sources, including aneurysmal dilation (especially of the posterior cerebral artery), uncal herniation, and inflammation of the cavernous sinus.

Noncontrast CT and lumbar puncture are very sensitive for making the diagnosis of sentinel bleeding within the first 24 hours,²⁹ whereas computed tomographic angiography and magnetic resonance angiography can reliably detect unruptured aneurysms as small as 3 mm.³⁰

Conditions that can lead to oculomotor palsy are unlikely to cause an acute gain in appendicular muscle tone, as noted by the catatonia this patient is demonstrating. Also, mass lesions or bleeding associated with oculomotor palsy is likely to cause acute loss of tone. Chronic upper-motor neuron lesions lead to spasticity rather than the waxy flexibility seen in this patient. In our patient, the findings of isolated anisocoria without further clinical evidence of oculomotor nerve compression make this diagnosis unlikely.

Toxic leukoencephalopathy

Toxic leukoencephalopathy—widespread destruction of myelin, particularly in the white matter tracts that support higher cortical functions—can be caused by antineoplastic agents, immunosuppressant agents, and industrial solvents, as well as by abuse of vaporized drugs such as heroin (“chasing the dragon”). In its mild forms it may cause behavioral disturbances or inattention. In severe forms, a neurobehavioral syndrome of akinetic mutism may be present and can mimic catatonia.³¹

The diagnosis is often based on the clinical history and neuroimaging, particularly MRI, which demonstrates hyperintensity of the white matter tracts in T2-weighted images.³²

This patient does not have a clear history of exposure to an agent typically associated with toxic leukoencephalopathy and does not have the corroborating MRI findings to support this diagnosis.

Because recent neuroimaging revealed no structural brain lesions and no cause for brain herniation, the patient receives a challenge of 2 mg of intravenous lorazepam to treat potential NCSE. Subsequent improvement is noted in her anisocoria, gaze deviation, and encephalopathy. EEG reveals frequent focal seizures arising from mesial frontal regions with bilateral hemisphere propagation, consistent with bifrontal focal NCSE.

As our patient is being transferred to a room for continuous EEG monitoring, her condition begins to deteriorate, and she again becomes more encephalopathic, with anisocoria and dysconjugate gaze. Additional doses of lorazepam are given (to complete a 0.1-mg/kg load), and additional therapy with intravenous fos­phenytoin (20-mg/kg load) is given. Intubation is done for airway protection.

Continuous EEG monitoring reveals multiple frequent electrographic seizures arising from the bifrontal territories, concerning for persistent focal NCSE. A midazolam drip is initiated for EEG burst suppression of cerebral activity. Over 24 hours, EEG shows resolution of seizure activity. As the patient is weaned from sedation, she awakens and follows commands consistently, tolerating extubation without complications. Her neurologic status remains stable over the next 48 hours, having returned to her neurologic baseline level of functioning. She is able to be transferred out of the ICU in stable condition while continuing on scheduled antiepileptic therapy with phenytoin.

ALTERED MENTAL STATUS IN INPATIENTS

Altered mental status is one of the most frequently encountered reasons for medical consultation from nonmedical services. The workup and management of metabolic, toxic, psychiatric, and neurologic causes requires a deep appreciation for the broad differential diagnosis and a multidisciplinary approach. Physicians caring for these patients should avoid prematurely drawing conclusions when the patient’s clinical condition fails to respond to typical measures.

Delirium is a challenging adverse event in older patients during hospitalization, with a significant national financial burden of $164 billion per year.³³ The prevalence of delirium in adults on hospital admission is estimated as 14% to 24%, with an inpatient hospitalization incidence ranging from 6% to 56% in general hospital patients.³⁴ In addition, postoperative delirium has been reported in 15% to 53% of older patients.³⁵

While delirium is preventable in 30% to 40% of cases,^36,37 it remains an important independent prognostic determinant of hospital outcomes.^38–40

Delirium in hospitalized patients requires a thorough, individualized workup. In our patient’s case, the clinical findings of hypoactive delirium were found to be manifestations of NCSE, a rare life-threatening and potentially reversible neurologic disease.

While establishing seizures as a diagnosis, careful attention must first be directed towards investigating environmental or metabolic triggers that may be inciting the disease. This often involves a similar workup for metabolic derangements, as seen in the approach to delirium.

The diagnosis of NCSE, while made in this patient’s case, remains challenging. Careful physical examination should assess for automatisms, “negative” symptoms (staring, aphasia, weakness), and “positive” symptoms (hallucinations, psychosis). Cataplexy, mutism, and other acute psychiatric features have been associated with NCSE,⁴⁴ highlighting the importance of EEG. A trial of a benzodiazepine in conjunction with clinical and EEG monitoring may help guide clinical decision- making.

As there is no current universally accepted definition for NCSE nor an accepted agreement on required EEG diagnostic features at this time,⁴¹ accurate diagnosis is most likely to be obtained in facilities with both subspecialty neurologic consultation and EEG capabilities.

Our patient’s family history of Pick disease is interesting, as this is a progressive form of frontotemporal dementia with both sporadic and genetically linked cases. Recent studies have shown evidence that patients with neurodegenerative disease have increased seizure frequency early in the disease course,³¹ and efforts are under way to establish the incidence of first unprovoked seizure in patients with frontotemporal dementia. In our patient’s case, resolution of seizure activity yielded a return to her baseline level of neurologic function.

Early use of selective serotonin reuptake inhibitors has been shown to help with the behavioral symptoms of frontotemporal dementia,⁴⁵ but increasing requirements over time may indicate progression of neurodegeneration and should warrant further appropriate investigation.

In our patient’s case, escalating dose requirements may have reflected worsening frontotemporal atrophy. However, the diagnosis of a neurodegenerative disease such as frontotemporal dementia in a patient such as ours is not definitively established at this time and is being investigated on an outpatient basis.

Given the frequency of delirium and its many risk factors in the inpatient setting, verifying a causative diagnosis can be difficult. Detailed consideration of the patient’s individual clinical circumstances, often in concert with appropriate subspecialty consultations, is essential to the evaluation. Although it is time-intensive, multidisciplinary intervention can lead to safer outcomes and shorter hospital stays.

During my training in Leiden, Netherlands, I was infused with the lessons of Herman Boerhaave (1668–1738), the professor who is considered the pioneer of bedside teaching.¹ This practice had begun in Padua and was then brought to Leiden, where Boerhaave transformed it into an art form. At the Caecilia hospital, the municipal clerics provided Boerhaave with 2 wards for teaching; 1 with 6 beds for men and the other with 6 beds for women. Medical historian Henry Sigerist² has commented that half the physicians of Europe were trained on these 12 beds.

See related article

Boerhaave made daily rounds with his students, examining the patients, reviewing their histories, and inspecting their urine. He considered postmortem examinations essential and made his students attend the autopsies of patients who died: “In spite of the most detailed description of all disease phenomena one does not know anything of the cause until one has opened the body.”²

What was once the basis of clinical medicine is now fading, with both clinical rounds and autopsies being replaced by imaging techniques of body parts and automated analysis of Vacutainer samples. These novelties provide us with far more diagnostic accuracy than Boer­haave had, and randomized controlled trials provide us with an evidence base. But bedside observation and case reports are still relevant,³ and autopsies still reveal important, clinically missed diagnoses.⁴

In this issue of the Journal, Imm et al⁵ describe a case of presumed postoperative delirium in a 64-year-old hospitalized patient. They remind us that crucial signs and symptoms can guide how to use our modern diagnostic tools.

DELIRIUM IS OFTEN OVERLOOKED

Delirium is often overlooked by physicians. But why? The characteristic disturbances in attention and cognition are easy to interpret, while the various observation scales have high sensitivity and should signal the need for further interrogation. Perhaps the reason we often overlook the signs and symptoms is that we assume that delirium is just normal sickness behavior.

Another reason we may fail to recognize the syndrome is more fundamental and closely related to how we practice medicine. These days, we place such trust in high-tech diagnostics that we feel the modern procedures supersede the classic examination of patients. But mental disturbances can only be detected by history-taking and clinical observation.

Moreover, the actual mental state is less important than the subtle changes in it. A continuously disturbed mind does not pose a problem, but a casual remark by a family member or informal caregiver that “his mood has changed” should seize our attention.⁶

Here, the fragmented and disconnected practice of modern medicine takes its toll. Shorter working hours have helped to preserve our own mental performance, but at the cost of being less able to follow the patient’s mental status over time and to recognize a change of behavior. Applying repeated, standardized assessments of these vital signs may help solve the problem, but repeated observations are easily neglected, as are body temperature, blood pressure, and others.

DELIRIUM IS SERIOUS

Imm et al also remind us that delirium is serious. The case-fatality rate in delirium equals that in acute cardiovascular events or metastatic cancer, even though its impact is often not thought to be as severe. Far too often the mental symptoms are dismissed and judged to be something to be handled in the outpatient clinic after the acute problems are addressed.

In part, this may be because no professional society or advocacy group is promoting the recognition, diagnosis, and treatment of delirium or pushing for incentives to do so. We have cardiologists and oncologists but not deliriologists. But in a way, it may be a good thing that no specialist group “owns” delirium, as the syndrome is elicited by various underlying disease mechanisms, and every physician should be vigilant to recognize it.

DELIRIUM REQUIRES PROMPT MANAGEMENT

If delirium is a life-threatening condition, it necessitates a prompt and coordinated series of diagnostic actions, judgments, and decisions.⁷ Although most delirious patients are not admitted to an intensive care unit, they should be considered critically ill and must be provided a corresponding level of care. Here, the old clinical aphorism holds: action should be taken before the sun sets or rises. Attention should be on worsening of the underlying disease, unexpected comorbid conditions, and side effects of our interventions.

