Cleveland Clinic Journal of Medicine

The treatment of early esophageal, gastric, and colorectal cancer is changing.¹ For many years, surgery was the mainstay of treatment for early-stage gastrointestinal cancer. Unfortunately, surgery leads to significant loss of function of the organ, resulting in increased morbidity and decreased quality of life.²

Endoscopic techniques, particularly endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), have been developed and are widely used in Japan, where gastrointestinal cancer is more common than in the West. This article reviews the indications, complications, and outcomes of ESD for early gastrointestinal neoplasms, so that readers will recognize the subset of patients who would benefit from ESD in a Western setting.

ENDOSCOPIC MUCOSAL RESECTION AND SUBMUCOSAL DISSECTION

Since the first therapeutic polypectomy was performed in Japan in 1974, several endoscopic techniques for tumor resection have been developed.³

EMR, one of the most successful and widely used techniques, involves elevating the lesion either with submucosal injection of a solution or with cap suction, and then removing it with a snare.⁴ Most lesions smaller than 20 mm can be removed in one piece (en bloc).⁵ Larger lesions are removed in multiple pieces (ie, piecemeal). Unfortunately, some fibrotic lesions, which are usually difficult to lift, cannot be completely removed by EMR.

ESD was first performed in the late 1990s with the aim of overcoming the limitations of EMR in resecting large or fibrotic tumors en bloc.^6,7 Since then, ESD technique has been standardized and training centers have been created, especially in Asia, where it is widely used for treatment of early gastric cancer.^3,8–10 Since 2012 it has been covered by the Japanese National Health Insurance for treatment of early gastric cancer, and since 2014 for treatment of colorectal malignant tumors measuring 2 to 5 cm.¹¹

Adoption of ESD has been slow in Western countries, where many patients are still referred for surgery or undergo EMR for removal of superficial neoplasms. Reasons for this slow adoption are that gastric cancer is much less common in Western countries, and also that ESD demands a high level of technical skill, is difficult to learn, and is expensive.^3,12,13 However, small groups of Western endoscopists have become interested and are advocating it, first studying it on their own and then training in a Japanese center and learning from experts performing the procedure.

Therefore, in a Western setting, ESD should be performed in specialized endoscopy centers and offered to selected patients.¹  

CANDIDATES SHOULD HAVE EARLY-STAGE, SUPERFICIAL TUMORS

Ideal candidates for endoscopic resection are patients who have early cancer with a negligible risk of lymph node metastasis, such as cancer limited to the mucosa (stage T1a).⁷ Therefore, to determine the best treatment for a patient with a newly diagnosed gastrointestinal neoplasm, it is mandatory to estimate the depth of invasion.

The depth of invasion is directly correlated with lymph node involvement, which is ultimately the main predictive factor for long-term adverse outcomes of gastrointestinal tumors.^4,14–17 Accurate multidisciplinary preprocedure estimations are mandatory, as incorrect evaluations may result in inappropriate therapy and residual cancer.¹⁸

Other factors that have been used to predict lymph node involvement include tumor size, macroscopic appearance, histologic differentiation, and lymphatic and vascular involvement.¹⁹ Some of these factors can be assessed by special endoscopic techniques (chromoendoscopy and narrow-band imaging with magnifying endoscopy) that allow accurate real-time estimation of the depth of invasion of the lesion.^5,17,20–27 Evaluation of microsurface and microvascular arrangements is especially useful for determining the feasibility of ESD in gastric tumors, evaluation of intracapillary loops is useful in esophageal lesions, and assessment of mucosal pit patterns is useful for colorectal lesions.^21–29

Endoscopic ultrasonography is another tool that has been used to estimate the depth of the tumor. Although it can differentiate between definite intramucosal and definite submucosal invasive cancers, its ability to confirm minute submucosal invasion is limited. Its use as the sole tumor staging modality is not encouraged, and it should always be used in conjunction with endoscopic evaluation.¹⁸

Though the aforementioned factors help stratify patients, pathologic staging is the best predictor of lymph node metastasis. ESD provides adequate specimens for accurate pathologic evaluation, as it removes lesions en bloc.³⁰

All patients found to have risk factors for lymph node metastasis on endoscopic, ultrasonographic, or pathologic analysis should be referred for surgical evaluation.^9,19,31,32

ENDOSCOPIC SUBMUCOSAL DISSECTION

Before the procedure, the patient’s physicians need to do the following:

Determine the best type of intervention (EMR, ESD, ablation, surgery) for the specific lesion.³ A multidisciplinary approach is encouraged, with involvement of the internist, gastroenterologist, and surgeon.

Plan for anesthesia, additional consultations, pre- and postprocedural hospital admission, and need for special equipment.³³

During the procedure

Define the lateral extent of the lesion using magnification chromoendoscopy or narrow-band imaging. In the stomach, a biopsy sample should be taken from the worst-looking segment and from normal-looking mucosa. Multiple biopsies should be avoided to prevent subsequent fibrosis.³³ In the colon, biopsy should be avoided.³⁴

Identify and circumferentially mark the target lesion. Cautery or argon plasma coagulation can be used for making markings at a distance of 5 to 10 mm from the edges.³³ This is done to recognize the borders of the lesion, because they can become distorted after submucosal injection.¹⁴ This step is unnecessary in colorectal cases, as tumor margins can be adequately visualized after chromoendoscopy.^16,35

Lift the lesion by injecting saline, 0.5% hyaluronate, or glycerin to create a submucosal fluid cushion.^19,33

Perform a circumferential incision lateral to the mucosal margins to allow for a normal tissue margin.³³ Partial incision is performed for esophageal and colorectal ESD to avoid fluid leakage from the submucosal layer, achieving a sustained submucosal lift and safer dissection.¹⁶

Submucosal dissection. The submucosal layer is dissected with an electrocautery knife until the lesion is completely removed. Dissection should be done carefully to keep the submucosal plane.³³ Hemoclips or hemostat forceps can be used to control visible bleeding. The resected specimen is then stretched and fixed to a board using small pins for further histopathologic evaluation.³⁵

Postprocedural monitoring.  All patients should be admitted for overnight observation. Those who undergo gastric ESD should receive high-dose acid suppression, and the next day they can be started on a liquid diet.¹⁹

STOMACH CANCER

Indications for ESD for stomach cancer in the East

The incidence of gastric cancer is higher in Japan and Korea, where widespread screening programs have led to early identification and early treatment of this disease.³⁶

Pathology studies³⁷ of samples from patients with gastric cancer identified the following as risk factors for lymph node metastasis, which would make ESD unsuitable:

• Undifferentiated type
• Tumors larger than 2 cm
• Lymphatic or venous involvement
• Submucosal invasion
• Ulcerative change.

Based on these findings, the situations in which there was no risk of lymph node involvement (ie, when none of the above factors are present) were accepted as absolute indications for endoscopic resection of early gastric cancer.³⁸ Further histologic studies identified a subset of patients with lesions with very low risk of lymph node metastasis, which outweighed the risk of surgery. Based on these findings, expanded criteria for gastric ESD were proposed,^39,40 and the Japanese gastric cancer treatment guidelines now include these expanded preoperative indications^9,17 (Table 1).

Based on information from the Japanese Gastric Cancer Association, reference 9.

The Japanese Gastric Cancer Association has proposed a treatment algorithm based on the histopathologic evaluation after resection (Figure 2).⁹

Outcomes

In the largest series of patients who underwent curative ESD for early gastric cancer, the 5-year survival rate was 92.6%, the 5-year disease-specific survival rate was 99.9%, and the 5-year relative survival rate was 105%.⁴¹

Similarly, in a Japanese population-based survival analysis, the relative 5-year survival rate for localized gastric cancer was 94.4%.⁴² Rates of en bloc resection and complete resection with ESD are higher than those with EMR, resulting in a lower risk of local recurrence in selected patients who undergo ESD.^8,43,44

Although rare, local recurrence after curative gastric ESD has been reported.⁴⁵ The annual incidence of local recurrence has been estimated to be 0.84%.⁴⁶

ESD entails a shorter hospital stay and requires fewer resources than surgery, resulting in lower medical costs (Table 2).⁴⁴ Additionally, as endoscopic resection is associated with less morbidity, fewer procedure-related adverse events, and fewer complications, ESD could be used as the standard treatment for early gastric cancer.^47,48

The Western perspective on endoscopic submucosal dissection for gastric cancer

Since the prevalence of gastric cancer in Western countries is significantly lower than in Japan and Korea, local data and experience are scarce. However, experts performing ESD in the West have adopted the indications of the Japan Gastroenterological Endoscopy Society. The European Society of Gastrointestinal Endoscopy recommends ESD for excision of most superficial gastric neoplasms, with EMR being preferred only in lesions smaller than 15 mm, Paris classification 0 or IIA.^5,32

Patients with gastric lesions measuring 15 mm or larger should undergo high-quality endoscopy, preferably chromoendoscopy, to evaluate the mucosal patterns and determine the depth of invasion. If superficial involvement is confirmed, other imaging techniques are not routinely recommended.⁵ A surgery consult is also recommended.

