Patients with localized prostate cancer who were smokers at the time of local therapy had a higher risk of experiencing adverse outcomes and death related to the disease, a systematic review and meta-analysis has shown.

Current smokers in the study had a higher risk of biochemical recurrence, metastasis, and cancer-specific mortality after undergoing primary radical prostatectomy or radiotherapy.

Brett Mulcahy/ThinkStock

Future studies need to more closely examine the link between smoking cessation and longer-term oncologic outcomes, as well as a more precise assessment of smoking exposure, the researchers concluded.

In the current study, results were inconclusive as to whether former smoking and time to cessation had any relationship to outcomes after radical prostatectomy or radiotherapy.

“Available data were sparse and heterogenous,” they noted.

Dr. Foerster is supported by the Scholarship Foundation of Swiss Urology. One coauthor reported disclosures related to Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff.

SOURCE: Foerster B et al. JAMA Oncol. 2018 May 24. doi: 10.1001/jamaoncol.2018.1071.

Patients with localized prostate cancer who were smokers at the time of local therapy had a higher risk of experiencing adverse outcomes and death related to the disease, a systematic review and meta-analysis has shown.

Current smokers in the study had a higher risk of biochemical recurrence, metastasis, and cancer-specific mortality after undergoing primary radical prostatectomy or radiotherapy.

Brett Mulcahy/ThinkStock

Future studies need to more closely examine the link between smoking cessation and longer-term oncologic outcomes, as well as a more precise assessment of smoking exposure, the researchers concluded.

In the current study, results were inconclusive as to whether former smoking and time to cessation had any relationship to outcomes after radical prostatectomy or radiotherapy.

“Available data were sparse and heterogenous,” they noted.

Dr. Foerster is supported by the Scholarship Foundation of Swiss Urology. One coauthor reported disclosures related to Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff.

SOURCE: Foerster B et al. JAMA Oncol. 2018 May 24. doi: 10.1001/jamaoncol.2018.1071.

Patients with localized prostate cancer who were smokers at the time of local therapy had a higher risk of experiencing adverse outcomes and death related to the disease, a systematic review and meta-analysis has shown.

Current smokers in the study had a higher risk of biochemical recurrence, metastasis, and cancer-specific mortality after undergoing primary radical prostatectomy or radiotherapy.

Brett Mulcahy/ThinkStock

Future studies need to more closely examine the link between smoking cessation and longer-term oncologic outcomes, as well as a more precise assessment of smoking exposure, the researchers concluded.

In the current study, results were inconclusive as to whether former smoking and time to cessation had any relationship to outcomes after radical prostatectomy or radiotherapy.

“Available data were sparse and heterogenous,” they noted.

Dr. Foerster is supported by the Scholarship Foundation of Swiss Urology. One coauthor reported disclosures related to Astellas, Cepheid, Ipsen, Jansen, Lilly, Olympus, Pfizer, Pierre Fabre, Sanochemia, Sanofi, and Wolff.

SOURCE: Foerster B et al. JAMA Oncol. 2018 May 24. doi: 10.1001/jamaoncol.2018.1071.

WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.

“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week^®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”

Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. Those that used MyChart messaging had significantly higher number of office visits and phone encounters (P = .0001), compared with non-MyChart users. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).

Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.

Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.

Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.

“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”

Dr. Hristov had no financial disclosures to report.

[email protected]

SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.

WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.

“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week^®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”

Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. Those that used MyChart messaging had significantly higher number of office visits and phone encounters (P = .0001), compared with non-MyChart users. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).

Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.

Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.

Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.

“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”

Dr. Hristov had no financial disclosures to report.

[email protected]

SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.

WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.

“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week^®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”

Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. Those that used MyChart messaging had significantly higher number of office visits and phone encounters (P = .0001), compared with non-MyChart users. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).

Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.

Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.

Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.

“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”

Dr. Hristov had no financial disclosures to report.

[email protected]

SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

The liver enzyme autotaxin may be a useful noninvasive marker of disease progression in people with primary biliary cholangitis (PBC), new research has suggested.

Satoru Joshita, MD, from the gastroenterology and hepatology department at Shinshu University in Matsumoto, Japan, and colleagues noted that the liver-specific autoimmune disease PBC is characterized by the destruction of bile ducts, leading to cirrhosis and liver failure, and is more often seen in women.

Symptoms at diagnosis, a lack of response to gold standard treatment with ursodeoxycholic acid, and more advanced histologic phase are linked to worse patient outcomes, the research team explained in Scientific Reports.