As the case reported by Imm et al shows, the causative factors may be recognized only after in-depth examination.⁴ The pathogenesis of delirium is poorly understood, and there is no specific therapy for it. There is not even conclusive evidence that the standard use of antipsychotics is beneficial, whereas their side effects cannot be overestimated.⁷ Our interventions are aimed at eliminating the underlying pathologies that have triggered the delirious state, as well as on preventing complications of the mental disturbance.

Many of us have had the experience of watching one of our children develop fever and confusion. When our older patients become delirious, it should raise the same level of alarm and activity as when it happens in a child.

During my training in Leiden, Netherlands, I was infused with the lessons of Herman Boerhaave (1668–1738), the professor who is considered the pioneer of bedside teaching.¹ This practice had begun in Padua and was then brought to Leiden, where Boerhaave transformed it into an art form. At the Caecilia hospital, the municipal clerics provided Boerhaave with 2 wards for teaching; 1 with 6 beds for men and the other with 6 beds for women. Medical historian Henry Sigerist² has commented that half the physicians of Europe were trained on these 12 beds.

See related article

Boerhaave made daily rounds with his students, examining the patients, reviewing their histories, and inspecting their urine. He considered postmortem examinations essential and made his students attend the autopsies of patients who died: “In spite of the most detailed description of all disease phenomena one does not know anything of the cause until one has opened the body.”²

What was once the basis of clinical medicine is now fading, with both clinical rounds and autopsies being replaced by imaging techniques of body parts and automated analysis of Vacutainer samples. These novelties provide us with far more diagnostic accuracy than Boer­haave had, and randomized controlled trials provide us with an evidence base. But bedside observation and case reports are still relevant,³ and autopsies still reveal important, clinically missed diagnoses.⁴

In this issue of the Journal, Imm et al⁵ describe a case of presumed postoperative delirium in a 64-year-old hospitalized patient. They remind us that crucial signs and symptoms can guide how to use our modern diagnostic tools.

DELIRIUM IS OFTEN OVERLOOKED

Delirium is often overlooked by physicians. But why? The characteristic disturbances in attention and cognition are easy to interpret, while the various observation scales have high sensitivity and should signal the need for further interrogation. Perhaps the reason we often overlook the signs and symptoms is that we assume that delirium is just normal sickness behavior.

Another reason we may fail to recognize the syndrome is more fundamental and closely related to how we practice medicine. These days, we place such trust in high-tech diagnostics that we feel the modern procedures supersede the classic examination of patients. But mental disturbances can only be detected by history-taking and clinical observation.

Moreover, the actual mental state is less important than the subtle changes in it. A continuously disturbed mind does not pose a problem, but a casual remark by a family member or informal caregiver that “his mood has changed” should seize our attention.⁶

Here, the fragmented and disconnected practice of modern medicine takes its toll. Shorter working hours have helped to preserve our own mental performance, but at the cost of being less able to follow the patient’s mental status over time and to recognize a change of behavior. Applying repeated, standardized assessments of these vital signs may help solve the problem, but repeated observations are easily neglected, as are body temperature, blood pressure, and others.

DELIRIUM IS SERIOUS

Imm et al also remind us that delirium is serious. The case-fatality rate in delirium equals that in acute cardiovascular events or metastatic cancer, even though its impact is often not thought to be as severe. Far too often the mental symptoms are dismissed and judged to be something to be handled in the outpatient clinic after the acute problems are addressed.

In part, this may be because no professional society or advocacy group is promoting the recognition, diagnosis, and treatment of delirium or pushing for incentives to do so. We have cardiologists and oncologists but not deliriologists. But in a way, it may be a good thing that no specialist group “owns” delirium, as the syndrome is elicited by various underlying disease mechanisms, and every physician should be vigilant to recognize it.

DELIRIUM REQUIRES PROMPT MANAGEMENT

If delirium is a life-threatening condition, it necessitates a prompt and coordinated series of diagnostic actions, judgments, and decisions.⁷ Although most delirious patients are not admitted to an intensive care unit, they should be considered critically ill and must be provided a corresponding level of care. Here, the old clinical aphorism holds: action should be taken before the sun sets or rises. Attention should be on worsening of the underlying disease, unexpected comorbid conditions, and side effects of our interventions.

As the case reported by Imm et al shows, the causative factors may be recognized only after in-depth examination.⁴ The pathogenesis of delirium is poorly understood, and there is no specific therapy for it. There is not even conclusive evidence that the standard use of antipsychotics is beneficial, whereas their side effects cannot be overestimated.⁷ Our interventions are aimed at eliminating the underlying pathologies that have triggered the delirious state, as well as on preventing complications of the mental disturbance.

Many of us have had the experience of watching one of our children develop fever and confusion. When our older patients become delirious, it should raise the same level of alarm and activity as when it happens in a child.

During my training in Leiden, Netherlands, I was infused with the lessons of Herman Boerhaave (1668–1738), the professor who is considered the pioneer of bedside teaching.¹ This practice had begun in Padua and was then brought to Leiden, where Boerhaave transformed it into an art form. At the Caecilia hospital, the municipal clerics provided Boerhaave with 2 wards for teaching; 1 with 6 beds for men and the other with 6 beds for women. Medical historian Henry Sigerist² has commented that half the physicians of Europe were trained on these 12 beds.

See related article

Boerhaave made daily rounds with his students, examining the patients, reviewing their histories, and inspecting their urine. He considered postmortem examinations essential and made his students attend the autopsies of patients who died: “In spite of the most detailed description of all disease phenomena one does not know anything of the cause until one has opened the body.”²

What was once the basis of clinical medicine is now fading, with both clinical rounds and autopsies being replaced by imaging techniques of body parts and automated analysis of Vacutainer samples. These novelties provide us with far more diagnostic accuracy than Boer­haave had, and randomized controlled trials provide us with an evidence base. But bedside observation and case reports are still relevant,³ and autopsies still reveal important, clinically missed diagnoses.⁴

In this issue of the Journal, Imm et al⁵ describe a case of presumed postoperative delirium in a 64-year-old hospitalized patient. They remind us that crucial signs and symptoms can guide how to use our modern diagnostic tools.

DELIRIUM IS OFTEN OVERLOOKED

Delirium is often overlooked by physicians. But why? The characteristic disturbances in attention and cognition are easy to interpret, while the various observation scales have high sensitivity and should signal the need for further interrogation. Perhaps the reason we often overlook the signs and symptoms is that we assume that delirium is just normal sickness behavior.

Another reason we may fail to recognize the syndrome is more fundamental and closely related to how we practice medicine. These days, we place such trust in high-tech diagnostics that we feel the modern procedures supersede the classic examination of patients. But mental disturbances can only be detected by history-taking and clinical observation.

Moreover, the actual mental state is less important than the subtle changes in it. A continuously disturbed mind does not pose a problem, but a casual remark by a family member or informal caregiver that “his mood has changed” should seize our attention.⁶

Here, the fragmented and disconnected practice of modern medicine takes its toll. Shorter working hours have helped to preserve our own mental performance, but at the cost of being less able to follow the patient’s mental status over time and to recognize a change of behavior. Applying repeated, standardized assessments of these vital signs may help solve the problem, but repeated observations are easily neglected, as are body temperature, blood pressure, and others.

DELIRIUM IS SERIOUS

Imm et al also remind us that delirium is serious. The case-fatality rate in delirium equals that in acute cardiovascular events or metastatic cancer, even though its impact is often not thought to be as severe. Far too often the mental symptoms are dismissed and judged to be something to be handled in the outpatient clinic after the acute problems are addressed.

In part, this may be because no professional society or advocacy group is promoting the recognition, diagnosis, and treatment of delirium or pushing for incentives to do so. We have cardiologists and oncologists but not deliriologists. But in a way, it may be a good thing that no specialist group “owns” delirium, as the syndrome is elicited by various underlying disease mechanisms, and every physician should be vigilant to recognize it.

DELIRIUM REQUIRES PROMPT MANAGEMENT

If delirium is a life-threatening condition, it necessitates a prompt and coordinated series of diagnostic actions, judgments, and decisions.⁷ Although most delirious patients are not admitted to an intensive care unit, they should be considered critically ill and must be provided a corresponding level of care. Here, the old clinical aphorism holds: action should be taken before the sun sets or rises. Attention should be on worsening of the underlying disease, unexpected comorbid conditions, and side effects of our interventions.

As the case reported by Imm et al shows, the causative factors may be recognized only after in-depth examination.⁴ The pathogenesis of delirium is poorly understood, and there is no specific therapy for it. There is not even conclusive evidence that the standard use of antipsychotics is beneficial, whereas their side effects cannot be overestimated.⁷ Our interventions are aimed at eliminating the underlying pathologies that have triggered the delirious state, as well as on preventing complications of the mental disturbance.

Many of us have had the experience of watching one of our children develop fever and confusion. When our older patients become delirious, it should raise the same level of alarm and activity as when it happens in a child.

What common message do a 64-year-old woman with postoperative cognitive changes and an 83-year-old man with red palms have for us as physicians? As I read their clinical scenarios and the editorial by Westendorp, I was struck by the value and significance of informed clinical observation, an activity that I fear is going the way of the music CD and handwritten letters.

As I read the descriptions of these patients I was reminded of the internal satisfaction that I feel when I pick up a clinical or historical finding that directs me to a specific diagnosis and therapeutic recommendation. Sherlock Holmes I am not. Those satisfying pickups are infrequent, and I have no idea how many clues I have missed. I do know that most come from taking the time to perform a methodical physical examination, directed and informed by the patient’s recounted history. Some, like red palms or anisocoria, may be readily apparent and diagnostically useful—if the observer recognizes their potential significance. The 2 patients described in this issue of the Journal highlight the value of both observation and the knowledge and experience to place what we observe into a clinical context. Watson (the computer) can provide data regarding the potential significance of a physical finding, but only if someone first detects its existence.