ESOPHAGEAL CANCER

Indications for ESD for esophageal cancer in the East

Due to the success of ESD for early gastric cancer, this technique is now also used for superficial esophageal neoplasms.^19,49 It should be done in a specialized center, as it is more technically difficult than gastric ESD: the esophageal lumen is narrow, the wall is thin, and the esophagus moves with respiration and heartbeat.⁵⁰ A multidisciplinary approach including an endoscopist, a surgeon, and a pathologist is highly recommended for evaluation and treatment.

EMR is preferred for removal of mucosal cancer, in view of its safety profile and success rates. ESD can be considered in cases of lesions larger than 15 mm, poorly lifting tumors, and those with the possibility of submucosal invasion (Table 3).^5,45,49,51

Circumference involvement is critical when determining eligible candidates, as a defect involving more than three-fourths of the esophageal circumference can lead to esophageal strictures.⁵² Controlled prospective studies have shown promising results from giving intralesional and oral steroids to prevent stricture after ESD, which could potentially overcome this size limitation.^53,54

Outcomes for esophageal cancer

ESD has been shown to be safe and effective, achieving en bloc resection in 85% to 100% of patients.^19,51 Its advantages over EMR include en bloc resection, complete resection, and high curative rates, resulting in higher recurrence-free survival.^2,55,56 Although the incidence of complications such as bleeding, perforation, and stricture formation are higher with ESD, patients usually recover uneventfully.^2,19,20

ESD in the esophagus: The Western perspective

As data on the efficacy of EMR vs ESD for the treatment of Barrett esophagus with adenocarcinoma are limited, EMR is the gold standard endoscopic technique for removal of visible esophageal dysplastic lesions.^5,51,57 ESD can be considered for tumors larger than 15 mm, for poorly lifting lesions, and if there is suspicion of submucosal invasion.⁵

Patients should be evaluated by an experienced endoscopist, using an advanced imaging technique such as narrow-band imaging or chromoendoscopy. If suspicious features are found, endoscopic ultrasonography should be considered to confirm submucosal invasion or lymph node involvement.⁵

Indications for ESD for colorectal cancer in the East

Colon cancer is one of the leading causes of cancer-related deaths worldwide.⁵⁸ Since ESD has been found to be effective and safe in treating gastric cancer, it has also been used to remove large colorectal tumors.⁵⁹ However, ESD is not universally accepted in the treatment of colorectal neoplasms due to its greater technical difficulty, longer procedural time, and higher risk of perforating the thinner colonic wall compared with EMR.^21,60

Outcomes for colorectal cancer

Tumor size of 50 mm or larger is a risk factor for complications, while a high procedure volume at the center is a protective factor.⁶⁰

Endoscopic treatment of colorectal cancer: The Western perspective

EMR is the gold standard for removal of superficial colorectal lesions. However, ESD can be considered if there is suspicion of superficial submucosal invasion, especially for lesions larger than 20 mm that cannot be resected en bloc by EMR.³² ESD can also be used for fibrotic lesions not amenable to complete EMR removal, or as a salvage procedure after recurrence after EMR.⁶⁷ Proper selection of cases is critical.¹

Patients who have a superficial colonic lesion should be evaluated by means of high-definition endoscopy and chromoendoscopy to assess the mucosal pattern and establish feasibility of endoscopic resection. If submucosal invasion is suspected, staging with endoscopic ultrasonography or magnetic resonance imaging should be considered.⁵

FOLLOW-UP AFTER ESD

Endoscopic surveillance after the procedure is recommended, given the persistent risk of metachronous cancer after curative ESD due to its organ-sparing quality.⁶⁸ Surveillance endoscopy aims to achieve early detection and subsequent endoscopic resection of metachronous lesions.

Histopathologic evaluation assessing the presence of malignant cells in the margins of a resected sample is mandatory for determining the next step in treatment. If margins are negative, follow-up endoscopy can be done every 6 to 12 months. If margins are positive, the approach includes surgery, reattempting ESD or endoscopic surveillance in 3 or 6 months.^3,32 Although the surveillance strategy varies according to individual risk of metachronous cancer, it should be continued indefinitely.⁶⁸

COMPLICATIONS OF ESD

The most common procedure-related complications of ESD are bleeding, perforation, and stricture. Most intraprocedural adverse events can be managed endoscopically.⁶⁹

Bleeding

Most bleeding occurs during the procedure or early after it and can be controlled with electrocautery.^49,69 No episodes of massive bleeding, defined as causing clinical symptoms and requiring transfusion or surgery, have been reported.^20,43,55

In gastric ESD, delayed bleeding rates have ranged from 0 to 15.6%.⁶⁹ Bleeding may be prevented with endoscopic coagulation of visible vessels after dissection has been completed and by proton pump inhibitor therapy.^70,71 Excessive coagulation should be avoided to lower the risk of perforation.³³

In colorectal ESD the bleeding rate has been reported to be 2.2%; applying coagulation to an area where a blood vessel is suspected before cutting (precoagulation) may prevent subsequent bleeding.²¹

Perforation

For gastric ESD, perforation rates range from 1.2% to 5.2%.⁶⁹ Esophageal perforation rates can be up to 4%.⁴⁹ In colorectal ESD, perforation rates have been reported to be 1.6% to 6.6%.^60,72

Although most of the cases were successfully managed with conservative treatment, some required emergency surgery.^60,73

Strictures

In a case series of 532 patients undergoing gastric ESD, stricture was reported in 5 patients, all of whom presented with obstructive symptoms.⁷⁴ Risk factors for post-ESD gastric stenosis are a mucosal defect with a circumferential extent of more than three-fourths or a longitudinal extent of more than 5 cm.⁷⁵

Strictures are common after esophageal ESD, with rates ranging from 2% to 26%. The risk is higher when longer segments are removed or circumferential resection is performed. As previously mentioned, this complication may be reduced with ingestion or injection of steroids  after the procedure.^53,54

Surprisingly, ESD of large colorectal lesions involving more than three-fourths of the circumference of the rectum is rarely complicated by stenosis.⁷⁶

ESD requires a high level of technical skill, is time-consuming, and has a higher rate of complications than conventional endoscopic resection. A standardized ESD training system is needed, as the procedure is more difficult than EMR. Training in porcine models has been shown to confer competency in ESD in a Western setting.^13,16,33

Colorectal ESD is an even more challenging procedure, given the potential for complications related to its anatomy. Training centers in Japan usually have their trainees first master gastric ESD, then assist in more than 20 colorectal ESDs conducted by experienced endoscopists, and accomplish 30 cases before performing the procedure safely and independently.

As the incidence of gastric cancer is low in Western countries, trainees may also begin with lower rectal lesions, which are easier to remove.⁷⁷ Incorporation of ESD in the West would require a clear treatment algorithm. It is a complex procedure, with higher rates of complications, a prolonged learning curve, and prolonged procedure time. Therefore, it should be performed in specialized centers and under the special situations discussed here to ensure that the benefits for the patients outweigh the risks.

VALUE OF ENDOSCOPIC SUBMUCOSAL DISSECTION

The optimal method for resecting gastrointestinal neoplasms should be safe, cost-effective, and quick and should also completely remove the lesion. The best treatment strategy takes into account the characteristics of the lesion and the comorbidities and wishes of the patient. Internists should be aware of the multiple options available to achieve the best outcome for the patient.¹

Endoscopic resection of superficial gastrointestinal neoplasms, including EMR and ESD, has been a subject of increasing interest due to its minimally invasive and potentially curative character. However, cancer can recur after endoscopic resection because the procedure is organ-sparing.