While liver biopsy could give vital information on the severity of disease, it is an invasive procedure that is limited by sampling error and interobserver disparity. “As advanced histological stage is associated with a worse prognosis in PBC patients, it is important for clinicians to know clinical stage noninvasively when deciding appropriate therapies,” they wrote.

Noninvasive measures of liver fibrosis and PBC progression are available, such as Wisteria floribunda agglutinin–positive Mac-2 binding protein, hyaluronic acid, and type IV collagen 7S, but the authors said their “diagnostic abilities remain under scrutiny” because of their “moderate” accuracy.

Previous research had described autotaxin (ATX), a secreted enzyme metabolized by liver sinusoidal endothelial cells, as a prognostic factor for overall survival in cirrhosis patients, which suggested “an important role of ATX in the progression of liver disease,” the researchers noted.

They therefore set out to assess its utility as a marker of primary biliary cholangitis disease progression by measuring the serum ATX values of 128 treatment-naive, histologically assessed PBC patients, 108 of whom were female and 20 were male. Their ATX levels were then compared with 80 healthy controls.

Results showed that the ATX levels of patients with PBC were significantly higher than those of controls (median, 0.97 mg/L vs. 0.76 mg/L, respectively; P less than .0001).

Autotaxin results were validated by biopsy-proven histologic assessment: Patients with PBC that was classified as Nakanuma’s stage I, II, III, and IV had median ATX concentrations of 0.70, 0.80, 0.87, 1.03, and 1.70 mg/L, respectively, which demonstrated significant increases in concentration of ATX with disease stage (r = 0.53; P less than .0001). The researchers confirmed this finding using Scheuer’s classification of the disease (r = 0.43; P less than .0001).

The researchers noted that their findings were also “well correlated with other established noninvasive fibrosis markers, indicating ATX to be a reliable clinical surrogate marker to predict disease progression in patients with PBC.”

For example, autotaxin levels correlated with W. floribunda agglutinin–positive Mac-2 binding protein (r = 0.51; P less than .0001) and the fibrosis index based on four factors index (r = 0.51; P less than .0001).

Interestingly, the researchers found a sex difference in ATX levels: Not only were ATX values in female patients significantly higher than those in female controls (median, 1.00 mg/L vs. 0.82 mg/L, respectively; P less than .001) but they also were higher than those of male patients (median, 0.78 mg/L; P = .005).

According to the authors, these findings highlighted a need for sex-specific benchmarks, as well as more research to clarify why the sex disparity existed.

A further longitudinal study conducted by the authors involving 29 patients seen at their clinic showed that ATX levels increased slowly but significantly over an 18-year period, with a median increase rate of 0.03 mg/L per year (P less than .00001).

Patients who died from their disease had a significantly higher autotaxin increase rate than did survivors (0.05 mg/L per year vs. 0.02 mg/L per year, respectively; P less than .01).

Based on their findings, the researchers concluded that serum ATX levels “represent an accurate, noninvasive biomarker for estimating disease progression in patients with PBC.”

However, they said a longer longitudinal study of patients with PBC looking at ATX levels and clinical features, as well as long-term prognosis and complicating hepatocellular carcinoma, was warranted.

Two coauthors are employees of TOSOH corporation and Inova Diagnostics. The remaining authors had no conflicts to declare related to this study.

SOURCE: Joshita S et al. Scientific Reports. 2018 May 25. doi: 10.1038/s41598-018-26531-0.

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

WASHINGTON – Treatment of hepatitis C infection with a direct-acting antiviral drug strongly linked with a rapid, 14% drop in the incidence of all nonhepatic cancers, based on analysis of data from more than 30,000 U.S. patients.

The data also showed statistically significant drops in the incidence rates of several specific nonliver cancers among hepatitis C–infected patients treated with a direct-acting antiviral (DAA) drug, compared with infected patients who had been treated with an interferon-based regimen during the period immediately preceding the availability of DAAs in late 2013. This included a 45% cut in lung cancers, a 49% cut in bladder cancer, a 62% relative risk reduction in leukemia, and a 29% drop in prostate cancer, Michael B. Charlton, MD, said at the annual Digestive Disease Week.^®

The relative reductions in nonhepatic cancer incidence appeared soon after DAA treatment. The data Dr. Charlton reported reflected a median follow-up of 1 year for DAA-treated patients and 2.6 years for the hepatitis C–infected patients who had received interferon and did not get a DAA. A major difference between these two regimens is their efficacy, with DAA regimens producing sustained virologic response rates of 90% or better, while the interferon regimens produced substantially lower eradication rates.

