Applied Evidence

Each year, an estimated 25% to 30% of the US population suffers from dyspepsia.¹ Most self-treat with home remedies and over-the-counter products, but others seek medical care. Dyspepsia accounts for an estimated 2% to 5% of primary care visits annually,² mostly by patients who are found to have no organic, or structural, cause for their symptoms.^1,3

Compared with the general public, patients with functional dyspepsia have higher levels of anxiety, chronic tension, hostility, and hypochondriasis, and a tendency to be more pessimistic.

Such patients are said to have functional dyspepsia (FD), a category that applies to about two-thirds of those with dyspepsia.¹ A small number of cases are categorized as organic dyspepsia, indicating the presence of a clear structural or anatomic cause, such as an ulcer or mass. The remainder are said to have undifferentiated dyspepsia, which simply means that their signs and symptoms do not rise to the level for which further investigation is warranted and thus it is not known whether it is functional or organic.

There are many possible causes of FD, ranging from medications^3,4 to abnormal gastroduodenal motility^5,6 to Helicobacter pylori infection,⁷ and a comprehensive differential diagnosis. The first step in an investigation is to rule out red flags suggestive of gastrointestinal (GI) cancer or other serious disorders.

Patients with FD, like the vast majority of those you’ll treat in a primary care setting, suffer significant morbidity. Most have chronic symptoms, with intermittent flare-ups interspersed with periods of remission.⁸ In the text and dyspepsia treatment ALGORITHM^5,7-12 that follow, you’ll find an evidence-based patient management approach.

Symptoms and causes: What to look for

The primary symptoms of dyspepsia include bothersome postprandial fullness, early satiety, and epigastric pain and burning. To meet the Rome criteria for dyspepsia, these symptoms must have been present for the last 3 months and have had an onset ≥6 months prior to diagnosis.² Recurrent belching and nausea are also common, but are not included in the Rome diagnostic criteria.

Symptom severity is a poor predictor of the seriousness of the condition, however, and more intense symptoms are no more likely than milder cases to have an organic cause.^13,14 Indeed, anxiety is a common comorbidity in patients with FD and a risk factor for the diagnosis. Compared with the general public, patients with FD have been found to have higher levels of anxiety, chronic tension, hostility, and hypochondriasis, and a tendency to be more pessimistic.¹⁵

Possible causes of FD

While the etiology of organic dyspepsia is clear, the cause of FD is often far more difficult to determine.

Medication use should always be considered, as many types of drugs—including bisphosphonates, antibiotics, narcotics, steroids, iron, metformin, and nonsteroidal anti-inflammatory drugs (NSAIDs)—are associated with dyspepsia.^3,4

Gastroduodenal motility and accommodation, which has been found in numerous studies of patients with FD, is a proposed etiology.^5,6

Visceral hypersensitivity also appears to play a role. In one study of patients with severe dyspepsia, 87% of those with FD had a reduced or altered GI pain threshold, compared with 20% of those with organic dyspepsia.¹⁶

H pylori, commonly linked to peptic ulcer disease (PUD), is also associated with both organic dyspepsia and FD.^17,18 The gram-negative rod-shaped bacterium is present in approximately half of the population worldwide, but is more common in developing nations.⁷H pylori immunoglobulin G (IgG) is more prevalent in patients with dyspepsia, particularly in those younger than 30 years of age. The exact mechanism by which H pylori causes non-ulcerative dyspepsia is not clear, but inflammation, dysmotility, visceral hypersensitivity, and alteration of acid secretion have all been proposed.¹⁷

Dysfunctional intestinal epithelium is increasingly being considered in the pathophysiology of dyspepsia, among other conditions. Researchers theorize that certain foods, toxins, infections, and/or other stressors lead to changes in the structure and function of tight junctions, resulting in increased intestinal permeability.¹⁹ This in turn is thought to allow the outflow of antigens through the leaky epithelium and to stimulate an immune response—a process that may play a role in the increased GI inflammation or hypersensitivity associated with dyspepsia. The “leaky gut” theory may eventually lead to new ways to treat dyspepsia, but thus far, highquality evidence of the efficacy of treatments aimed at this mechanism is lacking.

A range of disorders included in the differential

Symptom severity is a poor predictor of the seriousness of dyspepsia; more intense symptoms are no more likely than milder cases to have an organic cause.

The primary differential diagnosis for dyspepsia includes gastroesophageal reflux disease (GERD), esophagitis, chronic PUD (including both gastric and duodenal ulcers), and malignancy. The differential may also include biliary disorder, pancreatitis, hepatitis, or other liver disease; chronic abdominal wall pain, irritable bowel syndrome, motility disorders, or infiltrative diseases of the stomach (eosinophilic gastritis, Crohn’s disease, sarcoidosis); celiac disease and food sensitivities/allergies, including gluten, lactose, and other intolerances; cardiac disease, including acute coronary syndrome, myocardial infarction, and arrhythmias; intestinal angina; small intestine bacterial overgrowth; heavy metal toxicity; and hypercalcemia.⁸

Ulcers are found in approximately 10% of patients undergoing evaluation for dyspepsia.⁸ Previously, PUD was almost exclusively due to H pylori infection. In developed countries, however, chronic use of NSAIDs, including aspirin, has increased, and is now responsible for most ulcer diseases.^20,21 The combination of H pylori infection and NSAID usage appears to be synergistic, with the risk of uncomplicated PUD estimated to be 17.5 times higher among those who test positive for H pylori and take NSAIDs vs a 3- to 4-fold increase in ulcer incidence among those with either of these risk factors alone.²²

The work-up starts with a search for red flags

Symptom severity is a poor predictor of the seriousness of dyspepsia; more intense symptoms are no more likely than milder cases to have an organic cause.

Evaluation of a patient with dyspepsia begins with a thorough history. Start by determining whether the patient has any red flags, or alarm features, that may be associated with a more serious condition—particularly an underlying malignancy. One or more of the following is an indication for an esophagogastroduodenoscopy (EGD):^5,8,12
• family and/or personal history of upper GI cancer
• unintended weight loss
• GI bleeding
• progressive dysphagia
• unexplained iron-deficiency anemia
• persistent vomiting
• palpable mass or lymphadenopathy
• jaundice.

The “leaky gut” theory may eventually lead to new ways to treat dyspepsia, but thus far, high-quality evidence of the efficacy of treatments aimed at this mechanism is lacking.

While it is important to rule out these red flags, they are poor predictors of malignancy.^23,24 With the exception of a single study, their positive predictive value was a mere 1%.⁸ Their usefulness lies in their ability to exclude malignancy, however; when none of these features is present, the negative predictive value for malignancy is >97%.⁸

Age is also a risk factor. In addition to red flags, EGD is recommended by the American Gastroenterological Association (AGA) for patients with new-onset dyspepsia who are 55 years or older—an age at which upper GI malignancy becomes more common. A repeat EGD is rarely indicated, unless Barrett’s esophagus or severe erosive esophagitis is found on the initial EGD.²⁵

Physical exam, H pylori evaluation follow

A physical examination of all patients presenting with symptoms suggestive of dyspepsia is crucial. While the exam is usually normal, it may reveal epigastric tenderness on abdominal palpation. Rebound tenderness, guarding, or evidence of other abnormalities should raise the prospect of alternative diagnoses. GERD, for example, has many symptoms in common with dyspepsia, but is a more likely diagnosis in a patient who has retrosternal burning discomfort and regurgitation and reports that symptoms worsen at night and when lying down.

Lab work has limited value. Although laboratory work is not specifically addressed in the AGA guidelines (except for H pylori testing), a complete blood count is a reasonable part of an initial evaluation of dyspepsia to check for anemia. Other routine blood work is not needed, but further lab testing may be warranted based on the history, exam, and differential diagnosis.

H pylori risk. Because of the association between dyspepsia and H pylori, evaluating the patient’s risk for infection with this bacterium, based primarily on his or her current and previous living conditions (TABLE 1),⁹ is the next step. Although a test for H pylori could be included in the initial work-up of all patients with dyspepsia, a better—and more cost-effective—strategy is to initially test only those at high risk. (More on testing and treating H pylori in a bit.)

Initiate acid suppression therapy for low-risk patients

First-line treatment for patients with dyspepsia who have no red flags for malignancy or other serious conditions and either are not at high risk for H pylori or are at high risk but have been tested for it and had negative results is a 4- to 8-week course of acid suppression therapy. Patients at low risk for H pylori should be tested for the bacterium only if therapy fails to alleviate their symptoms.⁹

H2RAs or PPIs? A look at the evidence

In a Cochrane review, both H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) were significantly more effective than placebo for treating FD.²⁶ However, H2RAs can lead to tachyphylaxis—an acute decrease in response to a drug—within 2 to 6 weeks, thus limiting their long-term efficacy.²⁷

Suspect gastroesophageal reflux disease, rather than dyspepsia, in a patient who has retrosternal burning and regurgitation that worsen when lying down.

PPIs appear to be more effective than H2RAs, and are the AGA’s acid suppression drug of choice.¹¹ The CADET study, a randomized controlled trial comparing PPIs (omeprazole 20 mg/d) with an H2RA (ranitidine 150 mg BID) and a prokinetic agent (cisapride 20 mg BID) as well as placebo for dyspepsia, found the PPI to be superior to the H2RA at 6 months.²⁸ In a systematic review, the number needed to treat with PPI therapy for improvement of dyspepsia symptoms was 9.²⁹

There is no specified time limit for the use of PPIs. AGA guidelines recommend that patients who respond to initial therapy stop treatment after 4 to 8 weeks.¹¹ If symptoms recur, another course of the same treatment is justified; if necessary, therapy can continue long term. However, patients should be made aware of the risk for vitamin deficiency, osteoporosis, and fracture, as well as arrhythmias, Clostridium difficile infection, and rebound upon abrupt discontinuation of PPIs.

When to test for H pylori ...

Empiric treatment for H pylori is not recommended. Thus, testing is indicated for patients who have risk factors for the bacterium or who fail to respond to acid suppression therapy. There are various ways to test for the presence of H pylori. Which test you choose depends, in part, on patient-specific factors.

Serology. IgG serology testing is extremely useful in patients who have never been diagnosed with H pylori. It is best suited for those who are currently taking proton pump inhibitors (PPIs) or who recently completed a course of antibiotics, since neither medication affects the results of the serology test.

Serology testing should not be used, however, for any patient who was previously diagnosed with or treated for H pylori, because this type of test cannot distinguish between an active or past infection. The IgG serology test has a sensitivity of 87% and a specificity of 67%.³⁰

Stool antigen. Stool tests using monoclonal antibodies to detect the presence of H pylori have a sensitivity of 87% to 92% and a specificity of 70%. Stool antigen is also an excellent post-treatment test to confirm that H pylori has been eradicated.³¹

Stool testing has some drawbacks, however. PPIs can decrease the sensitivity and should be discontinued at least 2 weeks prior to stool testing.³² In addition, a stool test for H pylori is not accurate if the patient has an acute GI bleed.

Urea breath testing. This is the most sensitive and specific test for active H pylori infection (90%-96% sensitivity and 88%-96% specificity).³³ PPIs can lower the sensitivity of the test, however, and are typically discontinued at least 2 weeks prior to testing. Urea breath testing, like stool testing, is an excellent way to confirm that H pylori has been eradicated after treatment. However, it is more expensive than other tests for H pylori and often inconvenient to obtain.¹³

An EGD is indicated for a patient who has failed to respond to acid suppression therapy and has a negative serology, stool antigen, or urea breath test for H pylori.

Biopsy-based testing for H pylori is performed with EGD and is therefore reserved for patients who have red flags or other indications of a need for invasive testing. There are 3 types of biopsy-based tests: urease (sensitivity, 70%-90%; specificity, 95%); histology (87%-92% and 70%, respectively); and culture (85%-88% and 69%, respectively). Overall, the specificity is slightly better than that of noninvasive testing, but the sensitivity can be lowered by recent use of PPIs, bismuth, or antibiotics.^12,34

... and how to treat it

H pylori infection is associated with an increased risk of noncardiac gastric adenocarcinoma, but a decreased risk of cardiac gastric adenocarcinoma and esophageal adenocarcinoma.^35,36 Thus, the potential to reduce the risk of gastric cancer is not considered an indication for H pylori treatment. The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

IgG serology testing should not be used for any patient who was previously diagnosed with, or treated for, H pylori because this type of test can’t distinguish between an active or past infection.

In a 2006 Cochrane Review, treating H pylori had a small but statistically significant benefit for patients with FD (NNT=14).³⁷ A 2011 study on the effects of H pylori eradication on symptoms and quality of life in primary care patients with FD revealed a 12.5% improvement in quality of life and a 10.6% improvement in symptoms.³⁸

The triple therapy regimen (a PPI + amoxicillin + clarithromycin) is the most common first-line H pylori treatment in the United States, and a good initial choice in regions in which clarithromycin resistance is low (TABLE 2).^39-44 The standard duration is 7 days. A 2013 Cochrane Review showed that a longer duration (14 days) increased the rate of eradication (82% vs 73%), but this remains controversial.³⁹ The addition of bismuth subsalicylate to the triple therapy regimen has been shown to increase the eradication rate of H pylori by approximately 10%.⁴⁵ Adding probiotics (saccharomyces or lactobacillus) appears to increase eradication rates, as well.⁴⁰

Sequential therapy consists of a 5-day course of treatment in which a PPI and amoxicillin are taken twice a day, followed by another 5-day course of a PPI, clarithromycin, and metronidazole. A recent meta-analysis of sequential therapy showed that it is superior to 7-day triple therapy but equivalent to 14-day triple therapy.⁴⁰

LOAD (levofloxacin, omeprazole, nitazoxanide, and doxycycline) therapy for 7 to 10 days can be used in place of triple therapy in areas of high resistance or for persistent H pylori. In one study, the H pylori eradication rate for a 7-day course of LOAD therapy—levofloxacin and doxycycline taken once a day, omeprazole before breakfast, and nitazoxanide twice daily—was 90% vs 73.3% for a 7-day course of triple therapy.⁴¹

Quadruple therapy has 2 variations: bismuth-based and non-bismuth (concomitant) therapy. The latter uses the base triple therapy and adds either metronidazole or tinidazole for 7 to 14 days. In a multicenter randomized trial, this concomitant therapy was found to have similar efficacy to sequential therapy.⁴²

The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

Bismuth-based quad therapy includes a PPI, bismuth, metronidazole, and tetracycline. A meta-analysis found it to have a higher rate of eradication than triple therapy for patients with antibiotic resistance.^43,44

For persistent H pylori, a PPI, levofloxacin, and amoxicillin for 10 days has been shown to be more effective and better tolerated than quadruple therapy.¹²

Confirmation is indicated when symptoms persist

If dyspepsia symptoms persist after H pylori treatment, it is reasonable to retest to confirm that the infection has in fact been eradicated. Confirmation is also indicated if the patient has an H pylori-associated ulcer or a prior history of gastric cancer.

Retesting should be performed at least 4 to 6 weeks after treatment is completed. If H pylori has not been eradicated, you can try another regimen. If retesting confirms eradication and symptoms persist, EGD with biopsy is indicated. Although EGD typically has a very low yield, even for patients with red flags, this invasive test often provides reassurance and increased satisfaction for patients with persistent symptoms.⁴⁶

More options for challenging cases

Managing FD is challenging when both initial acid suppression therapy and H pylori eradication fail. Unproven but low-risk treatments include modification of eating habits (eg, eating slower, not gulping food), reducing stress, discontinuing medications that may be related to symptoms, avoiding foods that seem to exacerbate symptoms, and cutting down or eliminating tobacco, caffeine, alcohol, and carbonated beverages.⁸ Bismuth salts have been shown to be superior to placebo for the treatment of dyspepsia.²⁵ Small studies have also demonstrated a favorable risk–benefit ratio for peppermint oil and caraway oil for the treatment of FD.⁴⁷ Prokinetics have shown efficacy compared with placebo, although a Cochrane review questioned their efficacy based on publication bias.²⁶

There is no good evidence of efficacy for over-the-counter antacids, such as TUMS, or for GI “cocktails” (antacid, antispasmotic, and lidocaine), sucralfate, psychological interventions (eg, cognitive behavioral therapy, relaxation therapy, or hypnosis), or antidepressants.^48,49 Several recent randomized controlled trials have shown the efficacy of acupuncture for the treatment of dyspepsia.^49,50 Ginger may also be helpful; it has been found to help with nausea in other GI conditions, but it’s uncertain whether it can help patients with dyspepsia.⁵¹

CORRESPONDENCE 
Michael Malone, MD, 845 Fishburn Road, Hershey, PA 17053; [email protected]

Each year, an estimated 25% to 30% of the US population suffers from dyspepsia.¹ Most self-treat with home remedies and over-the-counter products, but others seek medical care. Dyspepsia accounts for an estimated 2% to 5% of primary care visits annually,² mostly by patients who are found to have no organic, or structural, cause for their symptoms.^1,3

Compared with the general public, patients with functional dyspepsia have higher levels of anxiety, chronic tension, hostility, and hypochondriasis, and a tendency to be more pessimistic.

Such patients are said to have functional dyspepsia (FD), a category that applies to about two-thirds of those with dyspepsia.¹ A small number of cases are categorized as organic dyspepsia, indicating the presence of a clear structural or anatomic cause, such as an ulcer or mass. The remainder are said to have undifferentiated dyspepsia, which simply means that their signs and symptoms do not rise to the level for which further investigation is warranted and thus it is not known whether it is functional or organic.