Once it is recognized (or pointed out), we can all pull out our smartphones and Google “palmar erythema and disease,” and on our screen up pops liver disease, pregnancy, and assorted other conditions, including malignancies. But how many of us in our clinic, as opposed to the artificial scenario of reading it in the Journal or attending a clinicopathologic conference, will spontaneously recognize palmar erythema as a potentially relevant clinical finding?

For many physicians, the sense of professional satisfaction in making these observations is diminished. The professional joy gleaned from these moments has been diluted. We are in jeopardy of losing the passion for the professional work that we do as well as the intellectual and emotional satisfaction that accompanies a nuanced professional job well done, while focusing instead on our contracted jobs, frequently evaluated by our ability to meet commercial needs. The absence of emotional and intellectual satisfaction that should come from these collected moments of patient interaction and reflection undoubtedly contributes to the rising rate of physician burnout.

There are so many pressures on us in the office. Did I record that my new patient with known rheumatoid arthritis (who has had a recent MI and pneumonia and who has tried several biologic therapies without success and is in need of a creative change in her medication) has a cousin with hypothyroidism so I could include family history in my electronic medical record note and thus bill at a “desired” level of complexity? Did I use the appropriate catchphrase stating that over 50% of my time was spent in education of the patient (after collecting and reading for 30 minutes the stack of prior records, preparing to do battle with her insurance company to get the next therapy approved for coverage)?

There is little wonder that an observation of red palms gets missed or, if it is noted, that the Google search is never actually done. And when we do recognize the finding and its clinical significance, we often don’t take a moment to reflect and bask in the glow of a job well done, the satisfaction of successfully applying both our knowledge and experience to help resolve a clinical problem.

As Westendorp points out, bedside observation is still relevant. And I will add that there still should be joy in the intellectual pursuit of the job well done as well as the patient well managed. It takes more than a smartphone to know when and how to look at the palms and the eyes before typing in a Google search or consulting the digital (not the doctor) Watson. Those are skills to be proud of.

What common message do a 64-year-old woman with postoperative cognitive changes and an 83-year-old man with red palms have for us as physicians? As I read their clinical scenarios and the editorial by Westendorp, I was struck by the value and significance of informed clinical observation, an activity that I fear is going the way of the music CD and handwritten letters.

As I read the descriptions of these patients I was reminded of the internal satisfaction that I feel when I pick up a clinical or historical finding that directs me to a specific diagnosis and therapeutic recommendation. Sherlock Holmes I am not. Those satisfying pickups are infrequent, and I have no idea how many clues I have missed. I do know that most come from taking the time to perform a methodical physical examination, directed and informed by the patient’s recounted history. Some, like red palms or anisocoria, may be readily apparent and diagnostically useful—if the observer recognizes their potential significance. The 2 patients described in this issue of the Journal highlight the value of both observation and the knowledge and experience to place what we observe into a clinical context. Watson (the computer) can provide data regarding the potential significance of a physical finding, but only if someone first detects its existence.

Once it is recognized (or pointed out), we can all pull out our smartphones and Google “palmar erythema and disease,” and on our screen up pops liver disease, pregnancy, and assorted other conditions, including malignancies. But how many of us in our clinic, as opposed to the artificial scenario of reading it in the Journal or attending a clinicopathologic conference, will spontaneously recognize palmar erythema as a potentially relevant clinical finding?

For many physicians, the sense of professional satisfaction in making these observations is diminished. The professional joy gleaned from these moments has been diluted. We are in jeopardy of losing the passion for the professional work that we do as well as the intellectual and emotional satisfaction that accompanies a nuanced professional job well done, while focusing instead on our contracted jobs, frequently evaluated by our ability to meet commercial needs. The absence of emotional and intellectual satisfaction that should come from these collected moments of patient interaction and reflection undoubtedly contributes to the rising rate of physician burnout.

There are so many pressures on us in the office. Did I record that my new patient with known rheumatoid arthritis (who has had a recent MI and pneumonia and who has tried several biologic therapies without success and is in need of a creative change in her medication) has a cousin with hypothyroidism so I could include family history in my electronic medical record note and thus bill at a “desired” level of complexity? Did I use the appropriate catchphrase stating that over 50% of my time was spent in education of the patient (after collecting and reading for 30 minutes the stack of prior records, preparing to do battle with her insurance company to get the next therapy approved for coverage)?

There is little wonder that an observation of red palms gets missed or, if it is noted, that the Google search is never actually done. And when we do recognize the finding and its clinical significance, we often don’t take a moment to reflect and bask in the glow of a job well done, the satisfaction of successfully applying both our knowledge and experience to help resolve a clinical problem.

As Westendorp points out, bedside observation is still relevant. And I will add that there still should be joy in the intellectual pursuit of the job well done as well as the patient well managed. It takes more than a smartphone to know when and how to look at the palms and the eyes before typing in a Google search or consulting the digital (not the doctor) Watson. Those are skills to be proud of.

What common message do a 64-year-old woman with postoperative cognitive changes and an 83-year-old man with red palms have for us as physicians? As I read their clinical scenarios and the editorial by Westendorp, I was struck by the value and significance of informed clinical observation, an activity that I fear is going the way of the music CD and handwritten letters.

As I read the descriptions of these patients I was reminded of the internal satisfaction that I feel when I pick up a clinical or historical finding that directs me to a specific diagnosis and therapeutic recommendation. Sherlock Holmes I am not. Those satisfying pickups are infrequent, and I have no idea how many clues I have missed. I do know that most come from taking the time to perform a methodical physical examination, directed and informed by the patient’s recounted history. Some, like red palms or anisocoria, may be readily apparent and diagnostically useful—if the observer recognizes their potential significance. The 2 patients described in this issue of the Journal highlight the value of both observation and the knowledge and experience to place what we observe into a clinical context. Watson (the computer) can provide data regarding the potential significance of a physical finding, but only if someone first detects its existence.

Once it is recognized (or pointed out), we can all pull out our smartphones and Google “palmar erythema and disease,” and on our screen up pops liver disease, pregnancy, and assorted other conditions, including malignancies. But how many of us in our clinic, as opposed to the artificial scenario of reading it in the Journal or attending a clinicopathologic conference, will spontaneously recognize palmar erythema as a potentially relevant clinical finding?

For many physicians, the sense of professional satisfaction in making these observations is diminished. The professional joy gleaned from these moments has been diluted. We are in jeopardy of losing the passion for the professional work that we do as well as the intellectual and emotional satisfaction that accompanies a nuanced professional job well done, while focusing instead on our contracted jobs, frequently evaluated by our ability to meet commercial needs. The absence of emotional and intellectual satisfaction that should come from these collected moments of patient interaction and reflection undoubtedly contributes to the rising rate of physician burnout.

There are so many pressures on us in the office. Did I record that my new patient with known rheumatoid arthritis (who has had a recent MI and pneumonia and who has tried several biologic therapies without success and is in need of a creative change in her medication) has a cousin with hypothyroidism so I could include family history in my electronic medical record note and thus bill at a “desired” level of complexity? Did I use the appropriate catchphrase stating that over 50% of my time was spent in education of the patient (after collecting and reading for 30 minutes the stack of prior records, preparing to do battle with her insurance company to get the next therapy approved for coverage)?

There is little wonder that an observation of red palms gets missed or, if it is noted, that the Google search is never actually done. And when we do recognize the finding and its clinical significance, we often don’t take a moment to reflect and bask in the glow of a job well done, the satisfaction of successfully applying both our knowledge and experience to help resolve a clinical problem.

As Westendorp points out, bedside observation is still relevant. And I will add that there still should be joy in the intellectual pursuit of the job well done as well as the patient well managed. It takes more than a smartphone to know when and how to look at the palms and the eyes before typing in a Google search or consulting the digital (not the doctor) Watson. Those are skills to be proud of.

A 53-year-old Native American woman with a history of liver cirrhosis secondary to alcohol abuse presents to the emergency department after 2 days of diffuse abdominal pain and weakness. The pain was sudden in onset and has progressed relentlessly over the last day, reaching 9 on a scale of 10 in severity. Family members say that her oral intake has been decreased for the last 2 days, but she has had no fever, vomiting, change in bowel habit, blood in stool, or black stool. She has never undergone surgery, and has had one uncomplicated pregnancy.

Physical examination

Vital signs:

• Blood pressure 82/57 mm Hg
• Heart rate 96 beats per minute
• Temperature 37.3°C (99.1°F)
• Respiratory rate 16 per minute
• Oxygen saturation 92% while receiving oxygen at 2 L/minute.

The patient is somnolent and has scleral icterus. Her cardiopulmonary examination is normal. Her abdomen is tense, distended, and diffusely tender. She has bilateral +2 pitting edema in her lower extremities. She is oriented to person only and is noted to have asterixis. Her baseline Model for End-stage Liver Disease score is 18 points on a scale of 6 (less ill) to 40 (gravely ill).

Laboratory studies:

• Hemoglobin 9.8 g/dL (reference range 11.5–15.5)
• Platelet count 100 × 10⁹/L (150–400)
• White blood cell count 9.9 × 10⁹/L (3.7–11.0)
• Serum creatinine 1.06 mg/dL (0.58–0.96)
• Bilirubin 6.3 mg/dL (0.2–1.3)
• International normalized ratio of the prothrombin time 2.15 (0.8–1.2)
• Blood urea nitrogen 13 mg/dL (7–21)
• Serum albumin 2.7 g/dL (3.9–4.9).

Intravenous fluid resuscitation is initiated but the patient remains hypotensive, and on repeat laboratory testing 4 hours later her hemoglobin level has dropped to 7.3 mg/dL.