“The most obvious hypothesis” to explain the observed effects is that “hepatitis C is a potent carcinogen,” possibly acting by inhibiting immune surveillance for new cancers in infected people, Dr. Charlton said in a video interview.

The study he reported used insurance-claims data from more than 146 million U.S. residents during 2007-2017 in the IQVIA PharMetrics Plus database, which included more than 367,000 adults infected with hepatitis C. Dr. Charlton and his associates pulled from this claims data on 10,989 of the infected patients who received interferon during January 2007-May 2011 (and followed through November 2013), and 22,894 infected patients treated with any type of DAA during December 2013 through March 2017. They used these two discrete time windows to completely separate the patients who received a DAA from those who did not.

The primary analysis calculated a hazard ratio for the development of any nonhepatic cancer after adjustment for a number of demographic and clinical covariates including age, smoking history, and weight, and also applied propensity-score weighting to the data. The Kaplan-Meier analysis of the data showed clear separation of the cancer-free survival curves of the two subgroups by 6 months of follow-up, and then showed steady further separation over time suggesting an ongoing carcinogenic effect from continued hepatitis C infection in patients who had received the less effective antiviral regimen. The analysis was able to reveal this effect because it had data from many thousands of treated hepatitis C patients, far more than had been enrolled in the pivotal trials for the DAAs, noted Dr. Charlton, professor and director of the Center for Liver Diseases at the University of Chicago.

The Centers for Disease Control and Prevention estimates that 3.5 million Americans have a chronic hepatitis C infection. Dr. Charlton believed the number today might be more like 1-2 million remaining chronic U.S. cases because of the strong impact of DAA treatment. These chronic infections largely remain because hepatitis C is mostly silent and many clinicians fail to act on screening recommendations. The new findings provide even greater incentive for more rigorous screening and treatment, Dr. Charlton suggested.

“As if you needed another reason to get rid of hepatitis C, lowering your cancer risk is now added to the list,” he said.

[email protected]

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

Extramammary Paget disease (EMPD) is a malignant epithelial tumor that most commonly affects the anogenital region and less frequently arises in the axillae. Most cases occur in locations where apocrine glands predominate.¹ Few cases of EMPD arising in nonapocrine-bearing regions, or ectopic EMPD, have been reported.² We describe a case of primary ectopic EMPD with an infiltrative growth pattern arising on the back of a 67-year-old Thai man.

Case Report

A 67-year-old Thai man presented to the dermatology clinic for evaluation of a persistent rash on the right lower back of approximately 30 years’ duration. He reported that the eruption had started out as a small coin-shaped area but had slowly increased in size. Over the last 2 years, the area had grown more rapidly and became pruritic. His medical history was remarkable for hypertension treated with losartan, but he was otherwise healthy. He had no history of cancer or gastrointestinal tract or genitourinary symptoms, and he had no recent fever, weight loss, or night sweats.

On physical examination a well-demarcated, asymmetric, erythematous to brown plaque was noted on the right lower back. The plaque was surfaced by scale and contained a central hyperkeratotic papule (Figure 1). The skin examination was otherwise unremarkable. The patient had no lymphadenopathy.

Two punch biopsies were performed. On low power, acanthosis and hyperkeratosis of the epidermis were noted. The epidermis contained a proliferation of large (tumor) cells with pleomorphic nuclei, prominent nucleoli, and abundant pale to clear cytoplasm. The cells were present singularly as well as in clusters and were most prominent along the basal layer but many were also seen extending to more superficial levels of the epidermis (Figure 2A). In one biopsy, the tumor cells were found in the dermis with an infiltrative growth pattern (Figure 2B). Immunohistochemistry (IHC) studies for cytokeratin 7 (Figure 3A and 3B) and carcinoembryonic antigen (Figure 3C) labeled the tumor cells. An IHC study for gross cystic disease fluid protein 15 labeled some of the tumor cells. Immunohistochemistry studies for S-100, human melanoma black 45 (HMB-45), p16, and renal cell carcinoma did not label the tumor cells. An IHC study for MIB-1 labeled many of the tumor cells, indicating a notably increased mitotic index. The patient was diagnosed with ectopic EMPD. He underwent an endoscopy, colonoscopy, and cystoscopy, all of which were normal.