ESD allows resection of early gastrointestinal tumors with a minimally invasive technique. It can achieve higher curative resection rates and lower recurrence rates compared with EMR. Compared with surgery, ESD leads to less morbidity, fewer procedure-related complications, and lower medical costs. Indications should be rigorously followed to achieve successful treatments in selected patients.

Multiple variables have to be taken into account when deciding which treatment is best, such as tumor characteristics, the patient’s baseline condition, physician expertise, and hospital resources.⁴⁸ Less-invasive treatments may improve the prognosis of patients. No matter the approach, patients should be treated in specialized treatment centers.

Internal medicine physicians should be aware of the advances in treatments for early gastrointestinal cancer so appropriate options can be considered.

The treatment of early esophageal, gastric, and colorectal cancer is changing.¹ For many years, surgery was the mainstay of treatment for early-stage gastrointestinal cancer. Unfortunately, surgery leads to significant loss of function of the organ, resulting in increased morbidity and decreased quality of life.²

Endoscopic techniques, particularly endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), have been developed and are widely used in Japan, where gastrointestinal cancer is more common than in the West. This article reviews the indications, complications, and outcomes of ESD for early gastrointestinal neoplasms, so that readers will recognize the subset of patients who would benefit from ESD in a Western setting.

ENDOSCOPIC MUCOSAL RESECTION AND SUBMUCOSAL DISSECTION

Since the first therapeutic polypectomy was performed in Japan in 1974, several endoscopic techniques for tumor resection have been developed.³

EMR, one of the most successful and widely used techniques, involves elevating the lesion either with submucosal injection of a solution or with cap suction, and then removing it with a snare.⁴ Most lesions smaller than 20 mm can be removed in one piece (en bloc).⁵ Larger lesions are removed in multiple pieces (ie, piecemeal). Unfortunately, some fibrotic lesions, which are usually difficult to lift, cannot be completely removed by EMR.

ESD was first performed in the late 1990s with the aim of overcoming the limitations of EMR in resecting large or fibrotic tumors en bloc.^6,7 Since then, ESD technique has been standardized and training centers have been created, especially in Asia, where it is widely used for treatment of early gastric cancer.^3,8–10 Since 2012 it has been covered by the Japanese National Health Insurance for treatment of early gastric cancer, and since 2014 for treatment of colorectal malignant tumors measuring 2 to 5 cm.¹¹

Adoption of ESD has been slow in Western countries, where many patients are still referred for surgery or undergo EMR for removal of superficial neoplasms. Reasons for this slow adoption are that gastric cancer is much less common in Western countries, and also that ESD demands a high level of technical skill, is difficult to learn, and is expensive.^3,12,13 However, small groups of Western endoscopists have become interested and are advocating it, first studying it on their own and then training in a Japanese center and learning from experts performing the procedure.

Therefore, in a Western setting, ESD should be performed in specialized endoscopy centers and offered to selected patients.¹  

CANDIDATES SHOULD HAVE EARLY-STAGE, SUPERFICIAL TUMORS

Ideal candidates for endoscopic resection are patients who have early cancer with a negligible risk of lymph node metastasis, such as cancer limited to the mucosa (stage T1a).⁷ Therefore, to determine the best treatment for a patient with a newly diagnosed gastrointestinal neoplasm, it is mandatory to estimate the depth of invasion.

The depth of invasion is directly correlated with lymph node involvement, which is ultimately the main predictive factor for long-term adverse outcomes of gastrointestinal tumors.^4,14–17 Accurate multidisciplinary preprocedure estimations are mandatory, as incorrect evaluations may result in inappropriate therapy and residual cancer.¹⁸

Other factors that have been used to predict lymph node involvement include tumor size, macroscopic appearance, histologic differentiation, and lymphatic and vascular involvement.¹⁹ Some of these factors can be assessed by special endoscopic techniques (chromoendoscopy and narrow-band imaging with magnifying endoscopy) that allow accurate real-time estimation of the depth of invasion of the lesion.^5,17,20–27 Evaluation of microsurface and microvascular arrangements is especially useful for determining the feasibility of ESD in gastric tumors, evaluation of intracapillary loops is useful in esophageal lesions, and assessment of mucosal pit patterns is useful for colorectal lesions.^21–29

Endoscopic ultrasonography is another tool that has been used to estimate the depth of the tumor. Although it can differentiate between definite intramucosal and definite submucosal invasive cancers, its ability to confirm minute submucosal invasion is limited. Its use as the sole tumor staging modality is not encouraged, and it should always be used in conjunction with endoscopic evaluation.¹⁸

Though the aforementioned factors help stratify patients, pathologic staging is the best predictor of lymph node metastasis. ESD provides adequate specimens for accurate pathologic evaluation, as it removes lesions en bloc.³⁰

All patients found to have risk factors for lymph node metastasis on endoscopic, ultrasonographic, or pathologic analysis should be referred for surgical evaluation.^9,19,31,32

ENDOSCOPIC SUBMUCOSAL DISSECTION

Before the procedure, the patient’s physicians need to do the following:

Determine the best type of intervention (EMR, ESD, ablation, surgery) for the specific lesion.³ A multidisciplinary approach is encouraged, with involvement of the internist, gastroenterologist, and surgeon.

Plan for anesthesia, additional consultations, pre- and postprocedural hospital admission, and need for special equipment.³³

During the procedure

Define the lateral extent of the lesion using magnification chromoendoscopy or narrow-band imaging. In the stomach, a biopsy sample should be taken from the worst-looking segment and from normal-looking mucosa. Multiple biopsies should be avoided to prevent subsequent fibrosis.³³ In the colon, biopsy should be avoided.³⁴

Identify and circumferentially mark the target lesion. Cautery or argon plasma coagulation can be used for making markings at a distance of 5 to 10 mm from the edges.³³ This is done to recognize the borders of the lesion, because they can become distorted after submucosal injection.¹⁴ This step is unnecessary in colorectal cases, as tumor margins can be adequately visualized after chromoendoscopy.^16,35

Lift the lesion by injecting saline, 0.5% hyaluronate, or glycerin to create a submucosal fluid cushion.^19,33

Perform a circumferential incision lateral to the mucosal margins to allow for a normal tissue margin.³³ Partial incision is performed for esophageal and colorectal ESD to avoid fluid leakage from the submucosal layer, achieving a sustained submucosal lift and safer dissection.¹⁶

Submucosal dissection. The submucosal layer is dissected with an electrocautery knife until the lesion is completely removed. Dissection should be done carefully to keep the submucosal plane.³³ Hemoclips or hemostat forceps can be used to control visible bleeding. The resected specimen is then stretched and fixed to a board using small pins for further histopathologic evaluation.³⁵

Postprocedural monitoring.  All patients should be admitted for overnight observation. Those who undergo gastric ESD should receive high-dose acid suppression, and the next day they can be started on a liquid diet.¹⁹

STOMACH CANCER

Indications for ESD for stomach cancer in the East

The incidence of gastric cancer is higher in Japan and Korea, where widespread screening programs have led to early identification and early treatment of this disease.³⁶

Pathology studies³⁷ of samples from patients with gastric cancer identified the following as risk factors for lymph node metastasis, which would make ESD unsuitable:

• Undifferentiated type
• Tumors larger than 2 cm
• Lymphatic or venous involvement
• Submucosal invasion
• Ulcerative change.

Based on these findings, the situations in which there was no risk of lymph node involvement (ie, when none of the above factors are present) were accepted as absolute indications for endoscopic resection of early gastric cancer.³⁸ Further histologic studies identified a subset of patients with lesions with very low risk of lymph node metastasis, which outweighed the risk of surgery. Based on these findings, expanded criteria for gastric ESD were proposed,^39,40 and the Japanese gastric cancer treatment guidelines now include these expanded preoperative indications^9,17 (Table 1).

Based on information from the Japanese Gastric Cancer Association, reference 9.