DIFFERENTIAL DIAGNOSIS

1. Which of the following are likely causes of this patient’s presentation?

• Splenic arterial aneurysm rupture
• Spontaneous bacterial peritonitis
• Variceal hemorrhage
• Portal vein thrombosis
• Abdominal aortic aneurysm rupture

Ruptured splenic artery aneurysm

Splenic artery aneurysms are the third most common intra-abdominal aneurysm, after those of the abdominal aorta and iliac artery.¹ They are often asymptomatic and are being detected more frequently because of increased use of computed tomography (CT).² Symptomatic splenic artery aneurysms may present with abdominal pain and have the potential to rupture, which can be life-threatening.^3,4

This patient may have a ruptured splenic artery aneurysm, given her hemodynamic shock.

Spontaneous bacterial peritonitis

Ten percent to 20% of hospitalized patients with cirrhosis and ascites develop spontaneous bacterial peritonitis. Patients may present with ascites and abdominal pain, tenderness to palpation, fever, encephalopathy, or worsening liver and renal function.

Diagnostic paracentesis is paramount to delineate the cause of ascites; one should calculate the serum-ascites albumin gradient and obtain a cell count and culture of the ascitic fluid. The diagnosis of spontaneous bacterial peritonitis can be made if the ascitic fluid polymorphonuclear cell count is 0.25 × 10⁹/L or higher, even if the ascitic fluid culture is negative.^5,6 Simultaneous blood cultures should also be collected, as 50% of cases are associated with bacteremia.

The in-hospital mortality rate of an episode of spontaneous bacterial peritonitis has been reduced to 10% to 20% thanks to prompt diagnosis and empiric treatment with third-generation cephalosporins.⁷

Five percent of cases of infected ascites fluid are due to secondary bacterial peritonitis from a perforated viscus or a loculated abscess, which cannot be differentiated clinically from spontaneous bacterial peritonitis but can be diagnosed with CT.⁸

This patient may be presenting with septic shock secondary to either of these causes.

Variceal hemorrhage

Half of patients with cirrhosis have gastroesophageal varices due to portal hypertension. Endoscopic surveillance is warranted, as the risk of hemorrhage is 12% to 15% per year, and the mortality rate approaches 15% to 20% with each episode. Prompt resuscitation, diagnosis, and control of bleeding is paramount.

Esophagogastroduodenoscopy is used for both diagnosis and intervention. Short-term prophylactic use of antibiotics improves survival by preventing infections in the event bleeding recurs.^9–11

Our patient may be presenting with hemodynamic shock from bleeding esophageal varices.

Portal vein thrombosis is a common complication of cirrhosis, occurring in 5% to 28% of patients. The risk increases with the severity of liver disease and in association with hepatocellular carcinoma.¹² Forty-three percent of cases are discovered incidentally in asymptomatic patients during ultrasonography, 39% present with upper gastrointestinal bleeding, and 18% present with abdominal pain.^13,14

Portal vein thrombosis is the complete or partial obstruction of blood flow due to a thrombus in the lumen of the portal vein. Contrast ultrasonography and CT can be used to establish the diagnosis.¹⁵

Anticoagulation is recommended in cases of complete thrombosis in candidates for living-donor liver transplant and for those at risk of mesenteric ischemia because of the thrombus extending into the mesenteric veins. In symptomatic patients, the decision to initiate anticoagulation should be made on a case-by-case basis after appropriate screening and management of varices.^16–18

Our patient’s thrombocytopenia reflects the severity of portal hypertension and increases her risk of portal vein thrombosis, but this is unlikely to be the sole cause of the hemodynamic compromise in this patient.

Ruptured abdominal aortic aneurysm

Rupture of an abdominal aortic aneurysm is a medical emergency, with a mortality rate approaching 90%. Risk factors for abdominal aortic aneurysms are smoking, male sex, age over 65, history of cardiovascular disease, hypertension, and a family history of abdominal aortic aneurysm, especially if a first-degree relative is affected.¹⁹ Endovascular repair is associated with lower rates of death and complications compared with open repair.²⁰

The patient does not have any of those risk factors, making this diagnosis less likely.

CASE CONTINUED: RUPTURED SPLENIC ARTERY ANEURYSM

Emergency CT of the abdomen and pelvis with contrast enhancement shows a large left intraperitoneal hematoma with active extravasation from a ruptured splenic artery aneurysm (Figure 1). The patient receives packed red blood cells and fresh-frozen plasma before being transferred to our hospital.

2. Which of the following is false regarding splenic artery aneurysms?

• They are the most common type of splanchnic arterial aneurysm
• True aneurysms are more common than pseudoaneurysms
• Asymptomatic aneurysms are discovered incidentally during assessment for other radiographic indications
• Splenic artery aneurysm in portal hypertension is the result of athero-sclerotic changes to the vascular intima

Splenic artery aneurysm in portal hypertension is not the result of atherosclerotic change to the vascular intima.

Splenic artery aneurysms are the most common type of splanchnic artery aneurysm.¹ True aneurysms involve all 3 layers of the arterial wall, ie, intima, media, and adventitia. Cirrhosis and portal hypertension are associated with true aneurysm formation. The proposed mechanism of aneurysm formation is increased splenic blood flow in response to portal congestion with resultant hemodynamic stress that disrupts arterial wall structure, leading to aneurysmal dilation.²¹

In earlier reports, the incidence of true splenic artery aneurysm in portal hypertension varied from 2.9% to 50%, the latter representing autopsy findings of small aneurysms that were found in the splenic hilum of patients with cirrhosis.^22–25 The incidence of clinically significant aneurysms in cirrhosis is unknown but incidental asymptomatic aneurysm is being detected more frequently on imaging studies pursued for screening purposes.²⁶

The risk of rupture is low, only 2% to 10% in older studies and likely even lower now due to increased incidental detection in asymptomatic patients.²⁷ However, emergent management of rupture at a tertiary care facility is paramount, as the mortality rate of ruptured splenic artery aneurysm is 29% to 36%.^1,26,28

Splenic artery pseudoaneurysm is rarer and has a different pathophysiologic process than true aneurysm. It usually arises in the setting of trauma, pancreatitis, or postsurgery.^29,30 Pseudoaneurysm is more likely to rupture, owing to compromise in the vascular wall integrity.^4,21,28 As a result, treatment is indicated for every pseudoaneurysm regardless of size.

RISK FACTORS FOR SPLENIC ARTERY ANEURYSM

3. Which of the following is true regarding our patient’s risk of splenic artery aneurysm?

• Liver cirrhosis and portal hypertension are her greatest risk factors for it
• Female sex and prior pregnancy are her greatest risk factors for it
• Being Native American makes it more likely that the patient has splenic artery aneurysm secondary to collagen vascular disease
• Her risk of rupture would diminish after receiving a liver transplant

Liver cirrhosis and portal hypertension are her greatest risk factors for splenic artery aneurysm.

Risk factors for true aneurysm include hypertension, atherosclerosis, portal hypertension with or without liver cirrhosis, liver transplant, third trimester of pregnancy, and multiparity.^1,4,26,28,31 Splenic artery aneurysm is  usually diagnosed in the sixth decade. It may be 4 times as common in women, given a hormonal influence.³² Cirrhosis is also associated with massive splenic artery aneurysm (≥ 5 cm). Although rare, massive splenic artery aneurysm is more frequent in men (the male-to-female ratio is 1.78:1) and has a heightened risk of rupture.²⁸ The incidence of rupture increases to around 3% to 4% after liver transplant.³³ Rare causes of true aneurysm include fibrodysplasia, collagen vascular disease (eg, Loeys-Dietz and type IV Ehler-Danlos syndromes), vasculitis (eg, polyarteritis nodosa due to amphetamine abuse), and mycotic aneurysms.^24,25,28,29

This patient’s age, sex, and history of cirrhosis puts her at increased risk of splenic artery aneurysm. The risk of rupture is highest in the peripartum period and in patients with cirrhosis who become pregnant. Although being Native American portends an increased risk for collagen vascular disease, the latter is unlikely to be a contributing factor.

4. Which of the following is false regarding treatment of splenic artery aneurysms?

• Aneurysms larger than 2 cm and those that are expanding require repair
• Treatment should be offered if the patient has symptoms attributable to the aneurysm
• Asymptomatic aneurysms in pregnant women can be followed with watchful waiting
• Minimally invasive therapies such as percutaneous embolization may be a good option in poor operative candidates

Asymptomatic aneurysms in pregnant women should not be followed with watchful waiting—they should be repaired, as rupture carries a maternal mortality rate of 75% and a fetal mortality rate of 95%.³⁴

Complications of splenic artery aneurysm depend on the type of aneurysm and its predisposing factors. Indications for treatment of true aneurysms include:

• Symptoms attributable to the aneurysm (hence, the second answer choice above is true)
• Diameter 2  cm or greater or enlarging diameter (hence, the first answer choice is true)
• Women of childbearing age in anticipation of pregnancy
• Need for surgical intervention such as portocaval shunt and liver transplant.

Conservative management is associated with a late mortality risk of 4.9%.² Interventional options include percutaneous embolization or stenting; or laparotomy with splenic artery ligation or excision with or without splenectomy.^1,28,35–37

Endovascular and open surgical repair have both been used to treat splenic artery aneurysms. The method used depends on the patient’s surgical history and aneurysm anatomy such as splenic artery tortuosity hindering passage of a catheter. Open surgery is associated with longer intraoperative time and length of hospital stay and higher rates of 30-day mortality and perioperative morbidity.^38–41 With endovascular repair, the complication of persistent or recurrent flow occurs in 3% to 5% of cases by 30 days; hence, postprocedural surveillance is recommended.^42–44 Endovascular repair has a higher reintervention rate but may still be more cost-effective than open surgical repair.