There are many possible causes of FD, ranging from medications^3,4 to abnormal gastroduodenal motility^5,6 to Helicobacter pylori infection,⁷ and a comprehensive differential diagnosis. The first step in an investigation is to rule out red flags suggestive of gastrointestinal (GI) cancer or other serious disorders.

Patients with FD, like the vast majority of those you’ll treat in a primary care setting, suffer significant morbidity. Most have chronic symptoms, with intermittent flare-ups interspersed with periods of remission.⁸ In the text and dyspepsia treatment ALGORITHM^5,7-12 that follow, you’ll find an evidence-based patient management approach.

Symptoms and causes: What to look for

The primary symptoms of dyspepsia include bothersome postprandial fullness, early satiety, and epigastric pain and burning. To meet the Rome criteria for dyspepsia, these symptoms must have been present for the last 3 months and have had an onset ≥6 months prior to diagnosis.² Recurrent belching and nausea are also common, but are not included in the Rome diagnostic criteria.

Symptom severity is a poor predictor of the seriousness of the condition, however, and more intense symptoms are no more likely than milder cases to have an organic cause.^13,14 Indeed, anxiety is a common comorbidity in patients with FD and a risk factor for the diagnosis. Compared with the general public, patients with FD have been found to have higher levels of anxiety, chronic tension, hostility, and hypochondriasis, and a tendency to be more pessimistic.¹⁵

Possible causes of FD

While the etiology of organic dyspepsia is clear, the cause of FD is often far more difficult to determine.

Medication use should always be considered, as many types of drugs—including bisphosphonates, antibiotics, narcotics, steroids, iron, metformin, and nonsteroidal anti-inflammatory drugs (NSAIDs)—are associated with dyspepsia.^3,4

Gastroduodenal motility and accommodation, which has been found in numerous studies of patients with FD, is a proposed etiology.^5,6

Visceral hypersensitivity also appears to play a role. In one study of patients with severe dyspepsia, 87% of those with FD had a reduced or altered GI pain threshold, compared with 20% of those with organic dyspepsia.¹⁶

H pylori, commonly linked to peptic ulcer disease (PUD), is also associated with both organic dyspepsia and FD.^17,18 The gram-negative rod-shaped bacterium is present in approximately half of the population worldwide, but is more common in developing nations.⁷H pylori immunoglobulin G (IgG) is more prevalent in patients with dyspepsia, particularly in those younger than 30 years of age. The exact mechanism by which H pylori causes non-ulcerative dyspepsia is not clear, but inflammation, dysmotility, visceral hypersensitivity, and alteration of acid secretion have all been proposed.¹⁷

Dysfunctional intestinal epithelium is increasingly being considered in the pathophysiology of dyspepsia, among other conditions. Researchers theorize that certain foods, toxins, infections, and/or other stressors lead to changes in the structure and function of tight junctions, resulting in increased intestinal permeability.¹⁹ This in turn is thought to allow the outflow of antigens through the leaky epithelium and to stimulate an immune response—a process that may play a role in the increased GI inflammation or hypersensitivity associated with dyspepsia. The “leaky gut” theory may eventually lead to new ways to treat dyspepsia, but thus far, highquality evidence of the efficacy of treatments aimed at this mechanism is lacking.

A range of disorders included in the differential

Symptom severity is a poor predictor of the seriousness of dyspepsia; more intense symptoms are no more likely than milder cases to have an organic cause.

The primary differential diagnosis for dyspepsia includes gastroesophageal reflux disease (GERD), esophagitis, chronic PUD (including both gastric and duodenal ulcers), and malignancy. The differential may also include biliary disorder, pancreatitis, hepatitis, or other liver disease; chronic abdominal wall pain, irritable bowel syndrome, motility disorders, or infiltrative diseases of the stomach (eosinophilic gastritis, Crohn’s disease, sarcoidosis); celiac disease and food sensitivities/allergies, including gluten, lactose, and other intolerances; cardiac disease, including acute coronary syndrome, myocardial infarction, and arrhythmias; intestinal angina; small intestine bacterial overgrowth; heavy metal toxicity; and hypercalcemia.⁸

Ulcers are found in approximately 10% of patients undergoing evaluation for dyspepsia.⁸ Previously, PUD was almost exclusively due to H pylori infection. In developed countries, however, chronic use of NSAIDs, including aspirin, has increased, and is now responsible for most ulcer diseases.^20,21 The combination of H pylori infection and NSAID usage appears to be synergistic, with the risk of uncomplicated PUD estimated to be 17.5 times higher among those who test positive for H pylori and take NSAIDs vs a 3- to 4-fold increase in ulcer incidence among those with either of these risk factors alone.²²

The work-up starts with a search for red flags

Symptom severity is a poor predictor of the seriousness of dyspepsia; more intense symptoms are no more likely than milder cases to have an organic cause.

Evaluation of a patient with dyspepsia begins with a thorough history. Start by determining whether the patient has any red flags, or alarm features, that may be associated with a more serious condition—particularly an underlying malignancy. One or more of the following is an indication for an esophagogastroduodenoscopy (EGD):^5,8,12
• family and/or personal history of upper GI cancer
• unintended weight loss
• GI bleeding
• progressive dysphagia
• unexplained iron-deficiency anemia
• persistent vomiting
• palpable mass or lymphadenopathy
• jaundice.

The “leaky gut” theory may eventually lead to new ways to treat dyspepsia, but thus far, high-quality evidence of the efficacy of treatments aimed at this mechanism is lacking.

While it is important to rule out these red flags, they are poor predictors of malignancy.^23,24 With the exception of a single study, their positive predictive value was a mere 1%.⁸ Their usefulness lies in their ability to exclude malignancy, however; when none of these features is present, the negative predictive value for malignancy is >97%.⁸

Age is also a risk factor. In addition to red flags, EGD is recommended by the American Gastroenterological Association (AGA) for patients with new-onset dyspepsia who are 55 years or older—an age at which upper GI malignancy becomes more common. A repeat EGD is rarely indicated, unless Barrett’s esophagus or severe erosive esophagitis is found on the initial EGD.²⁵

Physical exam, H pylori evaluation follow

A physical examination of all patients presenting with symptoms suggestive of dyspepsia is crucial. While the exam is usually normal, it may reveal epigastric tenderness on abdominal palpation. Rebound tenderness, guarding, or evidence of other abnormalities should raise the prospect of alternative diagnoses. GERD, for example, has many symptoms in common with dyspepsia, but is a more likely diagnosis in a patient who has retrosternal burning discomfort and regurgitation and reports that symptoms worsen at night and when lying down.

Lab work has limited value. Although laboratory work is not specifically addressed in the AGA guidelines (except for H pylori testing), a complete blood count is a reasonable part of an initial evaluation of dyspepsia to check for anemia. Other routine blood work is not needed, but further lab testing may be warranted based on the history, exam, and differential diagnosis.

H pylori risk. Because of the association between dyspepsia and H pylori, evaluating the patient’s risk for infection with this bacterium, based primarily on his or her current and previous living conditions (TABLE 1),⁹ is the next step. Although a test for H pylori could be included in the initial work-up of all patients with dyspepsia, a better—and more cost-effective—strategy is to initially test only those at high risk. (More on testing and treating H pylori in a bit.)

Initiate acid suppression therapy for low-risk patients

First-line treatment for patients with dyspepsia who have no red flags for malignancy or other serious conditions and either are not at high risk for H pylori or are at high risk but have been tested for it and had negative results is a 4- to 8-week course of acid suppression therapy. Patients at low risk for H pylori should be tested for the bacterium only if therapy fails to alleviate their symptoms.⁹

H2RAs or PPIs? A look at the evidence

In a Cochrane review, both H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) were significantly more effective than placebo for treating FD.²⁶ However, H2RAs can lead to tachyphylaxis—an acute decrease in response to a drug—within 2 to 6 weeks, thus limiting their long-term efficacy.²⁷

Suspect gastroesophageal reflux disease, rather than dyspepsia, in a patient who has retrosternal burning and regurgitation that worsen when lying down.

PPIs appear to be more effective than H2RAs, and are the AGA’s acid suppression drug of choice.¹¹ The CADET study, a randomized controlled trial comparing PPIs (omeprazole 20 mg/d) with an H2RA (ranitidine 150 mg BID) and a prokinetic agent (cisapride 20 mg BID) as well as placebo for dyspepsia, found the PPI to be superior to the H2RA at 6 months.²⁸ In a systematic review, the number needed to treat with PPI therapy for improvement of dyspepsia symptoms was 9.²⁹

There is no specified time limit for the use of PPIs. AGA guidelines recommend that patients who respond to initial therapy stop treatment after 4 to 8 weeks.¹¹ If symptoms recur, another course of the same treatment is justified; if necessary, therapy can continue long term. However, patients should be made aware of the risk for vitamin deficiency, osteoporosis, and fracture, as well as arrhythmias, Clostridium difficile infection, and rebound upon abrupt discontinuation of PPIs.

When to test for H pylori ...

Empiric treatment for H pylori is not recommended. Thus, testing is indicated for patients who have risk factors for the bacterium or who fail to respond to acid suppression therapy. There are various ways to test for the presence of H pylori. Which test you choose depends, in part, on patient-specific factors.

Serology. IgG serology testing is extremely useful in patients who have never been diagnosed with H pylori. It is best suited for those who are currently taking proton pump inhibitors (PPIs) or who recently completed a course of antibiotics, since neither medication affects the results of the serology test.

Serology testing should not be used, however, for any patient who was previously diagnosed with or treated for H pylori, because this type of test cannot distinguish between an active or past infection. The IgG serology test has a sensitivity of 87% and a specificity of 67%.³⁰

Stool antigen. Stool tests using monoclonal antibodies to detect the presence of H pylori have a sensitivity of 87% to 92% and a specificity of 70%. Stool antigen is also an excellent post-treatment test to confirm that H pylori has been eradicated.³¹

Stool testing has some drawbacks, however. PPIs can decrease the sensitivity and should be discontinued at least 2 weeks prior to stool testing.³² In addition, a stool test for H pylori is not accurate if the patient has an acute GI bleed.

Urea breath testing. This is the most sensitive and specific test for active H pylori infection (90%-96% sensitivity and 88%-96% specificity).³³ PPIs can lower the sensitivity of the test, however, and are typically discontinued at least 2 weeks prior to testing. Urea breath testing, like stool testing, is an excellent way to confirm that H pylori has been eradicated after treatment. However, it is more expensive than other tests for H pylori and often inconvenient to obtain.¹³

An EGD is indicated for a patient who has failed to respond to acid suppression therapy and has a negative serology, stool antigen, or urea breath test for H pylori.

Biopsy-based testing for H pylori is performed with EGD and is therefore reserved for patients who have red flags or other indications of a need for invasive testing. There are 3 types of biopsy-based tests: urease (sensitivity, 70%-90%; specificity, 95%); histology (87%-92% and 70%, respectively); and culture (85%-88% and 69%, respectively). Overall, the specificity is slightly better than that of noninvasive testing, but the sensitivity can be lowered by recent use of PPIs, bismuth, or antibiotics.^12,34

... and how to treat it

H pylori infection is associated with an increased risk of noncardiac gastric adenocarcinoma, but a decreased risk of cardiac gastric adenocarcinoma and esophageal adenocarcinoma.^35,36 Thus, the potential to reduce the risk of gastric cancer is not considered an indication for H pylori treatment. The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

IgG serology testing should not be used for any patient who was previously diagnosed with, or treated for, H pylori because this type of test can’t distinguish between an active or past infection.

In a 2006 Cochrane Review, treating H pylori had a small but statistically significant benefit for patients with FD (NNT=14).³⁷ A 2011 study on the effects of H pylori eradication on symptoms and quality of life in primary care patients with FD revealed a 12.5% improvement in quality of life and a 10.6% improvement in symptoms.³⁸

The triple therapy regimen (a PPI + amoxicillin + clarithromycin) is the most common first-line H pylori treatment in the United States, and a good initial choice in regions in which clarithromycin resistance is low (TABLE 2).^39-44 The standard duration is 7 days. A 2013 Cochrane Review showed that a longer duration (14 days) increased the rate of eradication (82% vs 73%), but this remains controversial.³⁹ The addition of bismuth subsalicylate to the triple therapy regimen has been shown to increase the eradication rate of H pylori by approximately 10%.⁴⁵ Adding probiotics (saccharomyces or lactobacillus) appears to increase eradication rates, as well.⁴⁰

Sequential therapy consists of a 5-day course of treatment in which a PPI and amoxicillin are taken twice a day, followed by another 5-day course of a PPI, clarithromycin, and metronidazole. A recent meta-analysis of sequential therapy showed that it is superior to 7-day triple therapy but equivalent to 14-day triple therapy.⁴⁰

LOAD (levofloxacin, omeprazole, nitazoxanide, and doxycycline) therapy for 7 to 10 days can be used in place of triple therapy in areas of high resistance or for persistent H pylori. In one study, the H pylori eradication rate for a 7-day course of LOAD therapy—levofloxacin and doxycycline taken once a day, omeprazole before breakfast, and nitazoxanide twice daily—was 90% vs 73.3% for a 7-day course of triple therapy.⁴¹

Quadruple therapy has 2 variations: bismuth-based and non-bismuth (concomitant) therapy. The latter uses the base triple therapy and adds either metronidazole or tinidazole for 7 to 14 days. In a multicenter randomized trial, this concomitant therapy was found to have similar efficacy to sequential therapy.⁴²

The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

Bismuth-based quad therapy includes a PPI, bismuth, metronidazole, and tetracycline. A meta-analysis found it to have a higher rate of eradication than triple therapy for patients with antibiotic resistance.^43,44

For persistent H pylori, a PPI, levofloxacin, and amoxicillin for 10 days has been shown to be more effective and better tolerated than quadruple therapy.¹²

Confirmation is indicated when symptoms persist

If dyspepsia symptoms persist after H pylori treatment, it is reasonable to retest to confirm that the infection has in fact been eradicated. Confirmation is also indicated if the patient has an H pylori-associated ulcer or a prior history of gastric cancer.

Retesting should be performed at least 4 to 6 weeks after treatment is completed. If H pylori has not been eradicated, you can try another regimen. If retesting confirms eradication and symptoms persist, EGD with biopsy is indicated. Although EGD typically has a very low yield, even for patients with red flags, this invasive test often provides reassurance and increased satisfaction for patients with persistent symptoms.⁴⁶

More options for challenging cases

Managing FD is challenging when both initial acid suppression therapy and H pylori eradication fail. Unproven but low-risk treatments include modification of eating habits (eg, eating slower, not gulping food), reducing stress, discontinuing medications that may be related to symptoms, avoiding foods that seem to exacerbate symptoms, and cutting down or eliminating tobacco, caffeine, alcohol, and carbonated beverages.⁸ Bismuth salts have been shown to be superior to placebo for the treatment of dyspepsia.²⁵ Small studies have also demonstrated a favorable risk–benefit ratio for peppermint oil and caraway oil for the treatment of FD.⁴⁷ Prokinetics have shown efficacy compared with placebo, although a Cochrane review questioned their efficacy based on publication bias.²⁶

There is no good evidence of efficacy for over-the-counter antacids, such as TUMS, or for GI “cocktails” (antacid, antispasmotic, and lidocaine), sucralfate, psychological interventions (eg, cognitive behavioral therapy, relaxation therapy, or hypnosis), or antidepressants.^48,49 Several recent randomized controlled trials have shown the efficacy of acupuncture for the treatment of dyspepsia.^49,50 Ginger may also be helpful; it has been found to help with nausea in other GI conditions, but it’s uncertain whether it can help patients with dyspepsia.⁵¹

CORRESPONDENCE 
Michael Malone, MD, 845 Fishburn Road, Hershey, PA 17053; [email protected]

Each year, an estimated 25% to 30% of the US population suffers from dyspepsia.¹ Most self-treat with home remedies and over-the-counter products, but others seek medical care. Dyspepsia accounts for an estimated 2% to 5% of primary care visits annually,² mostly by patients who are found to have no organic, or structural, cause for their symptoms.^1,3

Compared with the general public, patients with functional dyspepsia have higher levels of anxiety, chronic tension, hostility, and hypochondriasis, and a tendency to be more pessimistic.

Such patients are said to have functional dyspepsia (FD), a category that applies to about two-thirds of those with dyspepsia.¹ A small number of cases are categorized as organic dyspepsia, indicating the presence of a clear structural or anatomic cause, such as an ulcer or mass. The remainder are said to have undifferentiated dyspepsia, which simply means that their signs and symptoms do not rise to the level for which further investigation is warranted and thus it is not known whether it is functional or organic.

There are many possible causes of FD, ranging from medications^3,4 to abnormal gastroduodenal motility^5,6 to Helicobacter pylori infection,⁷ and a comprehensive differential diagnosis. The first step in an investigation is to rule out red flags suggestive of gastrointestinal (GI) cancer or other serious disorders.

Patients with FD, like the vast majority of those you’ll treat in a primary care setting, suffer significant morbidity. Most have chronic symptoms, with intermittent flare-ups interspersed with periods of remission.⁸ In the text and dyspepsia treatment ALGORITHM^5,7-12 that follow, you’ll find an evidence-based patient management approach.

Symptoms and causes: What to look for

The primary symptoms of dyspepsia include bothersome postprandial fullness, early satiety, and epigastric pain and burning. To meet the Rome criteria for dyspepsia, these symptoms must have been present for the last 3 months and have had an onset ≥6 months prior to diagnosis.² Recurrent belching and nausea are also common, but are not included in the Rome diagnostic criteria.