The Japanese Gastric Cancer Association has proposed a treatment algorithm based on the histopathologic evaluation after resection (Figure 2).⁹

Outcomes

In the largest series of patients who underwent curative ESD for early gastric cancer, the 5-year survival rate was 92.6%, the 5-year disease-specific survival rate was 99.9%, and the 5-year relative survival rate was 105%.⁴¹

Similarly, in a Japanese population-based survival analysis, the relative 5-year survival rate for localized gastric cancer was 94.4%.⁴² Rates of en bloc resection and complete resection with ESD are higher than those with EMR, resulting in a lower risk of local recurrence in selected patients who undergo ESD.^8,43,44

Although rare, local recurrence after curative gastric ESD has been reported.⁴⁵ The annual incidence of local recurrence has been estimated to be 0.84%.⁴⁶

ESD entails a shorter hospital stay and requires fewer resources than surgery, resulting in lower medical costs (Table 2).⁴⁴ Additionally, as endoscopic resection is associated with less morbidity, fewer procedure-related adverse events, and fewer complications, ESD could be used as the standard treatment for early gastric cancer.^47,48

The Western perspective on endoscopic submucosal dissection for gastric cancer

Since the prevalence of gastric cancer in Western countries is significantly lower than in Japan and Korea, local data and experience are scarce. However, experts performing ESD in the West have adopted the indications of the Japan Gastroenterological Endoscopy Society. The European Society of Gastrointestinal Endoscopy recommends ESD for excision of most superficial gastric neoplasms, with EMR being preferred only in lesions smaller than 15 mm, Paris classification 0 or IIA.^5,32

Patients with gastric lesions measuring 15 mm or larger should undergo high-quality endoscopy, preferably chromoendoscopy, to evaluate the mucosal patterns and determine the depth of invasion. If superficial involvement is confirmed, other imaging techniques are not routinely recommended.⁵ A surgery consult is also recommended.

ESOPHAGEAL CANCER

Indications for ESD for esophageal cancer in the East

Due to the success of ESD for early gastric cancer, this technique is now also used for superficial esophageal neoplasms.^19,49 It should be done in a specialized center, as it is more technically difficult than gastric ESD: the esophageal lumen is narrow, the wall is thin, and the esophagus moves with respiration and heartbeat.⁵⁰ A multidisciplinary approach including an endoscopist, a surgeon, and a pathologist is highly recommended for evaluation and treatment.

EMR is preferred for removal of mucosal cancer, in view of its safety profile and success rates. ESD can be considered in cases of lesions larger than 15 mm, poorly lifting tumors, and those with the possibility of submucosal invasion (Table 3).^5,45,49,51

Circumference involvement is critical when determining eligible candidates, as a defect involving more than three-fourths of the esophageal circumference can lead to esophageal strictures.⁵² Controlled prospective studies have shown promising results from giving intralesional and oral steroids to prevent stricture after ESD, which could potentially overcome this size limitation.^53,54

Outcomes for esophageal cancer

ESD has been shown to be safe and effective, achieving en bloc resection in 85% to 100% of patients.^19,51 Its advantages over EMR include en bloc resection, complete resection, and high curative rates, resulting in higher recurrence-free survival.^2,55,56 Although the incidence of complications such as bleeding, perforation, and stricture formation are higher with ESD, patients usually recover uneventfully.^2,19,20

ESD in the esophagus: The Western perspective

As data on the efficacy of EMR vs ESD for the treatment of Barrett esophagus with adenocarcinoma are limited, EMR is the gold standard endoscopic technique for removal of visible esophageal dysplastic lesions.^5,51,57 ESD can be considered for tumors larger than 15 mm, for poorly lifting lesions, and if there is suspicion of submucosal invasion.⁵

Patients should be evaluated by an experienced endoscopist, using an advanced imaging technique such as narrow-band imaging or chromoendoscopy. If suspicious features are found, endoscopic ultrasonography should be considered to confirm submucosal invasion or lymph node involvement.⁵

Indications for ESD for colorectal cancer in the East

Colon cancer is one of the leading causes of cancer-related deaths worldwide.⁵⁸ Since ESD has been found to be effective and safe in treating gastric cancer, it has also been used to remove large colorectal tumors.⁵⁹ However, ESD is not universally accepted in the treatment of colorectal neoplasms due to its greater technical difficulty, longer procedural time, and higher risk of perforating the thinner colonic wall compared with EMR.^21,60

Outcomes for colorectal cancer

Tumor size of 50 mm or larger is a risk factor for complications, while a high procedure volume at the center is a protective factor.⁶⁰

Endoscopic treatment of colorectal cancer: The Western perspective

EMR is the gold standard for removal of superficial colorectal lesions. However, ESD can be considered if there is suspicion of superficial submucosal invasion, especially for lesions larger than 20 mm that cannot be resected en bloc by EMR.³² ESD can also be used for fibrotic lesions not amenable to complete EMR removal, or as a salvage procedure after recurrence after EMR.⁶⁷ Proper selection of cases is critical.¹

Patients who have a superficial colonic lesion should be evaluated by means of high-definition endoscopy and chromoendoscopy to assess the mucosal pattern and establish feasibility of endoscopic resection. If submucosal invasion is suspected, staging with endoscopic ultrasonography or magnetic resonance imaging should be considered.⁵

FOLLOW-UP AFTER ESD

Endoscopic surveillance after the procedure is recommended, given the persistent risk of metachronous cancer after curative ESD due to its organ-sparing quality.⁶⁸ Surveillance endoscopy aims to achieve early detection and subsequent endoscopic resection of metachronous lesions.

Histopathologic evaluation assessing the presence of malignant cells in the margins of a resected sample is mandatory for determining the next step in treatment. If margins are negative, follow-up endoscopy can be done every 6 to 12 months. If margins are positive, the approach includes surgery, reattempting ESD or endoscopic surveillance in 3 or 6 months.^3,32 Although the surveillance strategy varies according to individual risk of metachronous cancer, it should be continued indefinitely.⁶⁸

COMPLICATIONS OF ESD

The most common procedure-related complications of ESD are bleeding, perforation, and stricture. Most intraprocedural adverse events can be managed endoscopically.⁶⁹

Bleeding

Most bleeding occurs during the procedure or early after it and can be controlled with electrocautery.^49,69 No episodes of massive bleeding, defined as causing clinical symptoms and requiring transfusion or surgery, have been reported.^20,43,55

In gastric ESD, delayed bleeding rates have ranged from 0 to 15.6%.⁶⁹ Bleeding may be prevented with endoscopic coagulation of visible vessels after dissection has been completed and by proton pump inhibitor therapy.^70,71 Excessive coagulation should be avoided to lower the risk of perforation.³³

In colorectal ESD the bleeding rate has been reported to be 2.2%; applying coagulation to an area where a blood vessel is suspected before cutting (precoagulation) may prevent subsequent bleeding.²¹

Perforation

For gastric ESD, perforation rates range from 1.2% to 5.2%.⁶⁹ Esophageal perforation rates can be up to 4%.⁴⁹ In colorectal ESD, perforation rates have been reported to be 1.6% to 6.6%.^60,72

Although most of the cases were successfully managed with conservative treatment, some required emergency surgery.^60,73

Strictures

In a case series of 532 patients undergoing gastric ESD, stricture was reported in 5 patients, all of whom presented with obstructive symptoms.⁷⁴ Risk factors for post-ESD gastric stenosis are a mucosal defect with a circumferential extent of more than three-fourths or a longitudinal extent of more than 5 cm.⁷⁵

Strictures are common after esophageal ESD, with rates ranging from 2% to 26%. The risk is higher when longer segments are removed or circumferential resection is performed. As previously mentioned, this complication may be reduced with ingestion or injection of steroids  after the procedure.^53,54

Surprisingly, ESD of large colorectal lesions involving more than three-fourths of the circumference of the rectum is rarely complicated by stenosis.⁷⁶

ESD requires a high level of technical skill, is time-consuming, and has a higher rate of complications than conventional endoscopic resection. A standardized ESD training system is needed, as the procedure is more difficult than EMR. Training in porcine models has been shown to confer competency in ESD in a Western setting.^13,16,33

Colorectal ESD is an even more challenging procedure, given the potential for complications related to its anatomy. Training centers in Japan usually have their trainees first master gastric ESD, then assist in more than 20 colorectal ESDs conducted by experienced endoscopists, and accomplish 30 cases before performing the procedure safely and independently.