Because patients with cirrhosis have a higher risk of surgical complications,⁴⁵ elective endovascular treatment may be an option for patients with aneurysms at high risk of rupturing. Endovascular treatment of visceral aneurysms is associated with complications such as postembolization syndrome (fever, abdominal pain, pleural effusion, and pancreatitis), access site hematoma, splenic infarction, and persistent abdominal pain.⁴²

Patients with cirrhosis as the cause of splenic artery aneurysm tend to need longer hospitalization after endovascular treatment, but there is insufficient evidence to suggest that they are at higher risk of other complications.³⁷

CASE CONTINUED: SPLENIC ARTERY EMBOLIZATION

The patient undergoes emergency splenic artery embolization, performed by an interventional radiology team (Figure 2 and Figure 3). Over the next few days, her mental status improves and her abdominal pain resolves. Her hemoglobin level remains stable after the procedure.

The surgical and interventional radiology teams discuss the risk of repeat intervention with the patient and her family, who prefer a nonoperative approach. She is managed supportively in the intensive care unit and is finally discharged home in stable condition and is scheduled for outpatient follow-up.

SUSPECT THIS FATAL CONDITION

The low prevalence of ruptured splenic artery aneurysm may lead physicians to attribute septic shock to spontaneous bacterial peritonitis or hemorrhagic shock from gastroesophageal varices in patients with cirrhosis, but a high index of suspicion and early recognition of this rare disease can lead to timely diagnosis and treatment of this highly fatal complication.

KEY POINTS

• Splenic artery aneurysm is a common complication of cirrhosis, often diagnosed incidentally.
• Elective embolization should be considered for asymptomatic splenic artery aneurysms larger than 2 cm in diameter, clinically symptomatic aneurysms, women of childbearing age, and patients who are candidates for liver transplant.
• Although splenic artery aneurysm rupture is rare, it has a high mortality rate and warrants a high index of suspicion to institute prompt specialized intervention.
• We recommend that physicians consider splenic artery aneurysm rupture in their differential diagnoses in patients with liver cirrhosis presenting with abdominal pain, altered mental status, and hemodynamic shock.

A 53-year-old Native American woman with a history of liver cirrhosis secondary to alcohol abuse presents to the emergency department after 2 days of diffuse abdominal pain and weakness. The pain was sudden in onset and has progressed relentlessly over the last day, reaching 9 on a scale of 10 in severity. Family members say that her oral intake has been decreased for the last 2 days, but she has had no fever, vomiting, change in bowel habit, blood in stool, or black stool. She has never undergone surgery, and has had one uncomplicated pregnancy.

Physical examination

Vital signs:

• Blood pressure 82/57 mm Hg
• Heart rate 96 beats per minute
• Temperature 37.3°C (99.1°F)
• Respiratory rate 16 per minute
• Oxygen saturation 92% while receiving oxygen at 2 L/minute.

The patient is somnolent and has scleral icterus. Her cardiopulmonary examination is normal. Her abdomen is tense, distended, and diffusely tender. She has bilateral +2 pitting edema in her lower extremities. She is oriented to person only and is noted to have asterixis. Her baseline Model for End-stage Liver Disease score is 18 points on a scale of 6 (less ill) to 40 (gravely ill).

Laboratory studies:

• Hemoglobin 9.8 g/dL (reference range 11.5–15.5)
• Platelet count 100 × 10⁹/L (150–400)
• White blood cell count 9.9 × 10⁹/L (3.7–11.0)
• Serum creatinine 1.06 mg/dL (0.58–0.96)
• Bilirubin 6.3 mg/dL (0.2–1.3)
• International normalized ratio of the prothrombin time 2.15 (0.8–1.2)
• Blood urea nitrogen 13 mg/dL (7–21)
• Serum albumin 2.7 g/dL (3.9–4.9).

Intravenous fluid resuscitation is initiated but the patient remains hypotensive, and on repeat laboratory testing 4 hours later her hemoglobin level has dropped to 7.3 mg/dL.

DIFFERENTIAL DIAGNOSIS

1. Which of the following are likely causes of this patient’s presentation?

• Splenic arterial aneurysm rupture
• Spontaneous bacterial peritonitis
• Variceal hemorrhage
• Portal vein thrombosis
• Abdominal aortic aneurysm rupture

Ruptured splenic artery aneurysm

Splenic artery aneurysms are the third most common intra-abdominal aneurysm, after those of the abdominal aorta and iliac artery.¹ They are often asymptomatic and are being detected more frequently because of increased use of computed tomography (CT).² Symptomatic splenic artery aneurysms may present with abdominal pain and have the potential to rupture, which can be life-threatening.^3,4

This patient may have a ruptured splenic artery aneurysm, given her hemodynamic shock.

Spontaneous bacterial peritonitis

Ten percent to 20% of hospitalized patients with cirrhosis and ascites develop spontaneous bacterial peritonitis. Patients may present with ascites and abdominal pain, tenderness to palpation, fever, encephalopathy, or worsening liver and renal function.

Diagnostic paracentesis is paramount to delineate the cause of ascites; one should calculate the serum-ascites albumin gradient and obtain a cell count and culture of the ascitic fluid. The diagnosis of spontaneous bacterial peritonitis can be made if the ascitic fluid polymorphonuclear cell count is 0.25 × 10⁹/L or higher, even if the ascitic fluid culture is negative.^5,6 Simultaneous blood cultures should also be collected, as 50% of cases are associated with bacteremia.

The in-hospital mortality rate of an episode of spontaneous bacterial peritonitis has been reduced to 10% to 20% thanks to prompt diagnosis and empiric treatment with third-generation cephalosporins.⁷

Five percent of cases of infected ascites fluid are due to secondary bacterial peritonitis from a perforated viscus or a loculated abscess, which cannot be differentiated clinically from spontaneous bacterial peritonitis but can be diagnosed with CT.⁸

This patient may be presenting with septic shock secondary to either of these causes.

Variceal hemorrhage

Half of patients with cirrhosis have gastroesophageal varices due to portal hypertension. Endoscopic surveillance is warranted, as the risk of hemorrhage is 12% to 15% per year, and the mortality rate approaches 15% to 20% with each episode. Prompt resuscitation, diagnosis, and control of bleeding is paramount.

Esophagogastroduodenoscopy is used for both diagnosis and intervention. Short-term prophylactic use of antibiotics improves survival by preventing infections in the event bleeding recurs.^9–11

Our patient may be presenting with hemodynamic shock from bleeding esophageal varices.

Portal vein thrombosis is a common complication of cirrhosis, occurring in 5% to 28% of patients. The risk increases with the severity of liver disease and in association with hepatocellular carcinoma.¹² Forty-three percent of cases are discovered incidentally in asymptomatic patients during ultrasonography, 39% present with upper gastrointestinal bleeding, and 18% present with abdominal pain.^13,14

Portal vein thrombosis is the complete or partial obstruction of blood flow due to a thrombus in the lumen of the portal vein. Contrast ultrasonography and CT can be used to establish the diagnosis.¹⁵

Anticoagulation is recommended in cases of complete thrombosis in candidates for living-donor liver transplant and for those at risk of mesenteric ischemia because of the thrombus extending into the mesenteric veins. In symptomatic patients, the decision to initiate anticoagulation should be made on a case-by-case basis after appropriate screening and management of varices.^16–18

Our patient’s thrombocytopenia reflects the severity of portal hypertension and increases her risk of portal vein thrombosis, but this is unlikely to be the sole cause of the hemodynamic compromise in this patient.

Ruptured abdominal aortic aneurysm

Rupture of an abdominal aortic aneurysm is a medical emergency, with a mortality rate approaching 90%. Risk factors for abdominal aortic aneurysms are smoking, male sex, age over 65, history of cardiovascular disease, hypertension, and a family history of abdominal aortic aneurysm, especially if a first-degree relative is affected.¹⁹ Endovascular repair is associated with lower rates of death and complications compared with open repair.²⁰

The patient does not have any of those risk factors, making this diagnosis less likely.

CASE CONTINUED: RUPTURED SPLENIC ARTERY ANEURYSM

Emergency CT of the abdomen and pelvis with contrast enhancement shows a large left intraperitoneal hematoma with active extravasation from a ruptured splenic artery aneurysm (Figure 1). The patient receives packed red blood cells and fresh-frozen plasma before being transferred to our hospital.

2. Which of the following is false regarding splenic artery aneurysms?

• They are the most common type of splanchnic arterial aneurysm
• True aneurysms are more common than pseudoaneurysms
• Asymptomatic aneurysms are discovered incidentally during assessment for other radiographic indications
• Splenic artery aneurysm in portal hypertension is the result of athero-sclerotic changes to the vascular intima

Splenic artery aneurysm in portal hypertension is not the result of atherosclerotic change to the vascular intima.

Splenic artery aneurysms are the most common type of splanchnic artery aneurysm.¹ True aneurysms involve all 3 layers of the arterial wall, ie, intima, media, and adventitia. Cirrhosis and portal hypertension are associated with true aneurysm formation. The proposed mechanism of aneurysm formation is increased splenic blood flow in response to portal congestion with resultant hemodynamic stress that disrupts arterial wall structure, leading to aneurysmal dilation.²¹

In earlier reports, the incidence of true splenic artery aneurysm in portal hypertension varied from 2.9% to 50%, the latter representing autopsy findings of small aneurysms that were found in the splenic hilum of patients with cirrhosis.^22–25 The incidence of clinically significant aneurysms in cirrhosis is unknown but incidental asymptomatic aneurysm is being detected more frequently on imaging studies pursued for screening purposes.²⁶

The risk of rupture is low, only 2% to 10% in older studies and likely even lower now due to increased incidental detection in asymptomatic patients.²⁷ However, emergent management of rupture at a tertiary care facility is paramount, as the mortality rate of ruptured splenic artery aneurysm is 29% to 36%.^1,26,28

Splenic artery pseudoaneurysm is rarer and has a different pathophysiologic process than true aneurysm. It usually arises in the setting of trauma, pancreatitis, or postsurgery.^29,30 Pseudoaneurysm is more likely to rupture, owing to compromise in the vascular wall integrity.^4,21,28 As a result, treatment is indicated for every pseudoaneurysm regardless of size.