Symptom severity is a poor predictor of the seriousness of the condition, however, and more intense symptoms are no more likely than milder cases to have an organic cause.^13,14 Indeed, anxiety is a common comorbidity in patients with FD and a risk factor for the diagnosis. Compared with the general public, patients with FD have been found to have higher levels of anxiety, chronic tension, hostility, and hypochondriasis, and a tendency to be more pessimistic.¹⁵

Possible causes of FD

While the etiology of organic dyspepsia is clear, the cause of FD is often far more difficult to determine.

Medication use should always be considered, as many types of drugs—including bisphosphonates, antibiotics, narcotics, steroids, iron, metformin, and nonsteroidal anti-inflammatory drugs (NSAIDs)—are associated with dyspepsia.^3,4

Gastroduodenal motility and accommodation, which has been found in numerous studies of patients with FD, is a proposed etiology.^5,6

Visceral hypersensitivity also appears to play a role. In one study of patients with severe dyspepsia, 87% of those with FD had a reduced or altered GI pain threshold, compared with 20% of those with organic dyspepsia.¹⁶

H pylori, commonly linked to peptic ulcer disease (PUD), is also associated with both organic dyspepsia and FD.^17,18 The gram-negative rod-shaped bacterium is present in approximately half of the population worldwide, but is more common in developing nations.⁷H pylori immunoglobulin G (IgG) is more prevalent in patients with dyspepsia, particularly in those younger than 30 years of age. The exact mechanism by which H pylori causes non-ulcerative dyspepsia is not clear, but inflammation, dysmotility, visceral hypersensitivity, and alteration of acid secretion have all been proposed.¹⁷

Dysfunctional intestinal epithelium is increasingly being considered in the pathophysiology of dyspepsia, among other conditions. Researchers theorize that certain foods, toxins, infections, and/or other stressors lead to changes in the structure and function of tight junctions, resulting in increased intestinal permeability.¹⁹ This in turn is thought to allow the outflow of antigens through the leaky epithelium and to stimulate an immune response—a process that may play a role in the increased GI inflammation or hypersensitivity associated with dyspepsia. The “leaky gut” theory may eventually lead to new ways to treat dyspepsia, but thus far, highquality evidence of the efficacy of treatments aimed at this mechanism is lacking.

A range of disorders included in the differential

Symptom severity is a poor predictor of the seriousness of dyspepsia; more intense symptoms are no more likely than milder cases to have an organic cause.

The primary differential diagnosis for dyspepsia includes gastroesophageal reflux disease (GERD), esophagitis, chronic PUD (including both gastric and duodenal ulcers), and malignancy. The differential may also include biliary disorder, pancreatitis, hepatitis, or other liver disease; chronic abdominal wall pain, irritable bowel syndrome, motility disorders, or infiltrative diseases of the stomach (eosinophilic gastritis, Crohn’s disease, sarcoidosis); celiac disease and food sensitivities/allergies, including gluten, lactose, and other intolerances; cardiac disease, including acute coronary syndrome, myocardial infarction, and arrhythmias; intestinal angina; small intestine bacterial overgrowth; heavy metal toxicity; and hypercalcemia.⁸

Ulcers are found in approximately 10% of patients undergoing evaluation for dyspepsia.⁸ Previously, PUD was almost exclusively due to H pylori infection. In developed countries, however, chronic use of NSAIDs, including aspirin, has increased, and is now responsible for most ulcer diseases.^20,21 The combination of H pylori infection and NSAID usage appears to be synergistic, with the risk of uncomplicated PUD estimated to be 17.5 times higher among those who test positive for H pylori and take NSAIDs vs a 3- to 4-fold increase in ulcer incidence among those with either of these risk factors alone.²²

The work-up starts with a search for red flags

Symptom severity is a poor predictor of the seriousness of dyspepsia; more intense symptoms are no more likely than milder cases to have an organic cause.

Evaluation of a patient with dyspepsia begins with a thorough history. Start by determining whether the patient has any red flags, or alarm features, that may be associated with a more serious condition—particularly an underlying malignancy. One or more of the following is an indication for an esophagogastroduodenoscopy (EGD):^5,8,12
• family and/or personal history of upper GI cancer
• unintended weight loss
• GI bleeding
• progressive dysphagia
• unexplained iron-deficiency anemia
• persistent vomiting
• palpable mass or lymphadenopathy
• jaundice.

The “leaky gut” theory may eventually lead to new ways to treat dyspepsia, but thus far, high-quality evidence of the efficacy of treatments aimed at this mechanism is lacking.

While it is important to rule out these red flags, they are poor predictors of malignancy.^23,24 With the exception of a single study, their positive predictive value was a mere 1%.⁸ Their usefulness lies in their ability to exclude malignancy, however; when none of these features is present, the negative predictive value for malignancy is >97%.⁸

Age is also a risk factor. In addition to red flags, EGD is recommended by the American Gastroenterological Association (AGA) for patients with new-onset dyspepsia who are 55 years or older—an age at which upper GI malignancy becomes more common. A repeat EGD is rarely indicated, unless Barrett’s esophagus or severe erosive esophagitis is found on the initial EGD.²⁵

Physical exam, H pylori evaluation follow

A physical examination of all patients presenting with symptoms suggestive of dyspepsia is crucial. While the exam is usually normal, it may reveal epigastric tenderness on abdominal palpation. Rebound tenderness, guarding, or evidence of other abnormalities should raise the prospect of alternative diagnoses. GERD, for example, has many symptoms in common with dyspepsia, but is a more likely diagnosis in a patient who has retrosternal burning discomfort and regurgitation and reports that symptoms worsen at night and when lying down.

Lab work has limited value. Although laboratory work is not specifically addressed in the AGA guidelines (except for H pylori testing), a complete blood count is a reasonable part of an initial evaluation of dyspepsia to check for anemia. Other routine blood work is not needed, but further lab testing may be warranted based on the history, exam, and differential diagnosis.

H pylori risk. Because of the association between dyspepsia and H pylori, evaluating the patient’s risk for infection with this bacterium, based primarily on his or her current and previous living conditions (TABLE 1),⁹ is the next step. Although a test for H pylori could be included in the initial work-up of all patients with dyspepsia, a better—and more cost-effective—strategy is to initially test only those at high risk. (More on testing and treating H pylori in a bit.)

Initiate acid suppression therapy for low-risk patients

First-line treatment for patients with dyspepsia who have no red flags for malignancy or other serious conditions and either are not at high risk for H pylori or are at high risk but have been tested for it and had negative results is a 4- to 8-week course of acid suppression therapy. Patients at low risk for H pylori should be tested for the bacterium only if therapy fails to alleviate their symptoms.⁹

H2RAs or PPIs? A look at the evidence

In a Cochrane review, both H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) were significantly more effective than placebo for treating FD.²⁶ However, H2RAs can lead to tachyphylaxis—an acute decrease in response to a drug—within 2 to 6 weeks, thus limiting their long-term efficacy.²⁷

Suspect gastroesophageal reflux disease, rather than dyspepsia, in a patient who has retrosternal burning and regurgitation that worsen when lying down.

PPIs appear to be more effective than H2RAs, and are the AGA’s acid suppression drug of choice.¹¹ The CADET study, a randomized controlled trial comparing PPIs (omeprazole 20 mg/d) with an H2RA (ranitidine 150 mg BID) and a prokinetic agent (cisapride 20 mg BID) as well as placebo for dyspepsia, found the PPI to be superior to the H2RA at 6 months.²⁸ In a systematic review, the number needed to treat with PPI therapy for improvement of dyspepsia symptoms was 9.²⁹

There is no specified time limit for the use of PPIs. AGA guidelines recommend that patients who respond to initial therapy stop treatment after 4 to 8 weeks.¹¹ If symptoms recur, another course of the same treatment is justified; if necessary, therapy can continue long term. However, patients should be made aware of the risk for vitamin deficiency, osteoporosis, and fracture, as well as arrhythmias, Clostridium difficile infection, and rebound upon abrupt discontinuation of PPIs.

When to test for H pylori ...

Empiric treatment for H pylori is not recommended. Thus, testing is indicated for patients who have risk factors for the bacterium or who fail to respond to acid suppression therapy. There are various ways to test for the presence of H pylori. Which test you choose depends, in part, on patient-specific factors.

Serology. IgG serology testing is extremely useful in patients who have never been diagnosed with H pylori. It is best suited for those who are currently taking proton pump inhibitors (PPIs) or who recently completed a course of antibiotics, since neither medication affects the results of the serology test.

Serology testing should not be used, however, for any patient who was previously diagnosed with or treated for H pylori, because this type of test cannot distinguish between an active or past infection. The IgG serology test has a sensitivity of 87% and a specificity of 67%.³⁰

Stool antigen. Stool tests using monoclonal antibodies to detect the presence of H pylori have a sensitivity of 87% to 92% and a specificity of 70%. Stool antigen is also an excellent post-treatment test to confirm that H pylori has been eradicated.³¹

Stool testing has some drawbacks, however. PPIs can decrease the sensitivity and should be discontinued at least 2 weeks prior to stool testing.³² In addition, a stool test for H pylori is not accurate if the patient has an acute GI bleed.

Urea breath testing. This is the most sensitive and specific test for active H pylori infection (90%-96% sensitivity and 88%-96% specificity).³³ PPIs can lower the sensitivity of the test, however, and are typically discontinued at least 2 weeks prior to testing. Urea breath testing, like stool testing, is an excellent way to confirm that H pylori has been eradicated after treatment. However, it is more expensive than other tests for H pylori and often inconvenient to obtain.¹³

An EGD is indicated for a patient who has failed to respond to acid suppression therapy and has a negative serology, stool antigen, or urea breath test for H pylori.

Biopsy-based testing for H pylori is performed with EGD and is therefore reserved for patients who have red flags or other indications of a need for invasive testing. There are 3 types of biopsy-based tests: urease (sensitivity, 70%-90%; specificity, 95%); histology (87%-92% and 70%, respectively); and culture (85%-88% and 69%, respectively). Overall, the specificity is slightly better than that of noninvasive testing, but the sensitivity can be lowered by recent use of PPIs, bismuth, or antibiotics.^12,34

... and how to treat it

H pylori infection is associated with an increased risk of noncardiac gastric adenocarcinoma, but a decreased risk of cardiac gastric adenocarcinoma and esophageal adenocarcinoma.^35,36 Thus, the potential to reduce the risk of gastric cancer is not considered an indication for H pylori treatment. The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

IgG serology testing should not be used for any patient who was previously diagnosed with, or treated for, H pylori because this type of test can’t distinguish between an active or past infection.

In a 2006 Cochrane Review, treating H pylori had a small but statistically significant benefit for patients with FD (NNT=14).³⁷ A 2011 study on the effects of H pylori eradication on symptoms and quality of life in primary care patients with FD revealed a 12.5% improvement in quality of life and a 10.6% improvement in symptoms.³⁸

The triple therapy regimen (a PPI + amoxicillin + clarithromycin) is the most common first-line H pylori treatment in the United States, and a good initial choice in regions in which clarithromycin resistance is low (TABLE 2).^39-44 The standard duration is 7 days. A 2013 Cochrane Review showed that a longer duration (14 days) increased the rate of eradication (82% vs 73%), but this remains controversial.³⁹ The addition of bismuth subsalicylate to the triple therapy regimen has been shown to increase the eradication rate of H pylori by approximately 10%.⁴⁵ Adding probiotics (saccharomyces or lactobacillus) appears to increase eradication rates, as well.⁴⁰

Sequential therapy consists of a 5-day course of treatment in which a PPI and amoxicillin are taken twice a day, followed by another 5-day course of a PPI, clarithromycin, and metronidazole. A recent meta-analysis of sequential therapy showed that it is superior to 7-day triple therapy but equivalent to 14-day triple therapy.⁴⁰

LOAD (levofloxacin, omeprazole, nitazoxanide, and doxycycline) therapy for 7 to 10 days can be used in place of triple therapy in areas of high resistance or for persistent H pylori. In one study, the H pylori eradication rate for a 7-day course of LOAD therapy—levofloxacin and doxycycline taken once a day, omeprazole before breakfast, and nitazoxanide twice daily—was 90% vs 73.3% for a 7-day course of triple therapy.⁴¹

Quadruple therapy has 2 variations: bismuth-based and non-bismuth (concomitant) therapy. The latter uses the base triple therapy and adds either metronidazole or tinidazole for 7 to 14 days. In a multicenter randomized trial, this concomitant therapy was found to have similar efficacy to sequential therapy.⁴²

The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

Bismuth-based quad therapy includes a PPI, bismuth, metronidazole, and tetracycline. A meta-analysis found it to have a higher rate of eradication than triple therapy for patients with antibiotic resistance.^43,44

For persistent H pylori, a PPI, levofloxacin, and amoxicillin for 10 days has been shown to be more effective and better tolerated than quadruple therapy.¹²

Confirmation is indicated when symptoms persist

If dyspepsia symptoms persist after H pylori treatment, it is reasonable to retest to confirm that the infection has in fact been eradicated. Confirmation is also indicated if the patient has an H pylori-associated ulcer or a prior history of gastric cancer.

Retesting should be performed at least 4 to 6 weeks after treatment is completed. If H pylori has not been eradicated, you can try another regimen. If retesting confirms eradication and symptoms persist, EGD with biopsy is indicated. Although EGD typically has a very low yield, even for patients with red flags, this invasive test often provides reassurance and increased satisfaction for patients with persistent symptoms.⁴⁶

More options for challenging cases

Managing FD is challenging when both initial acid suppression therapy and H pylori eradication fail. Unproven but low-risk treatments include modification of eating habits (eg, eating slower, not gulping food), reducing stress, discontinuing medications that may be related to symptoms, avoiding foods that seem to exacerbate symptoms, and cutting down or eliminating tobacco, caffeine, alcohol, and carbonated beverages.⁸ Bismuth salts have been shown to be superior to placebo for the treatment of dyspepsia.²⁵ Small studies have also demonstrated a favorable risk–benefit ratio for peppermint oil and caraway oil for the treatment of FD.⁴⁷ Prokinetics have shown efficacy compared with placebo, although a Cochrane review questioned their efficacy based on publication bias.²⁶

There is no good evidence of efficacy for over-the-counter antacids, such as TUMS, or for GI “cocktails” (antacid, antispasmotic, and lidocaine), sucralfate, psychological interventions (eg, cognitive behavioral therapy, relaxation therapy, or hypnosis), or antidepressants.^48,49 Several recent randomized controlled trials have shown the efficacy of acupuncture for the treatment of dyspepsia.^49,50 Ginger may also be helpful; it has been found to help with nausea in other GI conditions, but it’s uncertain whether it can help patients with dyspepsia.⁵¹

CORRESPONDENCE 
Michael Malone, MD, 845 Fishburn Road, Hershey, PA 17053; [email protected]

For well over a century, the periodic health exam has been associated with the delivery of preventive services¹—a model widely accepted by physicians and patients alike. Approximately 8% of ambulatory care visits are for check-ups, and more than 20% of US residents schedule a health exam annually.²

Periodic health exams, however, do not result in optimal preventive care. Evidence suggests that important preventive services, such as dietary counseling, occur at only 8% of such visits; that just 10 seconds, on average, is devoted to smoking cessation; and that 80% of the preventive services patients receive are delivered outside of scheduled health exams.² Because physicians and patients alike understandably prioritize acute problems, any discussion of health maintenance issues during a periodic check-up is likely to occur despite the visit’s agenda, not as part of it.^3-7

Primary care physicians and practices are increasingly being held accountable for their performance on preventive measures. With that in mind, being familiar with evidence-based guidelines relating to the delivery of preventive services in ambulatory care settings, such as those developed by the US Preventive Services Task Force (USPSTF),⁸ is crucial. Identifying elements of the chronic care model that can be effectively applied to preventive care—and recognizing that the reactive acute care model is ineffective for both chronic illness and preventive services—is essential, as well.

Preventive care that's evidence-based

Good practice guidelines should have the following features, according to the Institute of Medicine:⁹
• Validity. Application would lead to the desired health and cost outcomes.
• Reliability/reproducibility. Others using the same data/interpretation would reach the same conclusion.
• Clinical applicability. Patient populations are appropriately defined.
• Clinical flexibility. Known or generally expected exceptions are identified.
• Clarity. Guideline uses unambiguous language with precise definitions.
• Multidisciplinary process. Developed with the participation of all key stakeholders.
• Scheduled review. Periodically reviewed and revised to incorporate new evidence/changing consensus.
• Documentation. Procedures used in development are well documented.

It’s estimated that a primary care physician with an average-sized patient panel would need an additional 7.4 hours per day to achieve 100% compliance with all of the USPSTF recommendations.

The USPSTF guidelines are consistent with these attributes.⁸

Some brief interventions fail

Guidelines are useful as practice standards for establishing preventive care goals, but their existence alone does not ensure the delivery of high-quality preventive services in an office setting. One key factor is time. It is estimated that a primary care physician with an average-sized patient panel would require an additional 7.4 hours per day to achieve 100% compliance with all of the USPSTF recommendations.¹⁰

Counseling, in particular, is an intervention that may be more effective in theory than in practice. Evidence suggests that even when primary care providers are trained in preventive counseling (and many are not), many brief interventions are not effective at creating sustained behavior change or health improvement.¹¹

Others are effective

That’s not to say that there’s little that can be done. Use of standing orders for influenza vaccination is one example of an effective and easily implemented preventive measure that requires little or no additional physician time. Yet some doctors are resistant, fearing loss of control or lawsuits. In fact, the National Vaccine Injury Compensation Program specifically provides protection against vaccinerelated malpractice claims.¹² A standing order for office staff to arrange a screening mammogram is another effective intervention; it has been shown to improve screening rates by as much as 30%.¹³

Lessons from chronic illness management

Chronic illness care and preventive care have much in common.¹⁴ Both acknowledge the need for proactive screening and counseling to bring about behavior change. In addition, both require ongoing care and follow-up, as well as depend on links to community resources. And finally, both are resource-intensive—too resource-intensive, some say, to be delivered in a cost-effective manner.