Comment

Extramammary Paget disease is a malignant tumor typically found in apocrine-rich areas of the skin, particularly the anogenital skin. It is categorized as primary or secondary EMPD. Primary EMPD arises as an intraepithelial adenocarcinoma, with the Toker cell as the cell of origin.³ Secondary EMPD represents a cutaneous extension of an underlying malignancy (eg, colorectal, urothelial, prostatic, gynecologic).⁴

Ectopic EMPD arises in nonapocrine-bearing areas, specifically the nongerminative milk line. A review of the literature using Google Scholar and the search term ectopic extramammary Paget disease showed that there have been at least 30 cases of ectopic EMPD reported. Older men are more commonly affected, with a mean age at diagnosis of approximately 68 years. Although the tumor is most commonly seen on the trunk, cases on the head, arms, and legs have been reported.⁵

This tumor is most frequently seen in Asian individuals, as in our patient, with a ratio of approximately 3:1.⁵ Interestingly, triple or quadruple EMPD was reported in 68 Japanese patients but rarely has been reported outside of Japan.⁶ It is thought that some germinative apocrine-differentiating cells might preferentially exist on the trunk of Asians, leading to an increased incidence of EMPD in this population⁵; however, the exact reason for this racial preference is not completely understood, and more studies are needed to investigate this association.

Diagnosis of ectopic EMPD is made histologically. Tumor cells have abundant pale cytoplasm and large pleomorphic nuclei with prominent nucleoli. The cells are arranged in small groups or singly within the basal regions of the epidermis. In longstanding lesions, the entire thickness of the epidermis may be involved. Uncommonly, the tumor cells may invade the dermis, such as in our patient. On immunohistochemistry, the tumor cells stain positive for carcinoembryonic antigen, epithelial membrane antigen, and low-molecular-weight cytokeratins (eg, cytokeratin 7). Many of the tumor cells also express gross cystic disease fluid protein 15, which helps exclude cutaneous invasion of secondary EMPD.^7-9 Cases of primary cutaneous apocrine carcinoma can have similar histologic and immunohistochemical findings to invasive EMPD, which further supports the possible apocrine derivation of Paget disease. In our patient, we considered the diagnosis of primary cutaneous apocrine adenocarcinoma with epidermotropism; however, we favored the diagnosis of ectopic EMPD with dermal invasion given the extensive epidermal-only involvement seen in one of the biopsies, which would be unusual for primary cutaneous apocrine adenocarcinoma.

Our patient had no identified underlying malignancy upon further workup; however, many cases of EMPD have been associated with an underlying malignancy.^9-15 Several authors have reported a range of underlying malignancies associated with EMPD, with the incidence ranging from 11% to 45%.^9-15 The location of the underlying internal malignancy appears to be closely related to the location of the EMPD.¹¹ It is recommended that a thorough workup for internal malignancies be performed, including a full skin examination, lymph node examination, colonoscopy, cystoscopy, and gynecologic/prostate examination, among others.

No known differences in the prognosis or associated underlying malignancies between ectopic and ordinary EMPD have been reported; however, it has been noted that EMPD with invasion into the dermis does correlate with a more aggressive course and worse prognosis.⁸ Treatment includes surgical removal by Mohs micrographic surgery or wide local excision. Long-term follow-up is required since recurrences can be frequent.^11-15

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

From the University of Texas Southwestern, Department of Internal Medicine, Dallas, TX.

Abstract

• Objective: To define intestinal failure and associated diseases that often lead to diarrhea and high-output states, and to provide a literature review on the current evidence and practice guidelines for the management of these conditions in the context of a clinical case.
• Methods: Database search on dietary and medical interventions as well as major societal guidelines for the management of intestinal failure and associated conditions.
• Results: Although major societal guidelines exist, the guidelines vary greatly amongst various specialties and are not supported by strong evidence from large randomized controlled trials. The majority of the guidelines recommend consideration of several drug classes, but do not specify medications within the drug class, optimal dose, frequency, mode of administration, and how long to trial a regimen before considering it a failure and adding additional medical therapies.
• Conclusions: Intestinal failure and high-output states affect a very heterogenous population with high morbidity and mortality. This subset of patients should be managed using a multidisciplinary approach involving surgery, gastroenterology, dietetics, internal medicine and ancillary services that include but are not limited to ostomy nurses and home health care. Implementation of a standardized protocol in the electronic medical record including both medical and nutritional therapies may be useful to help optimize efficacy of medications, aid in nutrient absorption, decrease cost, reduce hospital length of stay, and decrease hospital readmissions.