RISK FACTORS FOR SPLENIC ARTERY ANEURYSM

3. Which of the following is true regarding our patient’s risk of splenic artery aneurysm?

• Liver cirrhosis and portal hypertension are her greatest risk factors for it
• Female sex and prior pregnancy are her greatest risk factors for it
• Being Native American makes it more likely that the patient has splenic artery aneurysm secondary to collagen vascular disease
• Her risk of rupture would diminish after receiving a liver transplant

Liver cirrhosis and portal hypertension are her greatest risk factors for splenic artery aneurysm.

Risk factors for true aneurysm include hypertension, atherosclerosis, portal hypertension with or without liver cirrhosis, liver transplant, third trimester of pregnancy, and multiparity.^1,4,26,28,31 Splenic artery aneurysm is  usually diagnosed in the sixth decade. It may be 4 times as common in women, given a hormonal influence.³² Cirrhosis is also associated with massive splenic artery aneurysm (≥ 5 cm). Although rare, massive splenic artery aneurysm is more frequent in men (the male-to-female ratio is 1.78:1) and has a heightened risk of rupture.²⁸ The incidence of rupture increases to around 3% to 4% after liver transplant.³³ Rare causes of true aneurysm include fibrodysplasia, collagen vascular disease (eg, Loeys-Dietz and type IV Ehler-Danlos syndromes), vasculitis (eg, polyarteritis nodosa due to amphetamine abuse), and mycotic aneurysms.^24,25,28,29

This patient’s age, sex, and history of cirrhosis puts her at increased risk of splenic artery aneurysm. The risk of rupture is highest in the peripartum period and in patients with cirrhosis who become pregnant. Although being Native American portends an increased risk for collagen vascular disease, the latter is unlikely to be a contributing factor.

4. Which of the following is false regarding treatment of splenic artery aneurysms?

• Aneurysms larger than 2 cm and those that are expanding require repair
• Treatment should be offered if the patient has symptoms attributable to the aneurysm
• Asymptomatic aneurysms in pregnant women can be followed with watchful waiting
• Minimally invasive therapies such as percutaneous embolization may be a good option in poor operative candidates

Asymptomatic aneurysms in pregnant women should not be followed with watchful waiting—they should be repaired, as rupture carries a maternal mortality rate of 75% and a fetal mortality rate of 95%.³⁴

Complications of splenic artery aneurysm depend on the type of aneurysm and its predisposing factors. Indications for treatment of true aneurysms include:

• Symptoms attributable to the aneurysm (hence, the second answer choice above is true)
• Diameter 2  cm or greater or enlarging diameter (hence, the first answer choice is true)
• Women of childbearing age in anticipation of pregnancy
• Need for surgical intervention such as portocaval shunt and liver transplant.

Conservative management is associated with a late mortality risk of 4.9%.² Interventional options include percutaneous embolization or stenting; or laparotomy with splenic artery ligation or excision with or without splenectomy.^1,28,35–37

Endovascular and open surgical repair have both been used to treat splenic artery aneurysms. The method used depends on the patient’s surgical history and aneurysm anatomy such as splenic artery tortuosity hindering passage of a catheter. Open surgery is associated with longer intraoperative time and length of hospital stay and higher rates of 30-day mortality and perioperative morbidity.^38–41 With endovascular repair, the complication of persistent or recurrent flow occurs in 3% to 5% of cases by 30 days; hence, postprocedural surveillance is recommended.^42–44 Endovascular repair has a higher reintervention rate but may still be more cost-effective than open surgical repair.

Because patients with cirrhosis have a higher risk of surgical complications,⁴⁵ elective endovascular treatment may be an option for patients with aneurysms at high risk of rupturing. Endovascular treatment of visceral aneurysms is associated with complications such as postembolization syndrome (fever, abdominal pain, pleural effusion, and pancreatitis), access site hematoma, splenic infarction, and persistent abdominal pain.⁴²

Patients with cirrhosis as the cause of splenic artery aneurysm tend to need longer hospitalization after endovascular treatment, but there is insufficient evidence to suggest that they are at higher risk of other complications.³⁷

CASE CONTINUED: SPLENIC ARTERY EMBOLIZATION

The patient undergoes emergency splenic artery embolization, performed by an interventional radiology team (Figure 2 and Figure 3). Over the next few days, her mental status improves and her abdominal pain resolves. Her hemoglobin level remains stable after the procedure.

The surgical and interventional radiology teams discuss the risk of repeat intervention with the patient and her family, who prefer a nonoperative approach. She is managed supportively in the intensive care unit and is finally discharged home in stable condition and is scheduled for outpatient follow-up.

SUSPECT THIS FATAL CONDITION

The low prevalence of ruptured splenic artery aneurysm may lead physicians to attribute septic shock to spontaneous bacterial peritonitis or hemorrhagic shock from gastroesophageal varices in patients with cirrhosis, but a high index of suspicion and early recognition of this rare disease can lead to timely diagnosis and treatment of this highly fatal complication.

KEY POINTS

• Splenic artery aneurysm is a common complication of cirrhosis, often diagnosed incidentally.
• Elective embolization should be considered for asymptomatic splenic artery aneurysms larger than 2 cm in diameter, clinically symptomatic aneurysms, women of childbearing age, and patients who are candidates for liver transplant.
• Although splenic artery aneurysm rupture is rare, it has a high mortality rate and warrants a high index of suspicion to institute prompt specialized intervention.
• We recommend that physicians consider splenic artery aneurysm rupture in their differential diagnoses in patients with liver cirrhosis presenting with abdominal pain, altered mental status, and hemodynamic shock.

A 53-year-old Native American woman with a history of liver cirrhosis secondary to alcohol abuse presents to the emergency department after 2 days of diffuse abdominal pain and weakness. The pain was sudden in onset and has progressed relentlessly over the last day, reaching 9 on a scale of 10 in severity. Family members say that her oral intake has been decreased for the last 2 days, but she has had no fever, vomiting, change in bowel habit, blood in stool, or black stool. She has never undergone surgery, and has had one uncomplicated pregnancy.

Physical examination

Vital signs:

• Blood pressure 82/57 mm Hg
• Heart rate 96 beats per minute
• Temperature 37.3°C (99.1°F)
• Respiratory rate 16 per minute
• Oxygen saturation 92% while receiving oxygen at 2 L/minute.

The patient is somnolent and has scleral icterus. Her cardiopulmonary examination is normal. Her abdomen is tense, distended, and diffusely tender. She has bilateral +2 pitting edema in her lower extremities. She is oriented to person only and is noted to have asterixis. Her baseline Model for End-stage Liver Disease score is 18 points on a scale of 6 (less ill) to 40 (gravely ill).

Laboratory studies:

• Hemoglobin 9.8 g/dL (reference range 11.5–15.5)
• Platelet count 100 × 10⁹/L (150–400)
• White blood cell count 9.9 × 10⁹/L (3.7–11.0)
• Serum creatinine 1.06 mg/dL (0.58–0.96)
• Bilirubin 6.3 mg/dL (0.2–1.3)
• International normalized ratio of the prothrombin time 2.15 (0.8–1.2)
• Blood urea nitrogen 13 mg/dL (7–21)
• Serum albumin 2.7 g/dL (3.9–4.9).

Intravenous fluid resuscitation is initiated but the patient remains hypotensive, and on repeat laboratory testing 4 hours later her hemoglobin level has dropped to 7.3 mg/dL.

DIFFERENTIAL DIAGNOSIS

1. Which of the following are likely causes of this patient’s presentation?

• Splenic arterial aneurysm rupture
• Spontaneous bacterial peritonitis
• Variceal hemorrhage
• Portal vein thrombosis
• Abdominal aortic aneurysm rupture

Ruptured splenic artery aneurysm

Splenic artery aneurysms are the third most common intra-abdominal aneurysm, after those of the abdominal aorta and iliac artery.¹ They are often asymptomatic and are being detected more frequently because of increased use of computed tomography (CT).² Symptomatic splenic artery aneurysms may present with abdominal pain and have the potential to rupture, which can be life-threatening.^3,4

This patient may have a ruptured splenic artery aneurysm, given her hemodynamic shock.

Spontaneous bacterial peritonitis

Ten percent to 20% of hospitalized patients with cirrhosis and ascites develop spontaneous bacterial peritonitis. Patients may present with ascites and abdominal pain, tenderness to palpation, fever, encephalopathy, or worsening liver and renal function.

Diagnostic paracentesis is paramount to delineate the cause of ascites; one should calculate the serum-ascites albumin gradient and obtain a cell count and culture of the ascitic fluid. The diagnosis of spontaneous bacterial peritonitis can be made if the ascitic fluid polymorphonuclear cell count is 0.25 × 10⁹/L or higher, even if the ascitic fluid culture is negative.^5,6 Simultaneous blood cultures should also be collected, as 50% of cases are associated with bacteremia.

The in-hospital mortality rate of an episode of spontaneous bacterial peritonitis has been reduced to 10% to 20% thanks to prompt diagnosis and empiric treatment with third-generation cephalosporins.⁷

Five percent of cases of infected ascites fluid are due to secondary bacterial peritonitis from a perforated viscus or a loculated abscess, which cannot be differentiated clinically from spontaneous bacterial peritonitis but can be diagnosed with CT.⁸

This patient may be presenting with septic shock secondary to either of these causes.

Variceal hemorrhage

Half of patients with cirrhosis have gastroesophageal varices due to portal hypertension. Endoscopic surveillance is warranted, as the risk of hemorrhage is 12% to 15% per year, and the mortality rate approaches 15% to 20% with each episode. Prompt resuscitation, diagnosis, and control of bleeding is paramount.

Esophagogastroduodenoscopy is used for both diagnosis and intervention. Short-term prophylactic use of antibiotics improves survival by preventing infections in the event bleeding recurs.^9–11

Our patient may be presenting with hemodynamic shock from bleeding esophageal varices.