The Chronic Care Model has been proposed as a framework for improving preventive services (TABLE).^15,16 Evidence suggests adopting some key components of chronic care can lead to significant gains in the delivery of preventive care, with the largest improvement seen when multiple components are used simultaneously.^17-20

Self-management support. A growing body of evidence shows that self-management activities are associated with improved outcomes.²¹ Instituting a peer support group for pregnant women at a federally qualified health center, for example, led to a 7% absolute risk reduction in preterm births.²²

Not all efforts to encourage self-management are effective, however, and evaluation is crucial to determine what works. In one large-scale trial, the use of patient reminder cards to facilitate a reduction in health risk behaviors such as tobacco use, risky drinking, unhealthy dietary patterns, and physical inactivity led to fewer health risk assessments being performed, fewer individual counseling encounters, and no change in these behaviors.²³

Decision support. Clinical decision support systems, which generate patient-specific evidence-based assessments and/or recommendations that are actionable as part of the workflow at the point of care, have been found to improve care.^24,25 An example of this is a prompt that reminds the physician to discuss chemoprevention with a patient at high risk for breast cancer.

Delivery system design. The patient-centered medical home (PCMH) is a well-known example of a redesign of health care delivery.²⁶ Conversion to this model is associated with a small positive effect on preventive interventions.²⁷ However, the persistence of a fee-for-service payment system—which does not include physician reimbursement for some of the added services incorporated into the PCMH—limits the implementation of the PCMH model.²⁸

Many practices are improving health care delivery by using nonphysicians for various tasks related to preventive care. Care managers, for example, typically have smaller caseloads and focus on reducing unnecessary treatment for patients with high-risk conditions, such as congestive heart failure, while patient navigators generally have less clinical expertise but more knowledge of community services.

In one study, practice-initiated phone conversations with nonphysicians increased colorectal cancer screening by up to 40%.²⁹ And in one pilot program, the use of ancillary providers led to an increase in colorectal cancer screening by as much as 123%.³⁰ The human touch seems to be key to the success of these interventions. Passive reminders, such as videos being shown on waiting room televisions, have not proven to be effective.³¹ 

Clinical information systems. Early on, the power of electronic health records (EHRs) to improve practices’ delivery of preventive services was recognized. As early as 1995, the use of a reminder system to highlight such services during acute care visits was linked to improvements in counseling about smoking cessation and higher rates of cervical cancer screening, among other preventive measures.^32,33 Overall, the use of EHRs alone has been shown to improve rates of preventive services by as much as 66%, with most practices reporting improvements of at least 20%.³⁴

Use of standing orders for influenza vaccination is one example of an effective and easily implemented preventive measure that requires little or no additional physician time.

Today, EHRs that are Meaningful Use Stage 2-compliant have the tools needed to improve care. Requirements include the ability to generate patient registries of all those with a given disease and to identify patients on the registry who have not received needed care.³⁵ To improve preventive care, registries should focus on the mitigation of risk factors, such as identifying—and contacting—patients with diabetes who are in need of, or overdue for, an annual eye exam.

Trials using the registry function, in combination with automated messaging to deliver targeted information to various patient groups (identified by the demographic information available from the EHR), are ongoing.

Community resources. Many clinicians have informal referral relationships with community organizations, such as the YMCA. Physician practices that establish links to community resources have the potential to have a large effect on unhealthy behaviors. (See “Putting theory into practice: 2 cases”.) However, a systematic review found that, while evidence to support such connections is mainly positive, research is limited and further evaluation is needed.³⁶

The Practical Playbook (practicalplaybook.org)³⁷ developed by the deBeaumont Foundation, Duke Department of Community and Family Medicine, and the Centers for Disease Control and Prevention, offers concrete examples of how physician practices are linking with community resources to improve the health of the population. For example, Duke University’s “Just for Us” program provides in-home chronic illness care to 350 high-risk elderly individuals. The LATCH program connects thousands of Latino immigrants to health care services and culturally and linguistically appropriate health education classes.³⁷

Growing emphasis on quality

Systemic changes in the US health care system are occurring rapidly, with an emphasis on quality and improved outcomes. Many physicians are now required to submit data to external agencies for payment, and much of the data is grounded in preventive standards. Medicare’s Physicians Quality Reporting System requires that all Medicare providers provide data on preventive and chronic illness care. Rates of vaccination, obesity screening, and tobacco use screening are examples of preventive services that will be reported publicly on the Centers for Medicare & Medicaid Services’ Physician Compare Web site.³⁸

Physicians who work in accountable care organizations are required to meet quality standards on the delivery of certain preventive services, including breast cancer screening, colorectal cancer screening, influenza and pneumonia immunization, body mass index screening and follow-up, tobacco use screening and cessation intervention, screening for high blood pressure and followup, and screening for clinical depression and follow-up.³⁹ As patients discover that the Affordable Care Act mandates that preventive services be covered with no cost sharing, they are likely to become more receptive to physician attempts to provide them.^40,41

CORRESPONDENCE
Gerald Liu, MD, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604-3207; [email protected]

For well over a century, the periodic health exam has been associated with the delivery of preventive services¹—a model widely accepted by physicians and patients alike. Approximately 8% of ambulatory care visits are for check-ups, and more than 20% of US residents schedule a health exam annually.²

Periodic health exams, however, do not result in optimal preventive care. Evidence suggests that important preventive services, such as dietary counseling, occur at only 8% of such visits; that just 10 seconds, on average, is devoted to smoking cessation; and that 80% of the preventive services patients receive are delivered outside of scheduled health exams.² Because physicians and patients alike understandably prioritize acute problems, any discussion of health maintenance issues during a periodic check-up is likely to occur despite the visit’s agenda, not as part of it.^3-7

Primary care physicians and practices are increasingly being held accountable for their performance on preventive measures. With that in mind, being familiar with evidence-based guidelines relating to the delivery of preventive services in ambulatory care settings, such as those developed by the US Preventive Services Task Force (USPSTF),⁸ is crucial. Identifying elements of the chronic care model that can be effectively applied to preventive care—and recognizing that the reactive acute care model is ineffective for both chronic illness and preventive services—is essential, as well.

Preventive care that's evidence-based

Good practice guidelines should have the following features, according to the Institute of Medicine:⁹
• Validity. Application would lead to the desired health and cost outcomes.
• Reliability/reproducibility. Others using the same data/interpretation would reach the same conclusion.
• Clinical applicability. Patient populations are appropriately defined.
• Clinical flexibility. Known or generally expected exceptions are identified.
• Clarity. Guideline uses unambiguous language with precise definitions.
• Multidisciplinary process. Developed with the participation of all key stakeholders.
• Scheduled review. Periodically reviewed and revised to incorporate new evidence/changing consensus.
• Documentation. Procedures used in development are well documented.

It’s estimated that a primary care physician with an average-sized patient panel would need an additional 7.4 hours per day to achieve 100% compliance with all of the USPSTF recommendations.

The USPSTF guidelines are consistent with these attributes.⁸

Some brief interventions fail

Guidelines are useful as practice standards for establishing preventive care goals, but their existence alone does not ensure the delivery of high-quality preventive services in an office setting. One key factor is time. It is estimated that a primary care physician with an average-sized patient panel would require an additional 7.4 hours per day to achieve 100% compliance with all of the USPSTF recommendations.¹⁰

Counseling, in particular, is an intervention that may be more effective in theory than in practice. Evidence suggests that even when primary care providers are trained in preventive counseling (and many are not), many brief interventions are not effective at creating sustained behavior change or health improvement.¹¹

Others are effective

That’s not to say that there’s little that can be done. Use of standing orders for influenza vaccination is one example of an effective and easily implemented preventive measure that requires little or no additional physician time. Yet some doctors are resistant, fearing loss of control or lawsuits. In fact, the National Vaccine Injury Compensation Program specifically provides protection against vaccinerelated malpractice claims.¹² A standing order for office staff to arrange a screening mammogram is another effective intervention; it has been shown to improve screening rates by as much as 30%.¹³

Lessons from chronic illness management

Chronic illness care and preventive care have much in common.¹⁴ Both acknowledge the need for proactive screening and counseling to bring about behavior change. In addition, both require ongoing care and follow-up, as well as depend on links to community resources. And finally, both are resource-intensive—too resource-intensive, some say, to be delivered in a cost-effective manner.

The Chronic Care Model has been proposed as a framework for improving preventive services (TABLE).^15,16 Evidence suggests adopting some key components of chronic care can lead to significant gains in the delivery of preventive care, with the largest improvement seen when multiple components are used simultaneously.^17-20

Self-management support. A growing body of evidence shows that self-management activities are associated with improved outcomes.²¹ Instituting a peer support group for pregnant women at a federally qualified health center, for example, led to a 7% absolute risk reduction in preterm births.²²

Not all efforts to encourage self-management are effective, however, and evaluation is crucial to determine what works. In one large-scale trial, the use of patient reminder cards to facilitate a reduction in health risk behaviors such as tobacco use, risky drinking, unhealthy dietary patterns, and physical inactivity led to fewer health risk assessments being performed, fewer individual counseling encounters, and no change in these behaviors.²³

Decision support. Clinical decision support systems, which generate patient-specific evidence-based assessments and/or recommendations that are actionable as part of the workflow at the point of care, have been found to improve care.^24,25 An example of this is a prompt that reminds the physician to discuss chemoprevention with a patient at high risk for breast cancer.

Delivery system design. The patient-centered medical home (PCMH) is a well-known example of a redesign of health care delivery.²⁶ Conversion to this model is associated with a small positive effect on preventive interventions.²⁷ However, the persistence of a fee-for-service payment system—which does not include physician reimbursement for some of the added services incorporated into the PCMH—limits the implementation of the PCMH model.²⁸

Many practices are improving health care delivery by using nonphysicians for various tasks related to preventive care. Care managers, for example, typically have smaller caseloads and focus on reducing unnecessary treatment for patients with high-risk conditions, such as congestive heart failure, while patient navigators generally have less clinical expertise but more knowledge of community services.

In one study, practice-initiated phone conversations with nonphysicians increased colorectal cancer screening by up to 40%.²⁹ And in one pilot program, the use of ancillary providers led to an increase in colorectal cancer screening by as much as 123%.³⁰ The human touch seems to be key to the success of these interventions. Passive reminders, such as videos being shown on waiting room televisions, have not proven to be effective.³¹ 

Clinical information systems. Early on, the power of electronic health records (EHRs) to improve practices’ delivery of preventive services was recognized. As early as 1995, the use of a reminder system to highlight such services during acute care visits was linked to improvements in counseling about smoking cessation and higher rates of cervical cancer screening, among other preventive measures.^32,33 Overall, the use of EHRs alone has been shown to improve rates of preventive services by as much as 66%, with most practices reporting improvements of at least 20%.³⁴

Use of standing orders for influenza vaccination is one example of an effective and easily implemented preventive measure that requires little or no additional physician time.

Today, EHRs that are Meaningful Use Stage 2-compliant have the tools needed to improve care. Requirements include the ability to generate patient registries of all those with a given disease and to identify patients on the registry who have not received needed care.³⁵ To improve preventive care, registries should focus on the mitigation of risk factors, such as identifying—and contacting—patients with diabetes who are in need of, or overdue for, an annual eye exam.

Trials using the registry function, in combination with automated messaging to deliver targeted information to various patient groups (identified by the demographic information available from the EHR), are ongoing.

Community resources. Many clinicians have informal referral relationships with community organizations, such as the YMCA. Physician practices that establish links to community resources have the potential to have a large effect on unhealthy behaviors. (See “Putting theory into practice: 2 cases”.) However, a systematic review found that, while evidence to support such connections is mainly positive, research is limited and further evaluation is needed.³⁶

The Practical Playbook (practicalplaybook.org)³⁷ developed by the deBeaumont Foundation, Duke Department of Community and Family Medicine, and the Centers for Disease Control and Prevention, offers concrete examples of how physician practices are linking with community resources to improve the health of the population. For example, Duke University’s “Just for Us” program provides in-home chronic illness care to 350 high-risk elderly individuals. The LATCH program connects thousands of Latino immigrants to health care services and culturally and linguistically appropriate health education classes.³⁷

Growing emphasis on quality

Systemic changes in the US health care system are occurring rapidly, with an emphasis on quality and improved outcomes. Many physicians are now required to submit data to external agencies for payment, and much of the data is grounded in preventive standards. Medicare’s Physicians Quality Reporting System requires that all Medicare providers provide data on preventive and chronic illness care. Rates of vaccination, obesity screening, and tobacco use screening are examples of preventive services that will be reported publicly on the Centers for Medicare & Medicaid Services’ Physician Compare Web site.³⁸

Physicians who work in accountable care organizations are required to meet quality standards on the delivery of certain preventive services, including breast cancer screening, colorectal cancer screening, influenza and pneumonia immunization, body mass index screening and follow-up, tobacco use screening and cessation intervention, screening for high blood pressure and followup, and screening for clinical depression and follow-up.³⁹ As patients discover that the Affordable Care Act mandates that preventive services be covered with no cost sharing, they are likely to become more receptive to physician attempts to provide them.^40,41

CORRESPONDENCE
Gerald Liu, MD, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604-3207; [email protected]

For well over a century, the periodic health exam has been associated with the delivery of preventive services¹—a model widely accepted by physicians and patients alike. Approximately 8% of ambulatory care visits are for check-ups, and more than 20% of US residents schedule a health exam annually.²

Periodic health exams, however, do not result in optimal preventive care. Evidence suggests that important preventive services, such as dietary counseling, occur at only 8% of such visits; that just 10 seconds, on average, is devoted to smoking cessation; and that 80% of the preventive services patients receive are delivered outside of scheduled health exams.² Because physicians and patients alike understandably prioritize acute problems, any discussion of health maintenance issues during a periodic check-up is likely to occur despite the visit’s agenda, not as part of it.^3-7

Primary care physicians and practices are increasingly being held accountable for their performance on preventive measures. With that in mind, being familiar with evidence-based guidelines relating to the delivery of preventive services in ambulatory care settings, such as those developed by the US Preventive Services Task Force (USPSTF),⁸ is crucial. Identifying elements of the chronic care model that can be effectively applied to preventive care—and recognizing that the reactive acute care model is ineffective for both chronic illness and preventive services—is essential, as well.

Preventive care that's evidence-based

Good practice guidelines should have the following features, according to the Institute of Medicine:⁹
• Validity. Application would lead to the desired health and cost outcomes.
• Reliability/reproducibility. Others using the same data/interpretation would reach the same conclusion.
• Clinical applicability. Patient populations are appropriately defined.
• Clinical flexibility. Known or generally expected exceptions are identified.
• Clarity. Guideline uses unambiguous language with precise definitions.
• Multidisciplinary process. Developed with the participation of all key stakeholders.
• Scheduled review. Periodically reviewed and revised to incorporate new evidence/changing consensus.
• Documentation. Procedures used in development are well documented.

It’s estimated that a primary care physician with an average-sized patient panel would need an additional 7.4 hours per day to achieve 100% compliance with all of the USPSTF recommendations.

The USPSTF guidelines are consistent with these attributes.⁸

Some brief interventions fail

Guidelines are useful as practice standards for establishing preventive care goals, but their existence alone does not ensure the delivery of high-quality preventive services in an office setting. One key factor is time. It is estimated that a primary care physician with an average-sized patient panel would require an additional 7.4 hours per day to achieve 100% compliance with all of the USPSTF recommendations.¹⁰

Counseling, in particular, is an intervention that may be more effective in theory than in practice. Evidence suggests that even when primary care providers are trained in preventive counseling (and many are not), many brief interventions are not effective at creating sustained behavior change or health improvement.¹¹

Others are effective

That’s not to say that there’s little that can be done. Use of standing orders for influenza vaccination is one example of an effective and easily implemented preventive measure that requires little or no additional physician time. Yet some doctors are resistant, fearing loss of control or lawsuits. In fact, the National Vaccine Injury Compensation Program specifically provides protection against vaccinerelated malpractice claims.¹² A standing order for office staff to arrange a screening mammogram is another effective intervention; it has been shown to improve screening rates by as much as 30%.¹³

Lessons from chronic illness management

Chronic illness care and preventive care have much in common.¹⁴ Both acknowledge the need for proactive screening and counseling to bring about behavior change. In addition, both require ongoing care and follow-up, as well as depend on links to community resources. And finally, both are resource-intensive—too resource-intensive, some say, to be delivered in a cost-effective manner.