As the incidence of gastric cancer is low in Western countries, trainees may also begin with lower rectal lesions, which are easier to remove.⁷⁷ Incorporation of ESD in the West would require a clear treatment algorithm. It is a complex procedure, with higher rates of complications, a prolonged learning curve, and prolonged procedure time. Therefore, it should be performed in specialized centers and under the special situations discussed here to ensure that the benefits for the patients outweigh the risks.

VALUE OF ENDOSCOPIC SUBMUCOSAL DISSECTION

The optimal method for resecting gastrointestinal neoplasms should be safe, cost-effective, and quick and should also completely remove the lesion. The best treatment strategy takes into account the characteristics of the lesion and the comorbidities and wishes of the patient. Internists should be aware of the multiple options available to achieve the best outcome for the patient.¹

Endoscopic resection of superficial gastrointestinal neoplasms, including EMR and ESD, has been a subject of increasing interest due to its minimally invasive and potentially curative character. However, cancer can recur after endoscopic resection because the procedure is organ-sparing.

ESD allows resection of early gastrointestinal tumors with a minimally invasive technique. It can achieve higher curative resection rates and lower recurrence rates compared with EMR. Compared with surgery, ESD leads to less morbidity, fewer procedure-related complications, and lower medical costs. Indications should be rigorously followed to achieve successful treatments in selected patients.

Multiple variables have to be taken into account when deciding which treatment is best, such as tumor characteristics, the patient’s baseline condition, physician expertise, and hospital resources.⁴⁸ Less-invasive treatments may improve the prognosis of patients. No matter the approach, patients should be treated in specialized treatment centers.

Internal medicine physicians should be aware of the advances in treatments for early gastrointestinal cancer so appropriate options can be considered.

The treatment of early esophageal, gastric, and colorectal cancer is changing.¹ For many years, surgery was the mainstay of treatment for early-stage gastrointestinal cancer. Unfortunately, surgery leads to significant loss of function of the organ, resulting in increased morbidity and decreased quality of life.²

Endoscopic techniques, particularly endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), have been developed and are widely used in Japan, where gastrointestinal cancer is more common than in the West. This article reviews the indications, complications, and outcomes of ESD for early gastrointestinal neoplasms, so that readers will recognize the subset of patients who would benefit from ESD in a Western setting.

ENDOSCOPIC MUCOSAL RESECTION AND SUBMUCOSAL DISSECTION

Since the first therapeutic polypectomy was performed in Japan in 1974, several endoscopic techniques for tumor resection have been developed.³

EMR, one of the most successful and widely used techniques, involves elevating the lesion either with submucosal injection of a solution or with cap suction, and then removing it with a snare.⁴ Most lesions smaller than 20 mm can be removed in one piece (en bloc).⁵ Larger lesions are removed in multiple pieces (ie, piecemeal). Unfortunately, some fibrotic lesions, which are usually difficult to lift, cannot be completely removed by EMR.

ESD was first performed in the late 1990s with the aim of overcoming the limitations of EMR in resecting large or fibrotic tumors en bloc.^6,7 Since then, ESD technique has been standardized and training centers have been created, especially in Asia, where it is widely used for treatment of early gastric cancer.^3,8–10 Since 2012 it has been covered by the Japanese National Health Insurance for treatment of early gastric cancer, and since 2014 for treatment of colorectal malignant tumors measuring 2 to 5 cm.¹¹

Adoption of ESD has been slow in Western countries, where many patients are still referred for surgery or undergo EMR for removal of superficial neoplasms. Reasons for this slow adoption are that gastric cancer is much less common in Western countries, and also that ESD demands a high level of technical skill, is difficult to learn, and is expensive.^3,12,13 However, small groups of Western endoscopists have become interested and are advocating it, first studying it on their own and then training in a Japanese center and learning from experts performing the procedure.

Therefore, in a Western setting, ESD should be performed in specialized endoscopy centers and offered to selected patients.¹  

CANDIDATES SHOULD HAVE EARLY-STAGE, SUPERFICIAL TUMORS

Ideal candidates for endoscopic resection are patients who have early cancer with a negligible risk of lymph node metastasis, such as cancer limited to the mucosa (stage T1a).⁷ Therefore, to determine the best treatment for a patient with a newly diagnosed gastrointestinal neoplasm, it is mandatory to estimate the depth of invasion.

The depth of invasion is directly correlated with lymph node involvement, which is ultimately the main predictive factor for long-term adverse outcomes of gastrointestinal tumors.^4,14–17 Accurate multidisciplinary preprocedure estimations are mandatory, as incorrect evaluations may result in inappropriate therapy and residual cancer.¹⁸

Other factors that have been used to predict lymph node involvement include tumor size, macroscopic appearance, histologic differentiation, and lymphatic and vascular involvement.¹⁹ Some of these factors can be assessed by special endoscopic techniques (chromoendoscopy and narrow-band imaging with magnifying endoscopy) that allow accurate real-time estimation of the depth of invasion of the lesion.^5,17,20–27 Evaluation of microsurface and microvascular arrangements is especially useful for determining the feasibility of ESD in gastric tumors, evaluation of intracapillary loops is useful in esophageal lesions, and assessment of mucosal pit patterns is useful for colorectal lesions.^21–29

Endoscopic ultrasonography is another tool that has been used to estimate the depth of the tumor. Although it can differentiate between definite intramucosal and definite submucosal invasive cancers, its ability to confirm minute submucosal invasion is limited. Its use as the sole tumor staging modality is not encouraged, and it should always be used in conjunction with endoscopic evaluation.¹⁸

Though the aforementioned factors help stratify patients, pathologic staging is the best predictor of lymph node metastasis. ESD provides adequate specimens for accurate pathologic evaluation, as it removes lesions en bloc.³⁰

All patients found to have risk factors for lymph node metastasis on endoscopic, ultrasonographic, or pathologic analysis should be referred for surgical evaluation.^9,19,31,32

ENDOSCOPIC SUBMUCOSAL DISSECTION

Before the procedure, the patient’s physicians need to do the following:

Determine the best type of intervention (EMR, ESD, ablation, surgery) for the specific lesion.³ A multidisciplinary approach is encouraged, with involvement of the internist, gastroenterologist, and surgeon.

Plan for anesthesia, additional consultations, pre- and postprocedural hospital admission, and need for special equipment.³³

During the procedure

Define the lateral extent of the lesion using magnification chromoendoscopy or narrow-band imaging. In the stomach, a biopsy sample should be taken from the worst-looking segment and from normal-looking mucosa. Multiple biopsies should be avoided to prevent subsequent fibrosis.³³ In the colon, biopsy should be avoided.³⁴

Identify and circumferentially mark the target lesion. Cautery or argon plasma coagulation can be used for making markings at a distance of 5 to 10 mm from the edges.³³ This is done to recognize the borders of the lesion, because they can become distorted after submucosal injection.¹⁴ This step is unnecessary in colorectal cases, as tumor margins can be adequately visualized after chromoendoscopy.^16,35

Lift the lesion by injecting saline, 0.5% hyaluronate, or glycerin to create a submucosal fluid cushion.^19,33

Perform a circumferential incision lateral to the mucosal margins to allow for a normal tissue margin.³³ Partial incision is performed for esophageal and colorectal ESD to avoid fluid leakage from the submucosal layer, achieving a sustained submucosal lift and safer dissection.¹⁶

Submucosal dissection. The submucosal layer is dissected with an electrocautery knife until the lesion is completely removed. Dissection should be done carefully to keep the submucosal plane.³³ Hemoclips or hemostat forceps can be used to control visible bleeding. The resected specimen is then stretched and fixed to a board using small pins for further histopathologic evaluation.³⁵

Postprocedural monitoring.  All patients should be admitted for overnight observation. Those who undergo gastric ESD should receive high-dose acid suppression, and the next day they can be started on a liquid diet.¹⁹

STOMACH CANCER

Indications for ESD for stomach cancer in the East

The incidence of gastric cancer is higher in Japan and Korea, where widespread screening programs have led to early identification and early treatment of this disease.³⁶

Pathology studies³⁷ of samples from patients with gastric cancer identified the following as risk factors for lymph node metastasis, which would make ESD unsuitable:

• Undifferentiated type
• Tumors larger than 2 cm
• Lymphatic or venous involvement
• Submucosal invasion
• Ulcerative change.