Portal vein thrombosis is a common complication of cirrhosis, occurring in 5% to 28% of patients. The risk increases with the severity of liver disease and in association with hepatocellular carcinoma.¹² Forty-three percent of cases are discovered incidentally in asymptomatic patients during ultrasonography, 39% present with upper gastrointestinal bleeding, and 18% present with abdominal pain.^13,14

Portal vein thrombosis is the complete or partial obstruction of blood flow due to a thrombus in the lumen of the portal vein. Contrast ultrasonography and CT can be used to establish the diagnosis.¹⁵

Anticoagulation is recommended in cases of complete thrombosis in candidates for living-donor liver transplant and for those at risk of mesenteric ischemia because of the thrombus extending into the mesenteric veins. In symptomatic patients, the decision to initiate anticoagulation should be made on a case-by-case basis after appropriate screening and management of varices.^16–18

Our patient’s thrombocytopenia reflects the severity of portal hypertension and increases her risk of portal vein thrombosis, but this is unlikely to be the sole cause of the hemodynamic compromise in this patient.

Ruptured abdominal aortic aneurysm

Rupture of an abdominal aortic aneurysm is a medical emergency, with a mortality rate approaching 90%. Risk factors for abdominal aortic aneurysms are smoking, male sex, age over 65, history of cardiovascular disease, hypertension, and a family history of abdominal aortic aneurysm, especially if a first-degree relative is affected.¹⁹ Endovascular repair is associated with lower rates of death and complications compared with open repair.²⁰

The patient does not have any of those risk factors, making this diagnosis less likely.

CASE CONTINUED: RUPTURED SPLENIC ARTERY ANEURYSM

Emergency CT of the abdomen and pelvis with contrast enhancement shows a large left intraperitoneal hematoma with active extravasation from a ruptured splenic artery aneurysm (Figure 1). The patient receives packed red blood cells and fresh-frozen plasma before being transferred to our hospital.

2. Which of the following is false regarding splenic artery aneurysms?

• They are the most common type of splanchnic arterial aneurysm
• True aneurysms are more common than pseudoaneurysms
• Asymptomatic aneurysms are discovered incidentally during assessment for other radiographic indications
• Splenic artery aneurysm in portal hypertension is the result of athero-sclerotic changes to the vascular intima

Splenic artery aneurysm in portal hypertension is not the result of atherosclerotic change to the vascular intima.

Splenic artery aneurysms are the most common type of splanchnic artery aneurysm.¹ True aneurysms involve all 3 layers of the arterial wall, ie, intima, media, and adventitia. Cirrhosis and portal hypertension are associated with true aneurysm formation. The proposed mechanism of aneurysm formation is increased splenic blood flow in response to portal congestion with resultant hemodynamic stress that disrupts arterial wall structure, leading to aneurysmal dilation.²¹

In earlier reports, the incidence of true splenic artery aneurysm in portal hypertension varied from 2.9% to 50%, the latter representing autopsy findings of small aneurysms that were found in the splenic hilum of patients with cirrhosis.^22–25 The incidence of clinically significant aneurysms in cirrhosis is unknown but incidental asymptomatic aneurysm is being detected more frequently on imaging studies pursued for screening purposes.²⁶

The risk of rupture is low, only 2% to 10% in older studies and likely even lower now due to increased incidental detection in asymptomatic patients.²⁷ However, emergent management of rupture at a tertiary care facility is paramount, as the mortality rate of ruptured splenic artery aneurysm is 29% to 36%.^1,26,28

Splenic artery pseudoaneurysm is rarer and has a different pathophysiologic process than true aneurysm. It usually arises in the setting of trauma, pancreatitis, or postsurgery.^29,30 Pseudoaneurysm is more likely to rupture, owing to compromise in the vascular wall integrity.^4,21,28 As a result, treatment is indicated for every pseudoaneurysm regardless of size.

RISK FACTORS FOR SPLENIC ARTERY ANEURYSM

3. Which of the following is true regarding our patient’s risk of splenic artery aneurysm?

• Liver cirrhosis and portal hypertension are her greatest risk factors for it
• Female sex and prior pregnancy are her greatest risk factors for it
• Being Native American makes it more likely that the patient has splenic artery aneurysm secondary to collagen vascular disease
• Her risk of rupture would diminish after receiving a liver transplant

Liver cirrhosis and portal hypertension are her greatest risk factors for splenic artery aneurysm.

Risk factors for true aneurysm include hypertension, atherosclerosis, portal hypertension with or without liver cirrhosis, liver transplant, third trimester of pregnancy, and multiparity.^1,4,26,28,31 Splenic artery aneurysm is  usually diagnosed in the sixth decade. It may be 4 times as common in women, given a hormonal influence.³² Cirrhosis is also associated with massive splenic artery aneurysm (≥ 5 cm). Although rare, massive splenic artery aneurysm is more frequent in men (the male-to-female ratio is 1.78:1) and has a heightened risk of rupture.²⁸ The incidence of rupture increases to around 3% to 4% after liver transplant.³³ Rare causes of true aneurysm include fibrodysplasia, collagen vascular disease (eg, Loeys-Dietz and type IV Ehler-Danlos syndromes), vasculitis (eg, polyarteritis nodosa due to amphetamine abuse), and mycotic aneurysms.^24,25,28,29

This patient’s age, sex, and history of cirrhosis puts her at increased risk of splenic artery aneurysm. The risk of rupture is highest in the peripartum period and in patients with cirrhosis who become pregnant. Although being Native American portends an increased risk for collagen vascular disease, the latter is unlikely to be a contributing factor.

4. Which of the following is false regarding treatment of splenic artery aneurysms?

• Aneurysms larger than 2 cm and those that are expanding require repair
• Treatment should be offered if the patient has symptoms attributable to the aneurysm
• Asymptomatic aneurysms in pregnant women can be followed with watchful waiting
• Minimally invasive therapies such as percutaneous embolization may be a good option in poor operative candidates

Asymptomatic aneurysms in pregnant women should not be followed with watchful waiting—they should be repaired, as rupture carries a maternal mortality rate of 75% and a fetal mortality rate of 95%.³⁴

Complications of splenic artery aneurysm depend on the type of aneurysm and its predisposing factors. Indications for treatment of true aneurysms include:

• Symptoms attributable to the aneurysm (hence, the second answer choice above is true)
• Diameter 2  cm or greater or enlarging diameter (hence, the first answer choice is true)
• Women of childbearing age in anticipation of pregnancy
• Need for surgical intervention such as portocaval shunt and liver transplant.

Conservative management is associated with a late mortality risk of 4.9%.² Interventional options include percutaneous embolization or stenting; or laparotomy with splenic artery ligation or excision with or without splenectomy.^1,28,35–37

Endovascular and open surgical repair have both been used to treat splenic artery aneurysms. The method used depends on the patient’s surgical history and aneurysm anatomy such as splenic artery tortuosity hindering passage of a catheter. Open surgery is associated with longer intraoperative time and length of hospital stay and higher rates of 30-day mortality and perioperative morbidity.^38–41 With endovascular repair, the complication of persistent or recurrent flow occurs in 3% to 5% of cases by 30 days; hence, postprocedural surveillance is recommended.^42–44 Endovascular repair has a higher reintervention rate but may still be more cost-effective than open surgical repair.

Because patients with cirrhosis have a higher risk of surgical complications,⁴⁵ elective endovascular treatment may be an option for patients with aneurysms at high risk of rupturing. Endovascular treatment of visceral aneurysms is associated with complications such as postembolization syndrome (fever, abdominal pain, pleural effusion, and pancreatitis), access site hematoma, splenic infarction, and persistent abdominal pain.⁴²

Patients with cirrhosis as the cause of splenic artery aneurysm tend to need longer hospitalization after endovascular treatment, but there is insufficient evidence to suggest that they are at higher risk of other complications.³⁷

CASE CONTINUED: SPLENIC ARTERY EMBOLIZATION

The patient undergoes emergency splenic artery embolization, performed by an interventional radiology team (Figure 2 and Figure 3). Over the next few days, her mental status improves and her abdominal pain resolves. Her hemoglobin level remains stable after the procedure.

The surgical and interventional radiology teams discuss the risk of repeat intervention with the patient and her family, who prefer a nonoperative approach. She is managed supportively in the intensive care unit and is finally discharged home in stable condition and is scheduled for outpatient follow-up.

SUSPECT THIS FATAL CONDITION

The low prevalence of ruptured splenic artery aneurysm may lead physicians to attribute septic shock to spontaneous bacterial peritonitis or hemorrhagic shock from gastroesophageal varices in patients with cirrhosis, but a high index of suspicion and early recognition of this rare disease can lead to timely diagnosis and treatment of this highly fatal complication.

KEY POINTS

• Splenic artery aneurysm is a common complication of cirrhosis, often diagnosed incidentally.
• Elective embolization should be considered for asymptomatic splenic artery aneurysms larger than 2 cm in diameter, clinically symptomatic aneurysms, women of childbearing age, and patients who are candidates for liver transplant.
• Although splenic artery aneurysm rupture is rare, it has a high mortality rate and warrants a high index of suspicion to institute prompt specialized intervention.
• We recommend that physicians consider splenic artery aneurysm rupture in their differential diagnoses in patients with liver cirrhosis presenting with abdominal pain, altered mental status, and hemodynamic shock.

A 64-year-old man with end-stage renal disease was evaluated in the pulmonary clinic for persistent abnormalities on axial computed tomography (CT) of the chest. He was a lifelong nonsmoker and had no history of exposure to occupational dust or fumes. His oxygen saturation was 100% on room air, and he denied any respiratory symptoms.