The Chronic Care Model has been proposed as a framework for improving preventive services (TABLE).^15,16 Evidence suggests adopting some key components of chronic care can lead to significant gains in the delivery of preventive care, with the largest improvement seen when multiple components are used simultaneously.^17-20

Self-management support. A growing body of evidence shows that self-management activities are associated with improved outcomes.²¹ Instituting a peer support group for pregnant women at a federally qualified health center, for example, led to a 7% absolute risk reduction in preterm births.²²

Not all efforts to encourage self-management are effective, however, and evaluation is crucial to determine what works. In one large-scale trial, the use of patient reminder cards to facilitate a reduction in health risk behaviors such as tobacco use, risky drinking, unhealthy dietary patterns, and physical inactivity led to fewer health risk assessments being performed, fewer individual counseling encounters, and no change in these behaviors.²³

Decision support. Clinical decision support systems, which generate patient-specific evidence-based assessments and/or recommendations that are actionable as part of the workflow at the point of care, have been found to improve care.^24,25 An example of this is a prompt that reminds the physician to discuss chemoprevention with a patient at high risk for breast cancer.

Delivery system design. The patient-centered medical home (PCMH) is a well-known example of a redesign of health care delivery.²⁶ Conversion to this model is associated with a small positive effect on preventive interventions.²⁷ However, the persistence of a fee-for-service payment system—which does not include physician reimbursement for some of the added services incorporated into the PCMH—limits the implementation of the PCMH model.²⁸

Many practices are improving health care delivery by using nonphysicians for various tasks related to preventive care. Care managers, for example, typically have smaller caseloads and focus on reducing unnecessary treatment for patients with high-risk conditions, such as congestive heart failure, while patient navigators generally have less clinical expertise but more knowledge of community services.

In one study, practice-initiated phone conversations with nonphysicians increased colorectal cancer screening by up to 40%.²⁹ And in one pilot program, the use of ancillary providers led to an increase in colorectal cancer screening by as much as 123%.³⁰ The human touch seems to be key to the success of these interventions. Passive reminders, such as videos being shown on waiting room televisions, have not proven to be effective.³¹ 

Clinical information systems. Early on, the power of electronic health records (EHRs) to improve practices’ delivery of preventive services was recognized. As early as 1995, the use of a reminder system to highlight such services during acute care visits was linked to improvements in counseling about smoking cessation and higher rates of cervical cancer screening, among other preventive measures.^32,33 Overall, the use of EHRs alone has been shown to improve rates of preventive services by as much as 66%, with most practices reporting improvements of at least 20%.³⁴

Use of standing orders for influenza vaccination is one example of an effective and easily implemented preventive measure that requires little or no additional physician time.

Today, EHRs that are Meaningful Use Stage 2-compliant have the tools needed to improve care. Requirements include the ability to generate patient registries of all those with a given disease and to identify patients on the registry who have not received needed care.³⁵ To improve preventive care, registries should focus on the mitigation of risk factors, such as identifying—and contacting—patients with diabetes who are in need of, or overdue for, an annual eye exam.

Trials using the registry function, in combination with automated messaging to deliver targeted information to various patient groups (identified by the demographic information available from the EHR), are ongoing.

Community resources. Many clinicians have informal referral relationships with community organizations, such as the YMCA. Physician practices that establish links to community resources have the potential to have a large effect on unhealthy behaviors. (See “Putting theory into practice: 2 cases”.) However, a systematic review found that, while evidence to support such connections is mainly positive, research is limited and further evaluation is needed.³⁶

The Practical Playbook (practicalplaybook.org)³⁷ developed by the deBeaumont Foundation, Duke Department of Community and Family Medicine, and the Centers for Disease Control and Prevention, offers concrete examples of how physician practices are linking with community resources to improve the health of the population. For example, Duke University’s “Just for Us” program provides in-home chronic illness care to 350 high-risk elderly individuals. The LATCH program connects thousands of Latino immigrants to health care services and culturally and linguistically appropriate health education classes.³⁷

Growing emphasis on quality

Systemic changes in the US health care system are occurring rapidly, with an emphasis on quality and improved outcomes. Many physicians are now required to submit data to external agencies for payment, and much of the data is grounded in preventive standards. Medicare’s Physicians Quality Reporting System requires that all Medicare providers provide data on preventive and chronic illness care. Rates of vaccination, obesity screening, and tobacco use screening are examples of preventive services that will be reported publicly on the Centers for Medicare & Medicaid Services’ Physician Compare Web site.³⁸

Physicians who work in accountable care organizations are required to meet quality standards on the delivery of certain preventive services, including breast cancer screening, colorectal cancer screening, influenza and pneumonia immunization, body mass index screening and follow-up, tobacco use screening and cessation intervention, screening for high blood pressure and followup, and screening for clinical depression and follow-up.³⁹ As patients discover that the Affordable Care Act mandates that preventive services be covered with no cost sharing, they are likely to become more receptive to physician attempts to provide them.^40,41

CORRESPONDENCE
Gerald Liu, MD, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604-3207; [email protected]

CASE › Joe M, age 59, seeks care at the local emergency department (ED) for shortness of breath. He also complains that his abdomen has been getting “bigger and bigger.” The ED physician recognizes that he is suffering from cirrhosis with secondary ascites and admits him. A paracentesis is performed and 7 L of fluid are removed. The patient is started on furosemide 40 mg/d and the health care team educates him about the relationship between his alcohol consumption and his enlarging abdomen. At discharge, he is told to follow up with his primary care physician.

Two weeks later, the patient arrives at your clinic for followup. What is the next step in managing this patient?

Cirrhosis—the end stage of chronic liver disease characterized by inflammation and fibrosis—is a relatively common and often fatal diagnosis. In the United States, an estimated 633,000 adults have cirrhosis,¹ and each year approximately 32,000 people die from the condition.² The most common causes of cirrhosis are heavy alcohol use, chronic hepatitis B or C infection, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.³ Cirrhosis typically involves degeneration and necrosis of hepatocytes, which are replaced by fibrotic tissues and regenerative nodules, leading to loss of liver function.⁴

Patients with cirrhosis can be treated as outpatients—that is, until they decompensate. Obviously, treatment specific to the underlying causes of cirrhosis, such as interferon for a patient with hepatitis and abstinence for a patient with alcohol-related liver disease, should be the first concern. However, this article focuses on the family physician’s role in identifying and treating several of the most common complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, and hepatorenal syndrome. We will also cover which patients should be referred for evaluation for liver transplantation. (For a guide to providing patient education for individuals with cirrhosis, see “Dx cirrhosis: What to teach your patient”.^3,5-10)

Sodium restriction, diuretics are first steps for ascites

The goals of ascites treatment are to prevent or relieve dyspnea and abdominal pain and to prevent life-threatening complications, such as spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome.¹¹ Patient education is key regarding weight gain; that’s why it’s important to instruct patients to contact you if they gain more than 2 lbs/d for 3 consecutive days or more than 10 lbs.¹²

Approximately 10% of patients with ascites respond well to sodium restriction alone (1500-2000 mg/d).¹¹ In addition to sodium restriction, patients with grade 2 ascites (moderate ascites with proportionate abdominal distension) should receive a low-dose diuretic, such as spironolactone (initial dose, 50-100 mg/d; increase up to 200-300 mg/d)¹³ or amiloride (5-10 mg/d).⁵

Approximately 10% of patients with ascites respond well to sodium restriction alone.

Painful gynecomastia and hyperkalemia are the most common adverse effects of spironolactone.¹³ Amiloride has fewer adverse effects than spironolactone, but is less effective.¹¹ Low-dose furosemide (20-40 mg/d) may be added, although weight loss should be monitored to watch for excessive diuresis, which can lead to renal failure, hyponatremia, or encephalopathy.^5,13 Also monitor electrolytes to watch for hypokalemia or hyponatremia.¹³

Recommended weight loss to prevent renal failure is 300 to 500 g/d (.66-1.1 lbs/d) for patients without peripheral edema, and 800 to 1000 g/d (1.7-2.2 lbs/d) for patients with peripheral edema.^5,13

Patients with grade 3 (tense) or refractory ascites should have large-volume paracentesis (LVP) plus an albumin infusion.⁵ LVP (removal of >5 L of fluid) is more effective, faster, and has less risk of adverse effects than increasing the dosage of the patient’s diuretic.^5,13 LVP can be done in an outpatient setting and is considered safe—even for patients with a prolonged prothrombin time.^13,14 Rare complications of LVP include significant bleeding at the puncture site, infection, and intestinal perforation.⁵

Diuretics should be prescribed after LVP to prevent ascites recurrence.⁵ Plasma expanders can prevent hepatorenal syndrome, ascites recurrence, and dilutional hyponatremia.^5,11 Albumin is the most efficacious of these agents;^5,14 it is administered intravenously at a dose of 8 to 10 g/L of fluid removed.^13,15

Take steps to prevent variceal bleeding

Soon after a patient is diagnosed with cirrhosis, he or she should undergo esophagogastroduodenoscopy to screen for the presence and size of varices.¹⁶ Although they can’t prevent esophagogastric varices, nonselective beta-blockers (NSBBs) are the gold standard for preventing first variceal hemorrhage in patients with small varices with red wale signs on the varices and/or Child-Pugh Class B or C cirrhosis (TABLE¹⁷), and in all patients with medium or large varices.¹⁸ Propranolol is usually started at 20 mg BID, or nadolol is started at 20 to 40 mg/d.¹⁶ The NSBB dose is adjusted to the maximum tolerated dose, which occurs when the patient's heart rate is reduced to 55 to 60 beats/min.

NSBBs are associated with poor survival in patients with refractory ascites and thus are contraindicated in these patients.¹⁹ NSBBs also should not be taken by patients with SBP because use of these medications is associated with worse outcomes compared to those not receiving NSBBs.²⁰

Endoscopic variceal ligation is an alternative to NSBBs for the primary prophylaxis of variceal hemorrhage in patients with medium to large varices.¹⁸ In particular, ligation should be considered for patients with high-risk varices in whom beta-blockers are contraindicated or must be discontinued because of adverse effects.²¹

Avoid nitrates in patients with varices because these agents do not prevent first variceal hemorrhage and have been associated with higher mortality rates in patients older than 50.¹⁶ There is no significant additional benefit or mortality reduction associated with adding a nitrate to an NSBB.²² Transjugular intrahepatic portosystemic shunt (TIPS) or surgically created shunts are reserved for patients for whom medical therapy fails.¹⁸

Mental status changes suggest hepatic encephalopathy

Hepatic encephalopathy is a reversible impairment of neuropsychiatric function that is associated with impaired hepatic function. Because a patient with encephalopathy presents with an altered mental status, he or she may need to be admitted to the hospital for evaluation, diagnosis, and treatment.

The goals of hepatic encephalopathy treatment are to identify and correct precipitating causes and lower serum ammonia concentrations to improve mental status.¹⁵ Nutritional support should be provided without protein restriction unless the patient is severely proteinintolerant.²³ The recommended initial therapy is lactulose 30 to 45 mL 2 to 4 times per day, to decrease absorption of ammonia in the gut. The dose should be titrated until patients have 2 to 3 soft stools daily.²⁴

For patients who can’t tolerate lactulose or whose mental status doesn’t improve within 48 hours, rifaximin 400 mg orally 3 times daily or 550 mg 2 times daily is recommended.²⁵ Neomycin 500 mg orally 3 times a day or 1 g twice daily is a second-line agent reserved for patients who are unable to take rifaximin; however, its efficacy is not well established, and neomycin has been associated with ototoxicity and nephrotoxicity.²⁴

Watch for signs of kidney failure

Hepatorenal syndrome is renal failure induced by severe hepatic injury and characterized by azotemia and decreased renal blood flow and glomerular filtration rate.¹⁵ It is a diagnosis of exclusion. Hepatorenal syndrome is typically caused by arterial vasodilation in the splanchnic circulation in patients with portal hypertension.^15,26,27 Type 1 hepatorenal syndrome is characterized by at least a 2-fold increase in serum creatinine to a level of >2.5 mg/dL over more than 2 weeks. Patients typically have urine output <400 to 500 mL/d. Type 2 hepatorenal syndrome is characterized by less severe renal impairment; it is associated with ascites that does not improve with diuretics.²⁸

Endoscopic variceal ligation is an alternative to nonselective beta-blockers for preventing variceal hemorrhage in patients with medium to large varices.

Patients with hepatorenal syndrome should not use any nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs. Inpatient treatment is usually required and may include norepinephrine with albumin, terlipressin with midodrine, or octreotide and albumin. Patients who fail to respond to medical therapy may benefit from TIPS as a bridge until they can undergo liver transplantation.²⁹

When to consider liver transplantation

The appropriateness and timing of liver transplantation should be determined on a case-by-case basis. For some patients with cirrhosis, transplantation may be the definitive treatment. For example, in some patients with hepatocellular carcinoma (HCC), liver transplantation is an option because transplantation can cure the tumor and underlying cirrhosis. However, while transplantation is a suitable option for early HCC in patients with cirrhosis, it has been shown to have limited efficacy in patients with advanced disease who are not selected using specific criteria.³⁰

Referral for evaluation for transplantation should be considered once a patient with cirrhosis experiences a major complication (eg, ascites, variceal hemorrhage, or hepatic encephalopathy).³¹ Another criterion for timing and allocation of liver transplantation is based on the statistical model for end-stage liver disease (MELD), which is used to predict 3-month survival in patients with cirrhosis based on the relationships between serum bilirubin, serum creatinine, and international normalized ratio values.¹⁵ Liver transplantation should be considered for patients with a MELD score ≥15.^15,31 Such patients should be promptly referred to a liver transplantation specialist to allow sufficient time for the appropriate psychosocial assessments and medical evaluations, and for patients and their families to receive appropriate education on things like the risks and benefits of transplantation.¹⁵

CASE › After evaluating Mr. M, you prescribe spironolactone 100 mg/d and furosemide 40 mg twice a day to address ascites, and propranolol—which you titrate to 80 mg twice a day—to prevent variceal hemorrhage. Mr. M is maintained on these medications and returns with his daughter, as he has been doing every 2 to 3 months. He is excited that he breathes easily as long as he avoids salt and takes his medications. He continues to see his hepatologist regularly, and his last paracentesis was 4 months ago. He has not used any alcohol since he was taught about the relationship between alcohol and his breathing.

CORRESPONDENCE
Suzanne Minor, MD, FAAF P, Assistant Professor of Family Medicine, Department of Humanities, Health, & Society, Florida International University, Herbert Wertheim College of Medicine, 11200 SW 8th Street, AHC II, 554A, Miami, FL 33199; [email protected]

CASE › Joe M, age 59, seeks care at the local emergency department (ED) for shortness of breath. He also complains that his abdomen has been getting “bigger and bigger.” The ED physician recognizes that he is suffering from cirrhosis with secondary ascites and admits him. A paracentesis is performed and 7 L of fluid are removed. The patient is started on furosemide 40 mg/d and the health care team educates him about the relationship between his alcohol consumption and his enlarging abdomen. At discharge, he is told to follow up with his primary care physician.

Two weeks later, the patient arrives at your clinic for followup. What is the next step in managing this patient?

Cirrhosis—the end stage of chronic liver disease characterized by inflammation and fibrosis—is a relatively common and often fatal diagnosis. In the United States, an estimated 633,000 adults have cirrhosis,¹ and each year approximately 32,000 people die from the condition.² The most common causes of cirrhosis are heavy alcohol use, chronic hepatitis B or C infection, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.³ Cirrhosis typically involves degeneration and necrosis of hepatocytes, which are replaced by fibrotic tissues and regenerative nodules, leading to loss of liver function.⁴

Patients with cirrhosis can be treated as outpatients—that is, until they decompensate. Obviously, treatment specific to the underlying causes of cirrhosis, such as interferon for a patient with hepatitis and abstinence for a patient with alcohol-related liver disease, should be the first concern. However, this article focuses on the family physician’s role in identifying and treating several of the most common complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, and hepatorenal syndrome. We will also cover which patients should be referred for evaluation for liver transplantation. (For a guide to providing patient education for individuals with cirrhosis, see “Dx cirrhosis: What to teach your patient”.^3,5-10)

Sodium restriction, diuretics are first steps for ascites

The goals of ascites treatment are to prevent or relieve dyspnea and abdominal pain and to prevent life-threatening complications, such as spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome.¹¹ Patient education is key regarding weight gain; that’s why it’s important to instruct patients to contact you if they gain more than 2 lbs/d for 3 consecutive days or more than 10 lbs.¹²

Approximately 10% of patients with ascites respond well to sodium restriction alone (1500-2000 mg/d).¹¹ In addition to sodium restriction, patients with grade 2 ascites (moderate ascites with proportionate abdominal distension) should receive a low-dose diuretic, such as spironolactone (initial dose, 50-100 mg/d; increase up to 200-300 mg/d)¹³ or amiloride (5-10 mg/d).⁵

Approximately 10% of patients with ascites respond well to sodium restriction alone.