Based on these findings, the situations in which there was no risk of lymph node involvement (ie, when none of the above factors are present) were accepted as absolute indications for endoscopic resection of early gastric cancer.³⁸ Further histologic studies identified a subset of patients with lesions with very low risk of lymph node metastasis, which outweighed the risk of surgery. Based on these findings, expanded criteria for gastric ESD were proposed,^39,40 and the Japanese gastric cancer treatment guidelines now include these expanded preoperative indications^9,17 (Table 1).

Based on information from the Japanese Gastric Cancer Association, reference 9.

The Japanese Gastric Cancer Association has proposed a treatment algorithm based on the histopathologic evaluation after resection (Figure 2).⁹

Outcomes

In the largest series of patients who underwent curative ESD for early gastric cancer, the 5-year survival rate was 92.6%, the 5-year disease-specific survival rate was 99.9%, and the 5-year relative survival rate was 105%.⁴¹

Similarly, in a Japanese population-based survival analysis, the relative 5-year survival rate for localized gastric cancer was 94.4%.⁴² Rates of en bloc resection and complete resection with ESD are higher than those with EMR, resulting in a lower risk of local recurrence in selected patients who undergo ESD.^8,43,44

Although rare, local recurrence after curative gastric ESD has been reported.⁴⁵ The annual incidence of local recurrence has been estimated to be 0.84%.⁴⁶

ESD entails a shorter hospital stay and requires fewer resources than surgery, resulting in lower medical costs (Table 2).⁴⁴ Additionally, as endoscopic resection is associated with less morbidity, fewer procedure-related adverse events, and fewer complications, ESD could be used as the standard treatment for early gastric cancer.^47,48

The Western perspective on endoscopic submucosal dissection for gastric cancer

Since the prevalence of gastric cancer in Western countries is significantly lower than in Japan and Korea, local data and experience are scarce. However, experts performing ESD in the West have adopted the indications of the Japan Gastroenterological Endoscopy Society. The European Society of Gastrointestinal Endoscopy recommends ESD for excision of most superficial gastric neoplasms, with EMR being preferred only in lesions smaller than 15 mm, Paris classification 0 or IIA.^5,32

Patients with gastric lesions measuring 15 mm or larger should undergo high-quality endoscopy, preferably chromoendoscopy, to evaluate the mucosal patterns and determine the depth of invasion. If superficial involvement is confirmed, other imaging techniques are not routinely recommended.⁵ A surgery consult is also recommended.

ESOPHAGEAL CANCER

Indications for ESD for esophageal cancer in the East

Due to the success of ESD for early gastric cancer, this technique is now also used for superficial esophageal neoplasms.^19,49 It should be done in a specialized center, as it is more technically difficult than gastric ESD: the esophageal lumen is narrow, the wall is thin, and the esophagus moves with respiration and heartbeat.⁵⁰ A multidisciplinary approach including an endoscopist, a surgeon, and a pathologist is highly recommended for evaluation and treatment.

EMR is preferred for removal of mucosal cancer, in view of its safety profile and success rates. ESD can be considered in cases of lesions larger than 15 mm, poorly lifting tumors, and those with the possibility of submucosal invasion (Table 3).^5,45,49,51

Circumference involvement is critical when determining eligible candidates, as a defect involving more than three-fourths of the esophageal circumference can lead to esophageal strictures.⁵² Controlled prospective studies have shown promising results from giving intralesional and oral steroids to prevent stricture after ESD, which could potentially overcome this size limitation.^53,54

Outcomes for esophageal cancer

ESD has been shown to be safe and effective, achieving en bloc resection in 85% to 100% of patients.^19,51 Its advantages over EMR include en bloc resection, complete resection, and high curative rates, resulting in higher recurrence-free survival.^2,55,56 Although the incidence of complications such as bleeding, perforation, and stricture formation are higher with ESD, patients usually recover uneventfully.^2,19,20

ESD in the esophagus: The Western perspective

As data on the efficacy of EMR vs ESD for the treatment of Barrett esophagus with adenocarcinoma are limited, EMR is the gold standard endoscopic technique for removal of visible esophageal dysplastic lesions.^5,51,57 ESD can be considered for tumors larger than 15 mm, for poorly lifting lesions, and if there is suspicion of submucosal invasion.⁵

Patients should be evaluated by an experienced endoscopist, using an advanced imaging technique such as narrow-band imaging or chromoendoscopy. If suspicious features are found, endoscopic ultrasonography should be considered to confirm submucosal invasion or lymph node involvement.⁵

Indications for ESD for colorectal cancer in the East

Colon cancer is one of the leading causes of cancer-related deaths worldwide.⁵⁸ Since ESD has been found to be effective and safe in treating gastric cancer, it has also been used to remove large colorectal tumors.⁵⁹ However, ESD is not universally accepted in the treatment of colorectal neoplasms due to its greater technical difficulty, longer procedural time, and higher risk of perforating the thinner colonic wall compared with EMR.^21,60

Outcomes for colorectal cancer

Tumor size of 50 mm or larger is a risk factor for complications, while a high procedure volume at the center is a protective factor.⁶⁰

Endoscopic treatment of colorectal cancer: The Western perspective

EMR is the gold standard for removal of superficial colorectal lesions. However, ESD can be considered if there is suspicion of superficial submucosal invasion, especially for lesions larger than 20 mm that cannot be resected en bloc by EMR.³² ESD can also be used for fibrotic lesions not amenable to complete EMR removal, or as a salvage procedure after recurrence after EMR.⁶⁷ Proper selection of cases is critical.¹

Patients who have a superficial colonic lesion should be evaluated by means of high-definition endoscopy and chromoendoscopy to assess the mucosal pattern and establish feasibility of endoscopic resection. If submucosal invasion is suspected, staging with endoscopic ultrasonography or magnetic resonance imaging should be considered.⁵

FOLLOW-UP AFTER ESD

Endoscopic surveillance after the procedure is recommended, given the persistent risk of metachronous cancer after curative ESD due to its organ-sparing quality.⁶⁸ Surveillance endoscopy aims to achieve early detection and subsequent endoscopic resection of metachronous lesions.

Histopathologic evaluation assessing the presence of malignant cells in the margins of a resected sample is mandatory for determining the next step in treatment. If margins are negative, follow-up endoscopy can be done every 6 to 12 months. If margins are positive, the approach includes surgery, reattempting ESD or endoscopic surveillance in 3 or 6 months.^3,32 Although the surveillance strategy varies according to individual risk of metachronous cancer, it should be continued indefinitely.⁶⁸

COMPLICATIONS OF ESD

The most common procedure-related complications of ESD are bleeding, perforation, and stricture. Most intraprocedural adverse events can be managed endoscopically.⁶⁹

Bleeding

Most bleeding occurs during the procedure or early after it and can be controlled with electrocautery.^49,69 No episodes of massive bleeding, defined as causing clinical symptoms and requiring transfusion or surgery, have been reported.^20,43,55

In gastric ESD, delayed bleeding rates have ranged from 0 to 15.6%.⁶⁹ Bleeding may be prevented with endoscopic coagulation of visible vessels after dissection has been completed and by proton pump inhibitor therapy.^70,71 Excessive coagulation should be avoided to lower the risk of perforation.³³

In colorectal ESD the bleeding rate has been reported to be 2.2%; applying coagulation to an area where a blood vessel is suspected before cutting (precoagulation) may prevent subsequent bleeding.²¹

Perforation

For gastric ESD, perforation rates range from 1.2% to 5.2%.⁶⁹ Esophageal perforation rates can be up to 4%.⁴⁹ In colorectal ESD, perforation rates have been reported to be 1.6% to 6.6%.^60,72

Although most of the cases were successfully managed with conservative treatment, some required emergency surgery.^60,73

Strictures

In a case series of 532 patients undergoing gastric ESD, stricture was reported in 5 patients, all of whom presented with obstructive symptoms.⁷⁴ Risk factors for post-ESD gastric stenosis are a mucosal defect with a circumferential extent of more than three-fourths or a longitudinal extent of more than 5 cm.⁷⁵

Strictures are common after esophageal ESD, with rates ranging from 2% to 26%. The risk is higher when longer segments are removed or circumferential resection is performed. As previously mentioned, this complication may be reduced with ingestion or injection of steroids  after the procedure.^53,54

Surprisingly, ESD of large colorectal lesions involving more than three-fourths of the circumference of the rectum is rarely complicated by stenosis.⁷⁶

ESD requires a high level of technical skill, is time-consuming, and has a higher rate of complications than conventional endoscopic resection. A standardized ESD training system is needed, as the procedure is more difficult than EMR. Training in porcine models has been shown to confer competency in ESD in a Western setting.^13,16,33

Colorectal ESD is an even more challenging procedure, given the potential for complications related to its anatomy. Training centers in Japan usually have their trainees first master gastric ESD, then assist in more than 20 colorectal ESDs conducted by experienced endoscopists, and accomplish 30 cases before performing the procedure safely and independently.