WHEN TO CONSIDER METASTATIC PULMONARY CALCIFICATION

The differential diagnosis for chronic upper-lobe-predominant ground-glass nodules is broad and includes atypical infections, recurrent alveolar hemorrhage, hypersensitivity pneumonitis, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, occupational lung disease, and pulmonary alveolar microlithiasis. However, several aspects of our patient’s case suggested an often overlooked diagnosis, metastatic pulmonary calcification.

Metastatic pulmonary calcification is caused by deposition of calcium salts in lung tissue and is most commonly seen in patients on dialysis,^1,2 and our patient had been dependent on dialysis for many years. The chronically elevated calcium-phosphorus product and secondary hyperparathyroidism often seen with end-stage renal disease may explain this association.

Our patient’s lack of symptoms is also an important diagnostic clue. Unlike many other causes of chronic upper-lobe-predominant ground-glass nodules, metastatic pulmonary calcification does not usually cause symptoms and is often identified only at autopsy.³ Results of pulmonary function testing are often normal.⁴

Metastatic pulmonary calcification can appear as diffusely calcified nodules or high-attenuation areas of consolidation on CT. However, as in our patient’s case, CT may demonstrate fluffy, centrilobular ground-glass nodules due to the microscopic size of the deposited calcium crystals.¹ Identifying calcified vessels on imaging supports the diagnosis.⁴

Treatment of metastatic pulmonary calcification in a patient with end-stage renal disease is focused on correcting underlying metabolic abnormalities with phosphate binders, vitamin D supplementation, and dialysis.

A 64-year-old man with end-stage renal disease was evaluated in the pulmonary clinic for persistent abnormalities on axial computed tomography (CT) of the chest. He was a lifelong nonsmoker and had no history of exposure to occupational dust or fumes. His oxygen saturation was 100% on room air, and he denied any respiratory symptoms.

WHEN TO CONSIDER METASTATIC PULMONARY CALCIFICATION

The differential diagnosis for chronic upper-lobe-predominant ground-glass nodules is broad and includes atypical infections, recurrent alveolar hemorrhage, hypersensitivity pneumonitis, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, occupational lung disease, and pulmonary alveolar microlithiasis. However, several aspects of our patient’s case suggested an often overlooked diagnosis, metastatic pulmonary calcification.

Metastatic pulmonary calcification is caused by deposition of calcium salts in lung tissue and is most commonly seen in patients on dialysis,^1,2 and our patient had been dependent on dialysis for many years. The chronically elevated calcium-phosphorus product and secondary hyperparathyroidism often seen with end-stage renal disease may explain this association.

Our patient’s lack of symptoms is also an important diagnostic clue. Unlike many other causes of chronic upper-lobe-predominant ground-glass nodules, metastatic pulmonary calcification does not usually cause symptoms and is often identified only at autopsy.³ Results of pulmonary function testing are often normal.⁴

Metastatic pulmonary calcification can appear as diffusely calcified nodules or high-attenuation areas of consolidation on CT. However, as in our patient’s case, CT may demonstrate fluffy, centrilobular ground-glass nodules due to the microscopic size of the deposited calcium crystals.¹ Identifying calcified vessels on imaging supports the diagnosis.⁴

Treatment of metastatic pulmonary calcification in a patient with end-stage renal disease is focused on correcting underlying metabolic abnormalities with phosphate binders, vitamin D supplementation, and dialysis.

A 64-year-old man with end-stage renal disease was evaluated in the pulmonary clinic for persistent abnormalities on axial computed tomography (CT) of the chest. He was a lifelong nonsmoker and had no history of exposure to occupational dust or fumes. His oxygen saturation was 100% on room air, and he denied any respiratory symptoms.

WHEN TO CONSIDER METASTATIC PULMONARY CALCIFICATION

The differential diagnosis for chronic upper-lobe-predominant ground-glass nodules is broad and includes atypical infections, recurrent alveolar hemorrhage, hypersensitivity pneumonitis, vasculitis, sarcoidosis, chronic eosinophilic pneumonia, occupational lung disease, and pulmonary alveolar microlithiasis. However, several aspects of our patient’s case suggested an often overlooked diagnosis, metastatic pulmonary calcification.

Metastatic pulmonary calcification is caused by deposition of calcium salts in lung tissue and is most commonly seen in patients on dialysis,^1,2 and our patient had been dependent on dialysis for many years. The chronically elevated calcium-phosphorus product and secondary hyperparathyroidism often seen with end-stage renal disease may explain this association.

Our patient’s lack of symptoms is also an important diagnostic clue. Unlike many other causes of chronic upper-lobe-predominant ground-glass nodules, metastatic pulmonary calcification does not usually cause symptoms and is often identified only at autopsy.³ Results of pulmonary function testing are often normal.⁴

Metastatic pulmonary calcification can appear as diffusely calcified nodules or high-attenuation areas of consolidation on CT. However, as in our patient’s case, CT may demonstrate fluffy, centrilobular ground-glass nodules due to the microscopic size of the deposited calcium crystals.¹ Identifying calcified vessels on imaging supports the diagnosis.⁴

Treatment of metastatic pulmonary calcification in a patient with end-stage renal disease is focused on correcting underlying metabolic abnormalities with phosphate binders, vitamin D supplementation, and dialysis.

To the Editor: We read with great interest the article by Patnaik et al¹ about a patient who had a cardiac metastasis of ovarian cancer, and we would like to raise a few points.

It is important to clarify that metastatic cardiac tumors are not necessary malignant. Intravenous leiomyomatosis is a benign small-muscle tumor that can spread to the heart, causing various cardiac symptoms.² Even with extensive disease, patients with intravenous leiomyomatosis may remain asymptomatic until cardiac involvement occurs. The most common cardiac symptoms are dyspnea, syncope, and lower-extremity edema.

Cardiac involvement in intravenous leiomyomatosis may occur via direct invasion or hematogenous or lymphatic spread of the tumor. In leiomyoma and leiomyosarcoma, cardiac invasion usually occurs via direct spread through the inferior vena cava into the right atrium and ventricle. Thus, cardiac involvement with these tumors (except for nephroma) was reported to exclusively involve the right side of the heart.

In 2014, we reported a unique case of intravenous leiomyomatosis that extended from the right side into the left side of the heart and the aorta via an atrial septal defect.² Intracardiac extension of intravenous leiomyomatosis may result in pulmonary embolism, systemic embolization if involving the left side, and, rarely, sudden death.²

In patients with malignancy, differentiating between thrombosis and tumor is critical. These patients have a hypercoagulable state and a fourfold increase in thrombosis risk, and chemotherapy increases this risk even more.³ Although tissue pathology examination is important for differentiating thrombosis from tumor, visualization of the direct extension of the mass from the primary source into the heart through the inferior vena cava by ultrasonography, computed tomography, or magnetic resonance imaging may help in making this distinction.²

To the Editor: We read with great interest the article by Patnaik et al¹ about a patient who had a cardiac metastasis of ovarian cancer, and we would like to raise a few points.

It is important to clarify that metastatic cardiac tumors are not necessary malignant. Intravenous leiomyomatosis is a benign small-muscle tumor that can spread to the heart, causing various cardiac symptoms.² Even with extensive disease, patients with intravenous leiomyomatosis may remain asymptomatic until cardiac involvement occurs. The most common cardiac symptoms are dyspnea, syncope, and lower-extremity edema.

Cardiac involvement in intravenous leiomyomatosis may occur via direct invasion or hematogenous or lymphatic spread of the tumor. In leiomyoma and leiomyosarcoma, cardiac invasion usually occurs via direct spread through the inferior vena cava into the right atrium and ventricle. Thus, cardiac involvement with these tumors (except for nephroma) was reported to exclusively involve the right side of the heart.

In 2014, we reported a unique case of intravenous leiomyomatosis that extended from the right side into the left side of the heart and the aorta via an atrial septal defect.² Intracardiac extension of intravenous leiomyomatosis may result in pulmonary embolism, systemic embolization if involving the left side, and, rarely, sudden death.²

In patients with malignancy, differentiating between thrombosis and tumor is critical. These patients have a hypercoagulable state and a fourfold increase in thrombosis risk, and chemotherapy increases this risk even more.³ Although tissue pathology examination is important for differentiating thrombosis from tumor, visualization of the direct extension of the mass from the primary source into the heart through the inferior vena cava by ultrasonography, computed tomography, or magnetic resonance imaging may help in making this distinction.²

To the Editor: We read with great interest the article by Patnaik et al¹ about a patient who had a cardiac metastasis of ovarian cancer, and we would like to raise a few points.

It is important to clarify that metastatic cardiac tumors are not necessary malignant. Intravenous leiomyomatosis is a benign small-muscle tumor that can spread to the heart, causing various cardiac symptoms.² Even with extensive disease, patients with intravenous leiomyomatosis may remain asymptomatic until cardiac involvement occurs. The most common cardiac symptoms are dyspnea, syncope, and lower-extremity edema.

Cardiac involvement in intravenous leiomyomatosis may occur via direct invasion or hematogenous or lymphatic spread of the tumor. In leiomyoma and leiomyosarcoma, cardiac invasion usually occurs via direct spread through the inferior vena cava into the right atrium and ventricle. Thus, cardiac involvement with these tumors (except for nephroma) was reported to exclusively involve the right side of the heart.

In 2014, we reported a unique case of intravenous leiomyomatosis that extended from the right side into the left side of the heart and the aorta via an atrial septal defect.² Intracardiac extension of intravenous leiomyomatosis may result in pulmonary embolism, systemic embolization if involving the left side, and, rarely, sudden death.²

In patients with malignancy, differentiating between thrombosis and tumor is critical. These patients have a hypercoagulable state and a fourfold increase in thrombosis risk, and chemotherapy increases this risk even more.³ Although tissue pathology examination is important for differentiating thrombosis from tumor, visualization of the direct extension of the mass from the primary source into the heart through the inferior vena cava by ultrasonography, computed tomography, or magnetic resonance imaging may help in making this distinction.²