Painful gynecomastia and hyperkalemia are the most common adverse effects of spironolactone.¹³ Amiloride has fewer adverse effects than spironolactone, but is less effective.¹¹ Low-dose furosemide (20-40 mg/d) may be added, although weight loss should be monitored to watch for excessive diuresis, which can lead to renal failure, hyponatremia, or encephalopathy.^5,13 Also monitor electrolytes to watch for hypokalemia or hyponatremia.¹³

Recommended weight loss to prevent renal failure is 300 to 500 g/d (.66-1.1 lbs/d) for patients without peripheral edema, and 800 to 1000 g/d (1.7-2.2 lbs/d) for patients with peripheral edema.^5,13

Patients with grade 3 (tense) or refractory ascites should have large-volume paracentesis (LVP) plus an albumin infusion.⁵ LVP (removal of >5 L of fluid) is more effective, faster, and has less risk of adverse effects than increasing the dosage of the patient’s diuretic.^5,13 LVP can be done in an outpatient setting and is considered safe—even for patients with a prolonged prothrombin time.^13,14 Rare complications of LVP include significant bleeding at the puncture site, infection, and intestinal perforation.⁵

Diuretics should be prescribed after LVP to prevent ascites recurrence.⁵ Plasma expanders can prevent hepatorenal syndrome, ascites recurrence, and dilutional hyponatremia.^5,11 Albumin is the most efficacious of these agents;^5,14 it is administered intravenously at a dose of 8 to 10 g/L of fluid removed.^13,15

Take steps to prevent variceal bleeding

Soon after a patient is diagnosed with cirrhosis, he or she should undergo esophagogastroduodenoscopy to screen for the presence and size of varices.¹⁶ Although they can’t prevent esophagogastric varices, nonselective beta-blockers (NSBBs) are the gold standard for preventing first variceal hemorrhage in patients with small varices with red wale signs on the varices and/or Child-Pugh Class B or C cirrhosis (TABLE¹⁷), and in all patients with medium or large varices.¹⁸ Propranolol is usually started at 20 mg BID, or nadolol is started at 20 to 40 mg/d.¹⁶ The NSBB dose is adjusted to the maximum tolerated dose, which occurs when the patient's heart rate is reduced to 55 to 60 beats/min.

NSBBs are associated with poor survival in patients with refractory ascites and thus are contraindicated in these patients.¹⁹ NSBBs also should not be taken by patients with SBP because use of these medications is associated with worse outcomes compared to those not receiving NSBBs.²⁰

Endoscopic variceal ligation is an alternative to NSBBs for the primary prophylaxis of variceal hemorrhage in patients with medium to large varices.¹⁸ In particular, ligation should be considered for patients with high-risk varices in whom beta-blockers are contraindicated or must be discontinued because of adverse effects.²¹

Avoid nitrates in patients with varices because these agents do not prevent first variceal hemorrhage and have been associated with higher mortality rates in patients older than 50.¹⁶ There is no significant additional benefit or mortality reduction associated with adding a nitrate to an NSBB.²² Transjugular intrahepatic portosystemic shunt (TIPS) or surgically created shunts are reserved for patients for whom medical therapy fails.¹⁸

Mental status changes suggest hepatic encephalopathy

Hepatic encephalopathy is a reversible impairment of neuropsychiatric function that is associated with impaired hepatic function. Because a patient with encephalopathy presents with an altered mental status, he or she may need to be admitted to the hospital for evaluation, diagnosis, and treatment.

The goals of hepatic encephalopathy treatment are to identify and correct precipitating causes and lower serum ammonia concentrations to improve mental status.¹⁵ Nutritional support should be provided without protein restriction unless the patient is severely proteinintolerant.²³ The recommended initial therapy is lactulose 30 to 45 mL 2 to 4 times per day, to decrease absorption of ammonia in the gut. The dose should be titrated until patients have 2 to 3 soft stools daily.²⁴

For patients who can’t tolerate lactulose or whose mental status doesn’t improve within 48 hours, rifaximin 400 mg orally 3 times daily or 550 mg 2 times daily is recommended.²⁵ Neomycin 500 mg orally 3 times a day or 1 g twice daily is a second-line agent reserved for patients who are unable to take rifaximin; however, its efficacy is not well established, and neomycin has been associated with ototoxicity and nephrotoxicity.²⁴

Watch for signs of kidney failure

Hepatorenal syndrome is renal failure induced by severe hepatic injury and characterized by azotemia and decreased renal blood flow and glomerular filtration rate.¹⁵ It is a diagnosis of exclusion. Hepatorenal syndrome is typically caused by arterial vasodilation in the splanchnic circulation in patients with portal hypertension.^15,26,27 Type 1 hepatorenal syndrome is characterized by at least a 2-fold increase in serum creatinine to a level of >2.5 mg/dL over more than 2 weeks. Patients typically have urine output <400 to 500 mL/d. Type 2 hepatorenal syndrome is characterized by less severe renal impairment; it is associated with ascites that does not improve with diuretics.²⁸

Endoscopic variceal ligation is an alternative to nonselective beta-blockers for preventing variceal hemorrhage in patients with medium to large varices.

Patients with hepatorenal syndrome should not use any nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs. Inpatient treatment is usually required and may include norepinephrine with albumin, terlipressin with midodrine, or octreotide and albumin. Patients who fail to respond to medical therapy may benefit from TIPS as a bridge until they can undergo liver transplantation.²⁹

When to consider liver transplantation

The appropriateness and timing of liver transplantation should be determined on a case-by-case basis. For some patients with cirrhosis, transplantation may be the definitive treatment. For example, in some patients with hepatocellular carcinoma (HCC), liver transplantation is an option because transplantation can cure the tumor and underlying cirrhosis. However, while transplantation is a suitable option for early HCC in patients with cirrhosis, it has been shown to have limited efficacy in patients with advanced disease who are not selected using specific criteria.³⁰

Referral for evaluation for transplantation should be considered once a patient with cirrhosis experiences a major complication (eg, ascites, variceal hemorrhage, or hepatic encephalopathy).³¹ Another criterion for timing and allocation of liver transplantation is based on the statistical model for end-stage liver disease (MELD), which is used to predict 3-month survival in patients with cirrhosis based on the relationships between serum bilirubin, serum creatinine, and international normalized ratio values.¹⁵ Liver transplantation should be considered for patients with a MELD score ≥15.^15,31 Such patients should be promptly referred to a liver transplantation specialist to allow sufficient time for the appropriate psychosocial assessments and medical evaluations, and for patients and their families to receive appropriate education on things like the risks and benefits of transplantation.¹⁵

CASE › After evaluating Mr. M, you prescribe spironolactone 100 mg/d and furosemide 40 mg twice a day to address ascites, and propranolol—which you titrate to 80 mg twice a day—to prevent variceal hemorrhage. Mr. M is maintained on these medications and returns with his daughter, as he has been doing every 2 to 3 months. He is excited that he breathes easily as long as he avoids salt and takes his medications. He continues to see his hepatologist regularly, and his last paracentesis was 4 months ago. He has not used any alcohol since he was taught about the relationship between alcohol and his breathing.

CORRESPONDENCE
Suzanne Minor, MD, FAAF P, Assistant Professor of Family Medicine, Department of Humanities, Health, & Society, Florida International University, Herbert Wertheim College of Medicine, 11200 SW 8th Street, AHC II, 554A, Miami, FL 33199; [email protected]

CASE › Joe M, age 59, seeks care at the local emergency department (ED) for shortness of breath. He also complains that his abdomen has been getting “bigger and bigger.” The ED physician recognizes that he is suffering from cirrhosis with secondary ascites and admits him. A paracentesis is performed and 7 L of fluid are removed. The patient is started on furosemide 40 mg/d and the health care team educates him about the relationship between his alcohol consumption and his enlarging abdomen. At discharge, he is told to follow up with his primary care physician.

Two weeks later, the patient arrives at your clinic for followup. What is the next step in managing this patient?

Cirrhosis—the end stage of chronic liver disease characterized by inflammation and fibrosis—is a relatively common and often fatal diagnosis. In the United States, an estimated 633,000 adults have cirrhosis,¹ and each year approximately 32,000 people die from the condition.² The most common causes of cirrhosis are heavy alcohol use, chronic hepatitis B or C infection, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.³ Cirrhosis typically involves degeneration and necrosis of hepatocytes, which are replaced by fibrotic tissues and regenerative nodules, leading to loss of liver function.⁴

Patients with cirrhosis can be treated as outpatients—that is, until they decompensate. Obviously, treatment specific to the underlying causes of cirrhosis, such as interferon for a patient with hepatitis and abstinence for a patient with alcohol-related liver disease, should be the first concern. However, this article focuses on the family physician’s role in identifying and treating several of the most common complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, and hepatorenal syndrome. We will also cover which patients should be referred for evaluation for liver transplantation. (For a guide to providing patient education for individuals with cirrhosis, see “Dx cirrhosis: What to teach your patient”.^3,5-10)

Sodium restriction, diuretics are first steps for ascites

The goals of ascites treatment are to prevent or relieve dyspnea and abdominal pain and to prevent life-threatening complications, such as spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome.¹¹ Patient education is key regarding weight gain; that’s why it’s important to instruct patients to contact you if they gain more than 2 lbs/d for 3 consecutive days or more than 10 lbs.¹²

Approximately 10% of patients with ascites respond well to sodium restriction alone (1500-2000 mg/d).¹¹ In addition to sodium restriction, patients with grade 2 ascites (moderate ascites with proportionate abdominal distension) should receive a low-dose diuretic, such as spironolactone (initial dose, 50-100 mg/d; increase up to 200-300 mg/d)¹³ or amiloride (5-10 mg/d).⁵

Approximately 10% of patients with ascites respond well to sodium restriction alone.

Painful gynecomastia and hyperkalemia are the most common adverse effects of spironolactone.¹³ Amiloride has fewer adverse effects than spironolactone, but is less effective.¹¹ Low-dose furosemide (20-40 mg/d) may be added, although weight loss should be monitored to watch for excessive diuresis, which can lead to renal failure, hyponatremia, or encephalopathy.^5,13 Also monitor electrolytes to watch for hypokalemia or hyponatremia.¹³

Recommended weight loss to prevent renal failure is 300 to 500 g/d (.66-1.1 lbs/d) for patients without peripheral edema, and 800 to 1000 g/d (1.7-2.2 lbs/d) for patients with peripheral edema.^5,13

Patients with grade 3 (tense) or refractory ascites should have large-volume paracentesis (LVP) plus an albumin infusion.⁵ LVP (removal of >5 L of fluid) is more effective, faster, and has less risk of adverse effects than increasing the dosage of the patient’s diuretic.^5,13 LVP can be done in an outpatient setting and is considered safe—even for patients with a prolonged prothrombin time.^13,14 Rare complications of LVP include significant bleeding at the puncture site, infection, and intestinal perforation.⁵

Diuretics should be prescribed after LVP to prevent ascites recurrence.⁵ Plasma expanders can prevent hepatorenal syndrome, ascites recurrence, and dilutional hyponatremia.^5,11 Albumin is the most efficacious of these agents;^5,14 it is administered intravenously at a dose of 8 to 10 g/L of fluid removed.^13,15

Take steps to prevent variceal bleeding

Soon after a patient is diagnosed with cirrhosis, he or she should undergo esophagogastroduodenoscopy to screen for the presence and size of varices.¹⁶ Although they can’t prevent esophagogastric varices, nonselective beta-blockers (NSBBs) are the gold standard for preventing first variceal hemorrhage in patients with small varices with red wale signs on the varices and/or Child-Pugh Class B or C cirrhosis (TABLE¹⁷), and in all patients with medium or large varices.¹⁸ Propranolol is usually started at 20 mg BID, or nadolol is started at 20 to 40 mg/d.¹⁶ The NSBB dose is adjusted to the maximum tolerated dose, which occurs when the patient's heart rate is reduced to 55 to 60 beats/min.

NSBBs are associated with poor survival in patients with refractory ascites and thus are contraindicated in these patients.¹⁹ NSBBs also should not be taken by patients with SBP because use of these medications is associated with worse outcomes compared to those not receiving NSBBs.²⁰

Endoscopic variceal ligation is an alternative to NSBBs for the primary prophylaxis of variceal hemorrhage in patients with medium to large varices.¹⁸ In particular, ligation should be considered for patients with high-risk varices in whom beta-blockers are contraindicated or must be discontinued because of adverse effects.²¹

Avoid nitrates in patients with varices because these agents do not prevent first variceal hemorrhage and have been associated with higher mortality rates in patients older than 50.¹⁶ There is no significant additional benefit or mortality reduction associated with adding a nitrate to an NSBB.²² Transjugular intrahepatic portosystemic shunt (TIPS) or surgically created shunts are reserved for patients for whom medical therapy fails.¹⁸

Mental status changes suggest hepatic encephalopathy

Hepatic encephalopathy is a reversible impairment of neuropsychiatric function that is associated with impaired hepatic function. Because a patient with encephalopathy presents with an altered mental status, he or she may need to be admitted to the hospital for evaluation, diagnosis, and treatment.

The goals of hepatic encephalopathy treatment are to identify and correct precipitating causes and lower serum ammonia concentrations to improve mental status.¹⁵ Nutritional support should be provided without protein restriction unless the patient is severely proteinintolerant.²³ The recommended initial therapy is lactulose 30 to 45 mL 2 to 4 times per day, to decrease absorption of ammonia in the gut. The dose should be titrated until patients have 2 to 3 soft stools daily.²⁴

For patients who can’t tolerate lactulose or whose mental status doesn’t improve within 48 hours, rifaximin 400 mg orally 3 times daily or 550 mg 2 times daily is recommended.²⁵ Neomycin 500 mg orally 3 times a day or 1 g twice daily is a second-line agent reserved for patients who are unable to take rifaximin; however, its efficacy is not well established, and neomycin has been associated with ototoxicity and nephrotoxicity.²⁴

Watch for signs of kidney failure

Hepatorenal syndrome is renal failure induced by severe hepatic injury and characterized by azotemia and decreased renal blood flow and glomerular filtration rate.¹⁵ It is a diagnosis of exclusion. Hepatorenal syndrome is typically caused by arterial vasodilation in the splanchnic circulation in patients with portal hypertension.^15,26,27 Type 1 hepatorenal syndrome is characterized by at least a 2-fold increase in serum creatinine to a level of >2.5 mg/dL over more than 2 weeks. Patients typically have urine output <400 to 500 mL/d. Type 2 hepatorenal syndrome is characterized by less severe renal impairment; it is associated with ascites that does not improve with diuretics.²⁸

Endoscopic variceal ligation is an alternative to nonselective beta-blockers for preventing variceal hemorrhage in patients with medium to large varices.

Patients with hepatorenal syndrome should not use any nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs. Inpatient treatment is usually required and may include norepinephrine with albumin, terlipressin with midodrine, or octreotide and albumin. Patients who fail to respond to medical therapy may benefit from TIPS as a bridge until they can undergo liver transplantation.²⁹

When to consider liver transplantation

The appropriateness and timing of liver transplantation should be determined on a case-by-case basis. For some patients with cirrhosis, transplantation may be the definitive treatment. For example, in some patients with hepatocellular carcinoma (HCC), liver transplantation is an option because transplantation can cure the tumor and underlying cirrhosis. However, while transplantation is a suitable option for early HCC in patients with cirrhosis, it has been shown to have limited efficacy in patients with advanced disease who are not selected using specific criteria.³⁰

Referral for evaluation for transplantation should be considered once a patient with cirrhosis experiences a major complication (eg, ascites, variceal hemorrhage, or hepatic encephalopathy).³¹ Another criterion for timing and allocation of liver transplantation is based on the statistical model for end-stage liver disease (MELD), which is used to predict 3-month survival in patients with cirrhosis based on the relationships between serum bilirubin, serum creatinine, and international normalized ratio values.¹⁵ Liver transplantation should be considered for patients with a MELD score ≥15.^15,31 Such patients should be promptly referred to a liver transplantation specialist to allow sufficient time for the appropriate psychosocial assessments and medical evaluations, and for patients and their families to receive appropriate education on things like the risks and benefits of transplantation.¹⁵

CASE › After evaluating Mr. M, you prescribe spironolactone 100 mg/d and furosemide 40 mg twice a day to address ascites, and propranolol—which you titrate to 80 mg twice a day—to prevent variceal hemorrhage. Mr. M is maintained on these medications and returns with his daughter, as he has been doing every 2 to 3 months. He is excited that he breathes easily as long as he avoids salt and takes his medications. He continues to see his hepatologist regularly, and his last paracentesis was 4 months ago. He has not used any alcohol since he was taught about the relationship between alcohol and his breathing.

CORRESPONDENCE
Suzanne Minor, MD, FAAF P, Assistant Professor of Family Medicine, Department of Humanities, Health, & Society, Florida International University, Herbert Wertheim College of Medicine, 11200 SW 8th Street, AHC II, 554A, Miami, FL 33199; [email protected]

CASE ›  Your patient, Mark Q, age 80, is admitted to the hospital to undergo hemicolectomy for colon cancer. His medical history includes hypertension, benign prostatic hyperplasia, and colon cancer. He did well immediately postop, but when you make morning rounds the day after his surgery, you notice that he is confused and agitated. Mr. Q’s chart reveals that earlier that morning, he pulled out his Foley catheter and intravenous (IV) line when his nurse declined his request to walk him to the bathroom.

How would you proceed?

Up to 50% of older adults who undergo surgical procedures develop delirium—a disturbance in attention and awareness accompanied by changes in cognition.¹ Older adults are at heightened risk for this postoperative complication for several reasons. For one thing, older patients have a reduced capacity for homeostatic regulation when they undergo anesthesia and surgery.² For another, age-related changes in brain neurochemistry and drug metabolism increase the likelihood of adverse drug effects, including those that could precipitate delirirum.³

Risk factors for postop delirium include age >65 years, dementia, poor vision, decreased hearing, severe illness, and infection.

Although postop delirium is a common complication in older patients, it sometimes goes unrecognized. Missed or delayed diagnosis of delirium can result in patients exhibiting behaviors that can compromise their safety, delay recuperation, and result in longer hospital stays, a greater financial burden, and increased morbidity and mortality.⁴ The American Geriatric Society recently published clinical guidelines and a best practices statement for preventing and treating postop delirium in patients ages >65 years.^1,5 This article describes steps family physicians can take to assess their patients’ risk of delirium before they undergo surgery, and to recognize and treat delirium in the postop period.