As the incidence of gastric cancer is low in Western countries, trainees may also begin with lower rectal lesions, which are easier to remove.⁷⁷ Incorporation of ESD in the West would require a clear treatment algorithm. It is a complex procedure, with higher rates of complications, a prolonged learning curve, and prolonged procedure time. Therefore, it should be performed in specialized centers and under the special situations discussed here to ensure that the benefits for the patients outweigh the risks.

VALUE OF ENDOSCOPIC SUBMUCOSAL DISSECTION

The optimal method for resecting gastrointestinal neoplasms should be safe, cost-effective, and quick and should also completely remove the lesion. The best treatment strategy takes into account the characteristics of the lesion and the comorbidities and wishes of the patient. Internists should be aware of the multiple options available to achieve the best outcome for the patient.¹

Endoscopic resection of superficial gastrointestinal neoplasms, including EMR and ESD, has been a subject of increasing interest due to its minimally invasive and potentially curative character. However, cancer can recur after endoscopic resection because the procedure is organ-sparing.

ESD allows resection of early gastrointestinal tumors with a minimally invasive technique. It can achieve higher curative resection rates and lower recurrence rates compared with EMR. Compared with surgery, ESD leads to less morbidity, fewer procedure-related complications, and lower medical costs. Indications should be rigorously followed to achieve successful treatments in selected patients.

Multiple variables have to be taken into account when deciding which treatment is best, such as tumor characteristics, the patient’s baseline condition, physician expertise, and hospital resources.⁴⁸ Less-invasive treatments may improve the prognosis of patients. No matter the approach, patients should be treated in specialized treatment centers.

Internal medicine physicians should be aware of the advances in treatments for early gastrointestinal cancer so appropriate options can be considered.

A 71-year-old man with a history of hypertension, 4 prior myocardial infarctions (MIs), and well-compensated ischemic cardiomyopathy presented to the emergency department after 2 episodes of sharp pain in the left upper abdomen and chest. The episodes lasted 1 to 2 minutes and were not relieved by rest. Their location was similar to that of the pain he experienced with his MIs. He could not identify any exacerbating or ameliorating factors. The pain had resolved without specific therapy before he arrived.

He reported polydipsia and constipation over the past 2 weeks and generalized muscle weakness and acute exacerbations of chronic back pain in the past 2 days. Neither he nor a friend who accompanied him noticed any confusion. He had been taking as many as 15 calcium carbonate tablets a day for 6 weeks to self-treat dyspepsia refractory to once-daily ranitidine, and hydrochlorothiazide for his hypertension for 3 weeks.

FURTHER EVALUATION, CARDIOLOGY CONSULT

On physical examination, he had diffuse weakness, dry mucous membranes, and an irregular heart rhythm.

Laboratory testing showed the following:

• Troponin I 0.11 ng/mL (reference range ≤ 0.04); repeated, it was 0.12 ng/mL
• Serum creatinine 3.4 mg/dL (0.44–1.27) (9 months earlier it had been 0.99 mg/dL)
• Serum calcium 17.3 mg/dL (8.6–10.5)
• Parathyroid hormone 9 pg/mL (12–88)
• Serum bicarbonate 33 mmol/L (24–32); 2 weeks earlier, it had been 27 mmol/L.

DIAGNOSIS: MILK-ALKALI SYNDROME

The diagnosis, based on the presentation and the results of the workup, was milk-alkali syndrome complicated by recent hydrochlorothiazide use. This syndrome consists of the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury, all due to excessive ingestion of calcium and alkali, usually calcium carbonate.

His hydrochlorothiazide and calcium carbonate were discontinued. He was given intravenous normal saline and subcutaneous calcitonin, and his serum calcium level came down to 11.5 mg/dL within the next 24 hours. His dyspepsia was treated with pantoprazole.

The patient had no further episodes of chest pain, and the cardiology consult team again recommended against coronary angiography. Repeat ECG after the hypercalcemia resolved showed results identical to those 4 months before his admission. Two months later, his serum calcium level was 9.4 mg/dL and his creatinine level was 1.24 mg/dL.

A MIMIC OF STEMI

In numerous reported cases, these electrocardiographic findings coupled with chest pain led to misdiagnosis of STEMI.^1–3 While STEMI and occasionally hypercalcemia can cause ST elevation, hypercalcemia causes a significant shortening of the corrected QT interval that is not associated with STEMI.^4,5

Ultimately, the diagnosis of MI involves clinical, laboratory, and ECG findings, and if a strong clinical suspicion for myocardial ischemia exists, STEMI cannot reliably be distinguished from hypercalcemia by ECG alone. It is nonetheless important to be aware of this complication of hypercalcemia to avoid unnecessary cardiac interventions.

A 71-year-old man with a history of hypertension, 4 prior myocardial infarctions (MIs), and well-compensated ischemic cardiomyopathy presented to the emergency department after 2 episodes of sharp pain in the left upper abdomen and chest. The episodes lasted 1 to 2 minutes and were not relieved by rest. Their location was similar to that of the pain he experienced with his MIs. He could not identify any exacerbating or ameliorating factors. The pain had resolved without specific therapy before he arrived.

He reported polydipsia and constipation over the past 2 weeks and generalized muscle weakness and acute exacerbations of chronic back pain in the past 2 days. Neither he nor a friend who accompanied him noticed any confusion. He had been taking as many as 15 calcium carbonate tablets a day for 6 weeks to self-treat dyspepsia refractory to once-daily ranitidine, and hydrochlorothiazide for his hypertension for 3 weeks.

FURTHER EVALUATION, CARDIOLOGY CONSULT

On physical examination, he had diffuse weakness, dry mucous membranes, and an irregular heart rhythm.

Laboratory testing showed the following:

• Troponin I 0.11 ng/mL (reference range ≤ 0.04); repeated, it was 0.12 ng/mL
• Serum creatinine 3.4 mg/dL (0.44–1.27) (9 months earlier it had been 0.99 mg/dL)
• Serum calcium 17.3 mg/dL (8.6–10.5)
• Parathyroid hormone 9 pg/mL (12–88)
• Serum bicarbonate 33 mmol/L (24–32); 2 weeks earlier, it had been 27 mmol/L.

DIAGNOSIS: MILK-ALKALI SYNDROME

The diagnosis, based on the presentation and the results of the workup, was milk-alkali syndrome complicated by recent hydrochlorothiazide use. This syndrome consists of the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury, all due to excessive ingestion of calcium and alkali, usually calcium carbonate.

His hydrochlorothiazide and calcium carbonate were discontinued. He was given intravenous normal saline and subcutaneous calcitonin, and his serum calcium level came down to 11.5 mg/dL within the next 24 hours. His dyspepsia was treated with pantoprazole.

The patient had no further episodes of chest pain, and the cardiology consult team again recommended against coronary angiography. Repeat ECG after the hypercalcemia resolved showed results identical to those 4 months before his admission. Two months later, his serum calcium level was 9.4 mg/dL and his creatinine level was 1.24 mg/dL.

A MIMIC OF STEMI

In numerous reported cases, these electrocardiographic findings coupled with chest pain led to misdiagnosis of STEMI.^1–3 While STEMI and occasionally hypercalcemia can cause ST elevation, hypercalcemia causes a significant shortening of the corrected QT interval that is not associated with STEMI.^4,5

Ultimately, the diagnosis of MI involves clinical, laboratory, and ECG findings, and if a strong clinical suspicion for myocardial ischemia exists, STEMI cannot reliably be distinguished from hypercalcemia by ECG alone. It is nonetheless important to be aware of this complication of hypercalcemia to avoid unnecessary cardiac interventions.