Defining delirium

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), the criteria for delirium are:⁶
A. A disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).
B. The disturbance develops over a short time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.
C. An additional disturbance in cognition (eg, memory deficits, disorientation, language, visuospatial ability, perception).
D. The disturbances in attention, awareness, and cognition aren’t better explained by another preexisting or evolving neurocognitive disorder and don’t occur in the context of a severely reduced level of arousal.
E. History, physical, or laboratory findings show that the disturbance is caused by the direct physiologic consequences of a general medical condition, substance intoxication/withdrawal, exposure to a toxin, or multiple etiologies.

The 3 subtypes of delirium are based on patients’ psychomotor activity.⁷ In hyperactive delirium, patients exhibit heightened arousal, restlessness, agitation, hallucinations, and inappropriate behavior. Hypoactive delirium is characterized by lethargy, reduced motor activity, incoherent speech, and lack of interest. Mixed delirium consists of a combination of hyperactive and hypoactive signs and symptoms.

Gauge risk before patients undergo surgery

Family physicians can assess their patients’ risk for developing delirium by conducting baseline screening during routine office visits as well as during preoperative evaluations. Factors that increase postop delirium risk include:¹
• age >65 years
• dementia
• poor vision
• decreased hearing
• severe illness
• infection.

Routine cognitive screening can be done easily and efficiently using readily available tools such as the Alzheimer Association’s Cognitive Assessment Toolkit.⁸ This toolkit includes 3 brief, validated screening tools to identify patients with probable cognitive impairment: the General Practitioner Assessment of Cognition, the Memory Impairment Screen, and the Mini-Cog.

If preop screening indicates that the patient is at increased risk for delirium, the family physician should work with hospital’s interdisciplinary teams to institute prevention measures, such as the Hospital Elder Life Program (HELP).⁹ This program offers a structured curriculum for instructing volunteers to deliver daily orientation, early mobilization, feeding assistance, therapeutic activities, and other measures to help prevent delirium.

Prompt screening after surgery is essential, too

In addition to preop delirium risk assessment, all patients who undergo surgery should receive daily delirium screening during the first postoperative week. The Confusion Assessment Method (CAM) is a quick screening tool for assessing a patient’s level of arousal and consciousness.¹⁰ Based on the results of 7 high-quality studies (N=1071), CAM has a sensitivity of 94% (95% confidence interval [CI], 91%-97%) and specificity of 89% (95% CI, 85%-94%).^11,12

Common underlying causes of delirium include hypoxia, infection, dehydration, acute metabolic disturbance, and drug withdrawal.

Feature 1 of CAM, “Acute onset and fluctuating course,” requires that you compare the patient’s current mental status to his or her pre-hospital baseline mental status; the baseline status should be obtained from a family member, caretaker, or clinician who has observed the patient over time.¹⁰ This is intended to determine if the patient has experienced an acute change in mental status (eg, attention, orientation, cognition), usually over the course of hours to days.¹⁰ Feature 2, “Inattention,” is used to determine if the patient has a reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli, and if the patient is unaware or out of touch with the environment.¹⁰ Feature 3, “Disorganized thinking,” is used to assess the patient’s organization of thought as expressed by speech or writing. Disorganized thinking typically manifests as rambling and irrelevant or incoherent speech.¹⁰ Feature 4, “Altered level of consciousness,” is used to rate the patient’s alertness level.¹⁰

A positive screen for delirium requires the presence of Feature 1 (acute onset and/or fluctuation) and Feature 2, plus either Feature 3 or Feature 4.

Is delirium—or something else—at work?

If an older adult is exhibiting cognitive and/or behavioral disturbances after undergoing surgery, it’s important to discern if these manifestations are the result of delirium, a preexisting psychiatric disorder, or some other cause if the patient has a clear sensorium (ALGORITHM).^6,13,14

Delirium. If a patient’s CAM screen suggests delirium, conduct a thorough assessment for the signs and symptoms of delirium to determine if the patient meets DSM-5 criteria for the diagnosis.¹ In order to avoid missing hypoactive, subtle, or atypical cases of delirium, conduct a thorough medical record and medications review, and gather assessments from the nursing staff and other team members regarding the patient’s behavior.

Preexisting psychiatric disorder. It’s important to differentiate psychiatric symptoms from those of a superimposed delirium.¹³ Because patients with preoperative depressive symptoms may be at increased risk for postop delirium, pre-surgical psychiatric evaluations are important for identifying even subtle psychopathological symptoms.¹⁵ (The psychiatric interview is the gold standard for diagnosis.¹⁶) For patients who have an established psychiatric diagnosis, consider consulting with the psychiatrist who is managing the patient’s psychiatric care.¹³

Other causes. If a patient who is exhibiting postop cognitive and/or behavioral disturbances has a reasonably accurate memory and a correct orientation for time, place, and person, interviews with the patient and caregivers (along with the psychiatric interview) will likely reveal potential causes for the behavioral problems.¹³

Is the patient suffering from dehydration? Drug withdrawal?

Assessment for an underlying organic cause must be performed because specific treatment for the underlying diagnosis may improve delirium.¹⁷ Common causes include hypoxia, infection, dehydration, acute metabolic disturbance, endocrinopathies, cardiac or vascular disorders, and drug withdrawal.¹³ An appropriate diagnostic work-up might consist of serum urea, glucose, electrolytes, liver function tests, arterial blood gas analyses, urinalysis, nutritional evaluation, electrocardiogram, and a complete blood count.

Ask patients about their use of alcohol and benzodiazepines, and consider alcohol or drug withdrawal as potential etiologies.¹⁸ Patients with delirium should also be assessed for iatrogenic hospital-related factors that could be causing or contributing to the condition, such as immobilization or malnutrition.¹³

Medications are a common culprit: Approximately 40% of cases of delirium are related to medication use.¹⁸ Commonly used postop medications such as analgesics, sedatives, proton pump inhibitors, and others can cause delirium.¹⁹ Carefully review the patient’s medication list.¹³ Medication-induced delirium is influenced by the number of medications taken (generally >3),²⁰ the use of psychoactive medications,²¹ and the specific agent's anticholinergic potential.²² The 2012 updated Beers Criteria (American Geriatrics Society) is a useful resource for determining if “inappropriate polypharmacy” is the cause of postop delirium.²³

Inadequate pain control. In a multisite trial,²⁴ patients who received <10 mg/d of parenteral morphine sulfate equivalents were more likely to develop delirium than patients who received more analgesia. In cognitively intact patients, severe pain significantly increased the risk of delirium. With the exception of meperidine, opioids do not precipitate delirium in patients with acute pain.²⁴ Not treating pain or administering very low—or excessively high—doses of opioids is associated with an increased risk of delirium for both cognitively intact and impaired patients.²⁴

Constipation can contribute to the development of delirium.²⁵ After surgery, patients tend to be less mobile and may be receiving medications that can cause constipation, such as opioids, iron, calcium, and channel blockers. Preventing and treating constipation in postop patients can reduce delirium risk.²⁵

Begin treatment with nonpharmacologic measures

Preventing and treating constipation in postop patients can reduce delirium risk.

Regardless of whether a patient suffers from hyperactive, hypoactive, or mixed delirium, nonpharmacologic interventions are firstline treatment.¹⁹ Such interventions can help patients develop a sense of control over their environment, which can help relieve agitation.¹³ Because environmental shifts contribute to the development of delirium, avoiding transfers and securing a single room can be helpful.¹⁹ Patients with delirium have altered perceptions, and may view normal objects and routine clinician actions as harmful and threatening. Therefore, it is helpful to avoid sensory deprivation by making sure patients have access to their eyeglasses and hearing aids, and to provide nonthreatening cognitive/environmental stimulation.^1,13,19 Patients should be encouraged to resume walking as soon as possible.^1,19 Other nonpharmacologic interventions are listed in the TABLE.^1,13,19

Safety issues must also be addressed.¹⁷ Patients with mixed or hyperactive delirium may become agitated, which can lead them to pull tubes, drains, or lines, as occurred with Mr. Q. Patients with hypoactive delirium may be prone to wandering, or receive less attention due to their hypoactive state.¹⁷ All patients with delirium are at risk of falls.

Patients should be evaluated for these risks to determine whether assigning a "sitter" or transfer to a stepdown unit or intensive care unit is warranted.¹⁷ Restraints are not recommended because they can exacerbate delirium and lead to injuries.²⁶

Pharmacologic treatment should be reserved for patients whose behavior compromises their safety, and implemented only when the cause of the delirium is known. The primary objectives of drug therapy are to achieve and maintain safe and rapid behavioral control so the patient can receive necessary medical care, and to enhance functional recovery.¹⁴ The choice of a specific medication is individualized and depends on each patient’s clinical condition.¹⁴

For a patient with hyperactive delirium, an antipsychotic typically is the treatment of choice because these medications are dopamine receptor antagonists, and excessive dopamine transmission has been implicated in this type of delirium.²⁷ Haloperidol often is the preferred treatment; a low-dose oral form is recommended for older patients who exhibit severe agitation because there is less risk of QT prolongation compared to IV administration.²⁸

Avoid using benzodiazepines and other hypnotics in older patients with delirium, except when treating withdrawal.

Second-generation antipsychotics (eg, risperidone, olanzapine, and quetiapine) are increasingly used due to their lower risk for adverse extrapyramidal symptoms, which are common in older patients.^29-31 Despite this, increasing data show that morbidity with these agents may be underestimated, and the risks of adverse effects may vary among the medications in this class.³²

For hypoactive or mixed delirium, nonpharmacologic interventions should be the mainstay of treatment. When medications are used, they should be used to target the underlying etiology of delirium (eg, treating a urinary tract infection with an antibiotic).³³

A few final words about medication use for delirium ... Most medications that modify symptoms of delirium can actually prolong the delirium.³³ Therefore, it's important to carefully consider the balance between effectively managing symptoms and causing adverse effects. Because older adults have increased sensitivity to medications, always start with small dosages and titrate to effect.³⁴ Benzodiazepines and other hypnotics should be avoided in older patients, except when treating alcohol or benzodiazepine withdrawal.³⁵

CASE ›  Mr. Q’s postop delirium screen is positive, and assessment for underlying causes reveals that he is suffering from postoperative pain and is constipated. Due to roommate noise and insomnia, he is transferred to a private room, where quiet times are observed. He receives oxycodone 5 mg every 4 hours for his pain and senna 30 mg at bedtime and a bisacodyl rectal suppository 10 mg/d for constipation. After 3 days Mr. Q’s postop pain and delirium resolves, and he is discharged home.

CORRESPONDENCE
Jackson Ng, MD, Teresa Lang Research Center, New York Hospital Queens, 56-45 Main St., Flushing, NY 11355; [email protected]

CASE ›  Your patient, Mark Q, age 80, is admitted to the hospital to undergo hemicolectomy for colon cancer. His medical history includes hypertension, benign prostatic hyperplasia, and colon cancer. He did well immediately postop, but when you make morning rounds the day after his surgery, you notice that he is confused and agitated. Mr. Q’s chart reveals that earlier that morning, he pulled out his Foley catheter and intravenous (IV) line when his nurse declined his request to walk him to the bathroom.

How would you proceed?

Up to 50% of older adults who undergo surgical procedures develop delirium—a disturbance in attention and awareness accompanied by changes in cognition.¹ Older adults are at heightened risk for this postoperative complication for several reasons. For one thing, older patients have a reduced capacity for homeostatic regulation when they undergo anesthesia and surgery.² For another, age-related changes in brain neurochemistry and drug metabolism increase the likelihood of adverse drug effects, including those that could precipitate delirirum.³

Risk factors for postop delirium include age >65 years, dementia, poor vision, decreased hearing, severe illness, and infection.

Although postop delirium is a common complication in older patients, it sometimes goes unrecognized. Missed or delayed diagnosis of delirium can result in patients exhibiting behaviors that can compromise their safety, delay recuperation, and result in longer hospital stays, a greater financial burden, and increased morbidity and mortality.⁴ The American Geriatric Society recently published clinical guidelines and a best practices statement for preventing and treating postop delirium in patients ages >65 years.^1,5 This article describes steps family physicians can take to assess their patients’ risk of delirium before they undergo surgery, and to recognize and treat delirium in the postop period.

Defining delirium

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), the criteria for delirium are:⁶
A. A disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).
B. The disturbance develops over a short time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.
C. An additional disturbance in cognition (eg, memory deficits, disorientation, language, visuospatial ability, perception).
D. The disturbances in attention, awareness, and cognition aren’t better explained by another preexisting or evolving neurocognitive disorder and don’t occur in the context of a severely reduced level of arousal.
E. History, physical, or laboratory findings show that the disturbance is caused by the direct physiologic consequences of a general medical condition, substance intoxication/withdrawal, exposure to a toxin, or multiple etiologies.

The 3 subtypes of delirium are based on patients’ psychomotor activity.⁷ In hyperactive delirium, patients exhibit heightened arousal, restlessness, agitation, hallucinations, and inappropriate behavior. Hypoactive delirium is characterized by lethargy, reduced motor activity, incoherent speech, and lack of interest. Mixed delirium consists of a combination of hyperactive and hypoactive signs and symptoms.

Gauge risk before patients undergo surgery

Family physicians can assess their patients’ risk for developing delirium by conducting baseline screening during routine office visits as well as during preoperative evaluations. Factors that increase postop delirium risk include:¹
• age >65 years
• dementia
• poor vision
• decreased hearing
• severe illness
• infection.

Routine cognitive screening can be done easily and efficiently using readily available tools such as the Alzheimer Association’s Cognitive Assessment Toolkit.⁸ This toolkit includes 3 brief, validated screening tools to identify patients with probable cognitive impairment: the General Practitioner Assessment of Cognition, the Memory Impairment Screen, and the Mini-Cog.

If preop screening indicates that the patient is at increased risk for delirium, the family physician should work with hospital’s interdisciplinary teams to institute prevention measures, such as the Hospital Elder Life Program (HELP).⁹ This program offers a structured curriculum for instructing volunteers to deliver daily orientation, early mobilization, feeding assistance, therapeutic activities, and other measures to help prevent delirium.

Prompt screening after surgery is essential, too

In addition to preop delirium risk assessment, all patients who undergo surgery should receive daily delirium screening during the first postoperative week. The Confusion Assessment Method (CAM) is a quick screening tool for assessing a patient’s level of arousal and consciousness.¹⁰ Based on the results of 7 high-quality studies (N=1071), CAM has a sensitivity of 94% (95% confidence interval [CI], 91%-97%) and specificity of 89% (95% CI, 85%-94%).^11,12

Common underlying causes of delirium include hypoxia, infection, dehydration, acute metabolic disturbance, and drug withdrawal.

Feature 1 of CAM, “Acute onset and fluctuating course,” requires that you compare the patient’s current mental status to his or her pre-hospital baseline mental status; the baseline status should be obtained from a family member, caretaker, or clinician who has observed the patient over time.¹⁰ This is intended to determine if the patient has experienced an acute change in mental status (eg, attention, orientation, cognition), usually over the course of hours to days.¹⁰ Feature 2, “Inattention,” is used to determine if the patient has a reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli, and if the patient is unaware or out of touch with the environment.¹⁰ Feature 3, “Disorganized thinking,” is used to assess the patient’s organization of thought as expressed by speech or writing. Disorganized thinking typically manifests as rambling and irrelevant or incoherent speech.¹⁰ Feature 4, “Altered level of consciousness,” is used to rate the patient’s alertness level.¹⁰

A positive screen for delirium requires the presence of Feature 1 (acute onset and/or fluctuation) and Feature 2, plus either Feature 3 or Feature 4.

Is delirium—or something else—at work?

If an older adult is exhibiting cognitive and/or behavioral disturbances after undergoing surgery, it’s important to discern if these manifestations are the result of delirium, a preexisting psychiatric disorder, or some other cause if the patient has a clear sensorium (ALGORITHM).^6,13,14

Delirium. If a patient’s CAM screen suggests delirium, conduct a thorough assessment for the signs and symptoms of delirium to determine if the patient meets DSM-5 criteria for the diagnosis.¹ In order to avoid missing hypoactive, subtle, or atypical cases of delirium, conduct a thorough medical record and medications review, and gather assessments from the nursing staff and other team members regarding the patient’s behavior.

Preexisting psychiatric disorder. It’s important to differentiate psychiatric symptoms from those of a superimposed delirium.¹³ Because patients with preoperative depressive symptoms may be at increased risk for postop delirium, pre-surgical psychiatric evaluations are important for identifying even subtle psychopathological symptoms.¹⁵ (The psychiatric interview is the gold standard for diagnosis.¹⁶) For patients who have an established psychiatric diagnosis, consider consulting with the psychiatrist who is managing the patient’s psychiatric care.¹³

Other causes. If a patient who is exhibiting postop cognitive and/or behavioral disturbances has a reasonably accurate memory and a correct orientation for time, place, and person, interviews with the patient and caregivers (along with the psychiatric interview) will likely reveal potential causes for the behavioral problems.¹³

Is the patient suffering from dehydration? Drug withdrawal?

Assessment for an underlying organic cause must be performed because specific treatment for the underlying diagnosis may improve delirium.¹⁷ Common causes include hypoxia, infection, dehydration, acute metabolic disturbance, endocrinopathies, cardiac or vascular disorders, and drug withdrawal.¹³ An appropriate diagnostic work-up might consist of serum urea, glucose, electrolytes, liver function tests, arterial blood gas analyses, urinalysis, nutritional evaluation, electrocardiogram, and a complete blood count.

Ask patients about their use of alcohol and benzodiazepines, and consider alcohol or drug withdrawal as potential etiologies.¹⁸ Patients with delirium should also be assessed for iatrogenic hospital-related factors that could be causing or contributing to the condition, such as immobilization or malnutrition.¹³

Medications are a common culprit: Approximately 40% of cases of delirium are related to medication use.¹⁸ Commonly used postop medications such as analgesics, sedatives, proton pump inhibitors, and others can cause delirium.¹⁹ Carefully review the patient’s medication list.¹³ Medication-induced delirium is influenced by the number of medications taken (generally >3),²⁰ the use of psychoactive medications,²¹ and the specific agent's anticholinergic potential.²² The 2012 updated Beers Criteria (American Geriatrics Society) is a useful resource for determining if “inappropriate polypharmacy” is the cause of postop delirium.²³

Inadequate pain control. In a multisite trial,²⁴ patients who received <10 mg/d of parenteral morphine sulfate equivalents were more likely to develop delirium than patients who received more analgesia. In cognitively intact patients, severe pain significantly increased the risk of delirium. With the exception of meperidine, opioids do not precipitate delirium in patients with acute pain.²⁴ Not treating pain or administering very low—or excessively high—doses of opioids is associated with an increased risk of delirium for both cognitively intact and impaired patients.²⁴

Constipation can contribute to the development of delirium.²⁵ After surgery, patients tend to be less mobile and may be receiving medications that can cause constipation, such as opioids, iron, calcium, and channel blockers. Preventing and treating constipation in postop patients can reduce delirium risk.²⁵

Begin treatment with nonpharmacologic measures

Preventing and treating constipation in postop patients can reduce delirium risk.

Regardless of whether a patient suffers from hyperactive, hypoactive, or mixed delirium, nonpharmacologic interventions are firstline treatment.¹⁹ Such interventions can help patients develop a sense of control over their environment, which can help relieve agitation.¹³ Because environmental shifts contribute to the development of delirium, avoiding transfers and securing a single room can be helpful.¹⁹ Patients with delirium have altered perceptions, and may view normal objects and routine clinician actions as harmful and threatening. Therefore, it is helpful to avoid sensory deprivation by making sure patients have access to their eyeglasses and hearing aids, and to provide nonthreatening cognitive/environmental stimulation.^1,13,19 Patients should be encouraged to resume walking as soon as possible.^1,19 Other nonpharmacologic interventions are listed in the TABLE.^1,13,19

Safety issues must also be addressed.¹⁷ Patients with mixed or hyperactive delirium may become agitated, which can lead them to pull tubes, drains, or lines, as occurred with Mr. Q. Patients with hypoactive delirium may be prone to wandering, or receive less attention due to their hypoactive state.¹⁷ All patients with delirium are at risk of falls.

Patients should be evaluated for these risks to determine whether assigning a "sitter" or transfer to a stepdown unit or intensive care unit is warranted.¹⁷ Restraints are not recommended because they can exacerbate delirium and lead to injuries.²⁶

Pharmacologic treatment should be reserved for patients whose behavior compromises their safety, and implemented only when the cause of the delirium is known. The primary objectives of drug therapy are to achieve and maintain safe and rapid behavioral control so the patient can receive necessary medical care, and to enhance functional recovery.¹⁴ The choice of a specific medication is individualized and depends on each patient’s clinical condition.¹⁴

For a patient with hyperactive delirium, an antipsychotic typically is the treatment of choice because these medications are dopamine receptor antagonists, and excessive dopamine transmission has been implicated in this type of delirium.²⁷ Haloperidol often is the preferred treatment; a low-dose oral form is recommended for older patients who exhibit severe agitation because there is less risk of QT prolongation compared to IV administration.²⁸

Avoid using benzodiazepines and other hypnotics in older patients with delirium, except when treating withdrawal.

Second-generation antipsychotics (eg, risperidone, olanzapine, and quetiapine) are increasingly used due to their lower risk for adverse extrapyramidal symptoms, which are common in older patients.^29-31 Despite this, increasing data show that morbidity with these agents may be underestimated, and the risks of adverse effects may vary among the medications in this class.³²

For hypoactive or mixed delirium, nonpharmacologic interventions should be the mainstay of treatment. When medications are used, they should be used to target the underlying etiology of delirium (eg, treating a urinary tract infection with an antibiotic).³³

A few final words about medication use for delirium ... Most medications that modify symptoms of delirium can actually prolong the delirium.³³ Therefore, it's important to carefully consider the balance between effectively managing symptoms and causing adverse effects. Because older adults have increased sensitivity to medications, always start with small dosages and titrate to effect.³⁴ Benzodiazepines and other hypnotics should be avoided in older patients, except when treating alcohol or benzodiazepine withdrawal.³⁵

CASE ›  Mr. Q’s postop delirium screen is positive, and assessment for underlying causes reveals that he is suffering from postoperative pain and is constipated. Due to roommate noise and insomnia, he is transferred to a private room, where quiet times are observed. He receives oxycodone 5 mg every 4 hours for his pain and senna 30 mg at bedtime and a bisacodyl rectal suppository 10 mg/d for constipation. After 3 days Mr. Q’s postop pain and delirium resolves, and he is discharged home.

CORRESPONDENCE
Jackson Ng, MD, Teresa Lang Research Center, New York Hospital Queens, 56-45 Main St., Flushing, NY 11355; [email protected]

CASE ›  Your patient, Mark Q, age 80, is admitted to the hospital to undergo hemicolectomy for colon cancer. His medical history includes hypertension, benign prostatic hyperplasia, and colon cancer. He did well immediately postop, but when you make morning rounds the day after his surgery, you notice that he is confused and agitated. Mr. Q’s chart reveals that earlier that morning, he pulled out his Foley catheter and intravenous (IV) line when his nurse declined his request to walk him to the bathroom.

How would you proceed?

Up to 50% of older adults who undergo surgical procedures develop delirium—a disturbance in attention and awareness accompanied by changes in cognition.¹ Older adults are at heightened risk for this postoperative complication for several reasons. For one thing, older patients have a reduced capacity for homeostatic regulation when they undergo anesthesia and surgery.² For another, age-related changes in brain neurochemistry and drug metabolism increase the likelihood of adverse drug effects, including those that could precipitate delirirum.³

Risk factors for postop delirium include age >65 years, dementia, poor vision, decreased hearing, severe illness, and infection.

Although postop delirium is a common complication in older patients, it sometimes goes unrecognized. Missed or delayed diagnosis of delirium can result in patients exhibiting behaviors that can compromise their safety, delay recuperation, and result in longer hospital stays, a greater financial burden, and increased morbidity and mortality.⁴ The American Geriatric Society recently published clinical guidelines and a best practices statement for preventing and treating postop delirium in patients ages >65 years.^1,5 This article describes steps family physicians can take to assess their patients’ risk of delirium before they undergo surgery, and to recognize and treat delirium in the postop period.

Defining delirium

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), the criteria for delirium are:⁶
A. A disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).
B. The disturbance develops over a short time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.
C. An additional disturbance in cognition (eg, memory deficits, disorientation, language, visuospatial ability, perception).
D. The disturbances in attention, awareness, and cognition aren’t better explained by another preexisting or evolving neurocognitive disorder and don’t occur in the context of a severely reduced level of arousal.
E. History, physical, or laboratory findings show that the disturbance is caused by the direct physiologic consequences of a general medical condition, substance intoxication/withdrawal, exposure to a toxin, or multiple etiologies.

The 3 subtypes of delirium are based on patients’ psychomotor activity.⁷ In hyperactive delirium, patients exhibit heightened arousal, restlessness, agitation, hallucinations, and inappropriate behavior. Hypoactive delirium is characterized by lethargy, reduced motor activity, incoherent speech, and lack of interest. Mixed delirium consists of a combination of hyperactive and hypoactive signs and symptoms.

Gauge risk before patients undergo surgery

Family physicians can assess their patients’ risk for developing delirium by conducting baseline screening during routine office visits as well as during preoperative evaluations. Factors that increase postop delirium risk include:¹
• age >65 years
• dementia
• poor vision
• decreased hearing
• severe illness
• infection.

Routine cognitive screening can be done easily and efficiently using readily available tools such as the Alzheimer Association’s Cognitive Assessment Toolkit.⁸ This toolkit includes 3 brief, validated screening tools to identify patients with probable cognitive impairment: the General Practitioner Assessment of Cognition, the Memory Impairment Screen, and the Mini-Cog.

If preop screening indicates that the patient is at increased risk for delirium, the family physician should work with hospital’s interdisciplinary teams to institute prevention measures, such as the Hospital Elder Life Program (HELP).⁹ This program offers a structured curriculum for instructing volunteers to deliver daily orientation, early mobilization, feeding assistance, therapeutic activities, and other measures to help prevent delirium.

Prompt screening after surgery is essential, too

In addition to preop delirium risk assessment, all patients who undergo surgery should receive daily delirium screening during the first postoperative week. The Confusion Assessment Method (CAM) is a quick screening tool for assessing a patient’s level of arousal and consciousness.¹⁰ Based on the results of 7 high-quality studies (N=1071), CAM has a sensitivity of 94% (95% confidence interval [CI], 91%-97%) and specificity of 89% (95% CI, 85%-94%).^11,12

Common underlying causes of delirium include hypoxia, infection, dehydration, acute metabolic disturbance, and drug withdrawal.

Feature 1 of CAM, “Acute onset and fluctuating course,” requires that you compare the patient’s current mental status to his or her pre-hospital baseline mental status; the baseline status should be obtained from a family member, caretaker, or clinician who has observed the patient over time.¹⁰ This is intended to determine if the patient has experienced an acute change in mental status (eg, attention, orientation, cognition), usually over the course of hours to days.¹⁰ Feature 2, “Inattention,” is used to determine if the patient has a reduced ability to maintain attention to external stimuli and to appropriately shift attention to new external stimuli, and if the patient is unaware or out of touch with the environment.¹⁰ Feature 3, “Disorganized thinking,” is used to assess the patient’s organization of thought as expressed by speech or writing. Disorganized thinking typically manifests as rambling and irrelevant or incoherent speech.¹⁰ Feature 4, “Altered level of consciousness,” is used to rate the patient’s alertness level.¹⁰

A positive screen for delirium requires the presence of Feature 1 (acute onset and/or fluctuation) and Feature 2, plus either Feature 3 or Feature 4.

Is delirium—or something else—at work?

If an older adult is exhibiting cognitive and/or behavioral disturbances after undergoing surgery, it’s important to discern if these manifestations are the result of delirium, a preexisting psychiatric disorder, or some other cause if the patient has a clear sensorium (ALGORITHM).^6,13,14

Delirium. If a patient’s CAM screen suggests delirium, conduct a thorough assessment for the signs and symptoms of delirium to determine if the patient meets DSM-5 criteria for the diagnosis.¹ In order to avoid missing hypoactive, subtle, or atypical cases of delirium, conduct a thorough medical record and medications review, and gather assessments from the nursing staff and other team members regarding the patient’s behavior.

Preexisting psychiatric disorder. It’s important to differentiate psychiatric symptoms from those of a superimposed delirium.¹³ Because patients with preoperative depressive symptoms may be at increased risk for postop delirium, pre-surgical psychiatric evaluations are important for identifying even subtle psychopathological symptoms.¹⁵ (The psychiatric interview is the gold standard for diagnosis.¹⁶) For patients who have an established psychiatric diagnosis, consider consulting with the psychiatrist who is managing the patient’s psychiatric care.¹³

Other causes. If a patient who is exhibiting postop cognitive and/or behavioral disturbances has a reasonably accurate memory and a correct orientation for time, place, and person, interviews with the patient and caregivers (along with the psychiatric interview) will likely reveal potential causes for the behavioral problems.¹³

Is the patient suffering from dehydration? Drug withdrawal?

Assessment for an underlying organic cause must be performed because specific treatment for the underlying diagnosis may improve delirium.¹⁷ Common causes include hypoxia, infection, dehydration, acute metabolic disturbance, endocrinopathies, cardiac or vascular disorders, and drug withdrawal.¹³ An appropriate diagnostic work-up might consist of serum urea, glucose, electrolytes, liver function tests, arterial blood gas analyses, urinalysis, nutritional evaluation, electrocardiogram, and a complete blood count.

Ask patients about their use of alcohol and benzodiazepines, and consider alcohol or drug withdrawal as potential etiologies.¹⁸ Patients with delirium should also be assessed for iatrogenic hospital-related factors that could be causing or contributing to the condition, such as immobilization or malnutrition.¹³

Medications are a common culprit: Approximately 40% of cases of delirium are related to medication use.¹⁸ Commonly used postop medications such as analgesics, sedatives, proton pump inhibitors, and others can cause delirium.¹⁹ Carefully review the patient’s medication list.¹³ Medication-induced delirium is influenced by the number of medications taken (generally >3),²⁰ the use of psychoactive medications,²¹ and the specific agent's anticholinergic potential.²² The 2012 updated Beers Criteria (American Geriatrics Society) is a useful resource for determining if “inappropriate polypharmacy” is the cause of postop delirium.²³

Inadequate pain control. In a multisite trial,²⁴ patients who received <10 mg/d of parenteral morphine sulfate equivalents were more likely to develop delirium than patients who received more analgesia. In cognitively intact patients, severe pain significantly increased the risk of delirium. With the exception of meperidine, opioids do not precipitate delirium in patients with acute pain.²⁴ Not treating pain or administering very low—or excessively high—doses of opioids is associated with an increased risk of delirium for both cognitively intact and impaired patients.²⁴

Constipation can contribute to the development of delirium.²⁵ After surgery, patients tend to be less mobile and may be receiving medications that can cause constipation, such as opioids, iron, calcium, and channel blockers. Preventing and treating constipation in postop patients can reduce delirium risk.²⁵

Begin treatment with nonpharmacologic measures

Preventing and treating constipation in postop patients can reduce delirium risk.

Regardless of whether a patient suffers from hyperactive, hypoactive, or mixed delirium, nonpharmacologic interventions are firstline treatment.¹⁹ Such interventions can help patients develop a sense of control over their environment, which can help relieve agitation.¹³ Because environmental shifts contribute to the development of delirium, avoiding transfers and securing a single room can be helpful.¹⁹ Patients with delirium have altered perceptions, and may view normal objects and routine clinician actions as harmful and threatening. Therefore, it is helpful to avoid sensory deprivation by making sure patients have access to their eyeglasses and hearing aids, and to provide nonthreatening cognitive/environmental stimulation.^1,13,19 Patients should be encouraged to resume walking as soon as possible.^1,19 Other nonpharmacologic interventions are listed in the TABLE.^1,13,19

Safety issues must also be addressed.¹⁷ Patients with mixed or hyperactive delirium may become agitated, which can lead them to pull tubes, drains, or lines, as occurred with Mr. Q. Patients with hypoactive delirium may be prone to wandering, or receive less attention due to their hypoactive state.¹⁷ All patients with delirium are at risk of falls.

Patients should be evaluated for these risks to determine whether assigning a "sitter" or transfer to a stepdown unit or intensive care unit is warranted.¹⁷ Restraints are not recommended because they can exacerbate delirium and lead to injuries.²⁶

Pharmacologic treatment should be reserved for patients whose behavior compromises their safety, and implemented only when the cause of the delirium is known. The primary objectives of drug therapy are to achieve and maintain safe and rapid behavioral control so the patient can receive necessary medical care, and to enhance functional recovery.¹⁴ The choice of a specific medication is individualized and depends on each patient’s clinical condition.¹⁴

For a patient with hyperactive delirium, an antipsychotic typically is the treatment of choice because these medications are dopamine receptor antagonists, and excessive dopamine transmission has been implicated in this type of delirium.²⁷ Haloperidol often is the preferred treatment; a low-dose oral form is recommended for older patients who exhibit severe agitation because there is less risk of QT prolongation compared to IV administration.²⁸

Avoid using benzodiazepines and other hypnotics in older patients with delirium, except when treating withdrawal.

Second-generation antipsychotics (eg, risperidone, olanzapine, and quetiapine) are increasingly used due to their lower risk for adverse extrapyramidal symptoms, which are common in older patients.^29-31 Despite this, increasing data show that morbidity with these agents may be underestimated, and the risks of adverse effects may vary among the medications in this class.³²

For hypoactive or mixed delirium, nonpharmacologic interventions should be the mainstay of treatment. When medications are used, they should be used to target the underlying etiology of delirium (eg, treating a urinary tract infection with an antibiotic).³³

A few final words about medication use for delirium ... Most medications that modify symptoms of delirium can actually prolong the delirium.³³ Therefore, it's important to carefully consider the balance between effectively managing symptoms and causing adverse effects. Because older adults have increased sensitivity to medications, always start with small dosages and titrate to effect.³⁴ Benzodiazepines and other hypnotics should be avoided in older patients, except when treating alcohol or benzodiazepine withdrawal.³⁵

CASE ›  Mr. Q’s postop delirium screen is positive, and assessment for underlying causes reveals that he is suffering from postoperative pain and is constipated. Due to roommate noise and insomnia, he is transferred to a private room, where quiet times are observed. He receives oxycodone 5 mg every 4 hours for his pain and senna 30 mg at bedtime and a bisacodyl rectal suppository 10 mg/d for constipation. After 3 days Mr. Q’s postop pain and delirium resolves, and he is discharged home.

CORRESPONDENCE
Jackson Ng, MD, Teresa Lang Research Center, New York Hospital Queens, 56-45 Main St., Flushing, NY 11355; [email protected]