A 71-year-old man with a history of hypertension, 4 prior myocardial infarctions (MIs), and well-compensated ischemic cardiomyopathy presented to the emergency department after 2 episodes of sharp pain in the left upper abdomen and chest. The episodes lasted 1 to 2 minutes and were not relieved by rest. Their location was similar to that of the pain he experienced with his MIs. He could not identify any exacerbating or ameliorating factors. The pain had resolved without specific therapy before he arrived.

He reported polydipsia and constipation over the past 2 weeks and generalized muscle weakness and acute exacerbations of chronic back pain in the past 2 days. Neither he nor a friend who accompanied him noticed any confusion. He had been taking as many as 15 calcium carbonate tablets a day for 6 weeks to self-treat dyspepsia refractory to once-daily ranitidine, and hydrochlorothiazide for his hypertension for 3 weeks.

FURTHER EVALUATION, CARDIOLOGY CONSULT

On physical examination, he had diffuse weakness, dry mucous membranes, and an irregular heart rhythm.

Laboratory testing showed the following:

• Troponin I 0.11 ng/mL (reference range ≤ 0.04); repeated, it was 0.12 ng/mL
• Serum creatinine 3.4 mg/dL (0.44–1.27) (9 months earlier it had been 0.99 mg/dL)
• Serum calcium 17.3 mg/dL (8.6–10.5)
• Parathyroid hormone 9 pg/mL (12–88)
• Serum bicarbonate 33 mmol/L (24–32); 2 weeks earlier, it had been 27 mmol/L.

DIAGNOSIS: MILK-ALKALI SYNDROME

The diagnosis, based on the presentation and the results of the workup, was milk-alkali syndrome complicated by recent hydrochlorothiazide use. This syndrome consists of the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury, all due to excessive ingestion of calcium and alkali, usually calcium carbonate.

His hydrochlorothiazide and calcium carbonate were discontinued. He was given intravenous normal saline and subcutaneous calcitonin, and his serum calcium level came down to 11.5 mg/dL within the next 24 hours. His dyspepsia was treated with pantoprazole.

The patient had no further episodes of chest pain, and the cardiology consult team again recommended against coronary angiography. Repeat ECG after the hypercalcemia resolved showed results identical to those 4 months before his admission. Two months later, his serum calcium level was 9.4 mg/dL and his creatinine level was 1.24 mg/dL.

A MIMIC OF STEMI

In numerous reported cases, these electrocardiographic findings coupled with chest pain led to misdiagnosis of STEMI.^1–3 While STEMI and occasionally hypercalcemia can cause ST elevation, hypercalcemia causes a significant shortening of the corrected QT interval that is not associated with STEMI.^4,5

Ultimately, the diagnosis of MI involves clinical, laboratory, and ECG findings, and if a strong clinical suspicion for myocardial ischemia exists, STEMI cannot reliably be distinguished from hypercalcemia by ECG alone. It is nonetheless important to be aware of this complication of hypercalcemia to avoid unnecessary cardiac interventions.

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

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

Notable laboratory results:

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

Abdominal ultrasonography showed a dilated bile duct and gallstones.

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

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

IS MEASURING SERUM AMYLASE NECESSARY?

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

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

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

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

PRACTICE AT OUR HOSPITAL

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

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

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

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

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

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

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

ELIMINATING NEEDLESS EXPENSES

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

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

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

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

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

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

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

CLINICAL BOTTOM LINE

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

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

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

Notable laboratory results:

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

Abdominal ultrasonography showed a dilated bile duct and gallstones.

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

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

IS MEASURING SERUM AMYLASE NECESSARY?

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

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

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

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

PRACTICE AT OUR HOSPITAL

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

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

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

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

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

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

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

ELIMINATING NEEDLESS EXPENSES

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

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

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

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

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

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

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

CLINICAL BOTTOM LINE

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

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

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

Notable laboratory results:

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

Abdominal ultrasonography showed a dilated bile duct and gallstones.

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

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

IS MEASURING SERUM AMYLASE NECESSARY?

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

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

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

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

PRACTICE AT OUR HOSPITAL

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

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

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

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

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

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

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

ELIMINATING NEEDLESS EXPENSES

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

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

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

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

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

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

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

CLINICAL BOTTOM LINE

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

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

ANTIBIOTICS ARE DIFFERENT FROM OTHER DRUGS

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

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

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

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

ANTIBIOTIC USE IS HIGH

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

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

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

About one-third of use is unnecessary

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

ANTIBIOTIC EXPOSURE HAS NEGATIVE CONSEQUENCES

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

Disturbance of gut microbiome

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

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

Increase of C difficile infections

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

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

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

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

Stewardship improves clinical outcomes

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

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

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

DEVELOPING EFFECTIVE ANTIBIOTIC STEWARDSHIP PROGRAMS

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

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

What constitutes an antibiotic stewardship program?

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

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

Stewardship is harder in some settings

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

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

MEASURING IMPROVEMENT

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

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

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

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

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

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

Problems in measuring appropriate use

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

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

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

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

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

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

NATIONAL ACTIVITIES IN ANTIBIOTIC STEWARDSHIP

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

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

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

PROVEN INTERVENTIONS

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

Postprescription antibiotic reviews or antibiotic ‘time-outs’

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

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

Targeting specific infections

Some infections are especially important to target with improvement efforts.

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

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

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

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

Antibiotic time-out at hospital discharge

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

Targeting outpatient settings

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

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

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

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

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

ANTIBIOTICS ARE DIFFERENT FROM OTHER DRUGS

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

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

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

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

ANTIBIOTIC USE IS HIGH

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

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

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

About one-third of use is unnecessary

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

ANTIBIOTIC EXPOSURE HAS NEGATIVE CONSEQUENCES

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

Disturbance of gut microbiome

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

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

Increase of C difficile infections

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

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

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

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

Stewardship improves clinical outcomes

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

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

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

DEVELOPING EFFECTIVE ANTIBIOTIC STEWARDSHIP PROGRAMS

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

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

What constitutes an antibiotic stewardship program?

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

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

Stewardship is harder in some settings

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

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

MEASURING IMPROVEMENT

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

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

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

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

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

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

Problems in measuring appropriate use

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

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

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

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

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

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

NATIONAL ACTIVITIES IN ANTIBIOTIC STEWARDSHIP

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

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

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

PROVEN INTERVENTIONS

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

Postprescription antibiotic reviews or antibiotic ‘time-outs’

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

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

Targeting specific infections

Some infections are especially important to target with improvement efforts.

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

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

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

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

Antibiotic time-out at hospital discharge

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

Targeting outpatient settings

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

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

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

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

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

ANTIBIOTICS ARE DIFFERENT FROM OTHER DRUGS

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

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

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

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

ANTIBIOTIC USE IS HIGH

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

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

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

About one-third of use is unnecessary

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

ANTIBIOTIC EXPOSURE HAS NEGATIVE CONSEQUENCES

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

Disturbance of gut microbiome

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

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

Increase of C difficile infections

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

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

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

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

Stewardship improves clinical outcomes

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

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

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

DEVELOPING EFFECTIVE ANTIBIOTIC STEWARDSHIP PROGRAMS

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

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

What constitutes an antibiotic stewardship program?

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

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

Stewardship is harder in some settings

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

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

MEASURING IMPROVEMENT

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

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

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

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

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

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

Problems in measuring appropriate use

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

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

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

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

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

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

NATIONAL ACTIVITIES IN ANTIBIOTIC STEWARDSHIP

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

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

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

PROVEN INTERVENTIONS

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

Postprescription antibiotic reviews or antibiotic ‘time-outs’

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

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

Targeting specific infections

Some infections are especially important to target with improvement efforts.

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

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

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

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

Antibiotic time-out at hospital discharge

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

Targeting outpatient settings

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

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

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

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

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

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

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

PALMAR ERYTHEMA AND SYSTEMIC DISEASE

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

Conditions in the differential diagnosis

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

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

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

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

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

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

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

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

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

PALMAR ERYTHEMA AND SYSTEMIC DISEASE

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

Conditions in the differential diagnosis

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

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

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

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

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

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

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

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

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

PALMAR ERYTHEMA AND SYSTEMIC DISEASE

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

Conditions in the differential diagnosis

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

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

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

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

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

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