Key words: short bowel syndrome; high-output ostomy; entero-cutaneous fistula; diarrhea; malnutrition.

Intestinal failure includes but is not limited to short bowel syndrome (SBS), high-output enterostomy, and high-output related to entero-cutaneous fistulas (ECF). These conditions are unfortunate complications after major abdominal surgery requiring extensive intestinal resection leading to structural SBS. Absorption of macronutrients and micronutrients is most dependent on the length and specific segment of remaining intact small intestine [1]. The normal small intestine length varies greatly but ranges from 300 to 800 cm, while in those with structural SBS the typical length is 200 cm or less [2,3]. Certain malabsorptive enteropathies and severe intestinal dysmotility conditions may manifest as functional SBS as well. Factors that influence whether an individual will develop functional SBS despite having sufficient small intestinal absorptive area include the degree of jejunal absorptive efficacy and the ability to overcompensate with enough oral caloric intake despite high fecal energy losses, also known as hyperphagia [4].

Pathophysiology

Maintenance of normal bodily functions and homeostasis is dependent on sufficient intestinal absorption of essential macronutrients, micronutrients, and fluids. The hallmark of intestinal failure is based on the presence of decreased small bowel absorptive surface area and subsequent increased losses of key solutes and fluids [1]. Intestinal failure is a broad term that is comprised of 3 distinct phenotypes. The 3 functional classifications of intestinal failure include the following:

• Type 1. Acute intestinal failure is generally self-limiting, occurs after abdominal surgery, and typically lasts less than 28 days.
• Type 2. Subacute intestinal failure frequently occurs in septic, stressed, or metabolically unstable patients and may last up to several months.
• Type 3. Chronic intestinal failure occurs due to a chronic condition that generally requires indefinite parenteral nutrition (PN) [1,3,4].

SBS and enterostomy formation are often associated with excessive diarrhea, such that it is the most common etiology for postoperative readmissions. The definition of “high-output” varies amongst studies, but output is generally considered to be abnormally high if it is greater than 500 mL per 24 hours in ECFs and greater than 1500 mL per 24 hours for enterostomies. There is significant variability from patient to patient, as output largely depends on length of remaining bowel [2,4].

Epidemiology

SBS, high-output enterostomy, and high-output from ECFs comprise a wide spectrum of underlying disease states, including but not limited to inflammatory bowel disease, post-surgical fistula formation, intestinal ischemia, intestinal atresia, radiation enteritis, abdominal trauma, and intussusception [5]. Due to the absence of a United States registry of patients with intestinal failure, the prevalence of these conditions is difficult to ascertain. Most estimations are made using registries for patients on total parenteral nutrition (TPN). The Crohns and Colitis Foundation of America estimates 10,000 to 20,000 people suffer from SBS in the United States. This heterogenous patient population has significant morbidity and mortality for dehydration related to these high-output states. While these conditions are considered rare, they are relatively costly to the health care system. These patients are commonly managed by numerous medical and surgical services, including internal medicine, gastroenterology, surgery, dietitians, wound care nurses, and home health agencies. Management strategies differ amongst these specialties and between professional societies, which makes treatment strategies highly variable and perplexing to providers taking care of this patient population. Furthermore, most of the published guidelines are based on expert opinion and lack high-quality clinical evidence from randomized controlled trials (RCTs). Effectively treating SBS and reducing excess enterostomy output leads to reduced rates of dehydration, electrolyte imbalances, initiation of PN, weight loss and ultimately a reduction in malnutrition. Developing hospital-wide management protocols in the electronic medical record for this heterogenous condition may lead to less complications, fewer hospitalizations, and an improved quality of life for these patients.

Case Study

Initial Presentation

A 72-year-old man with history of rectal adenocarcinoma stage T4bN2 status post low anterior resection (LAR) with diverting loop ileostomy and neoadjuvant chemoradiation presented to the hospital with a 3-day history of nausea, vomiting, fatigue, and productive cough.

Additional History

On further questioning, the patient also reported odynophagia and dysphagia related to thrush. Because of his decreased oral intake, he stopped taking his usual insulin regimen prior to admission. His cancer treatment course was notable for a LAR with diverting loop ileostomy which was performed 5 months prior. He had also completed 3 out of 8 cycles of capecitabine and oxaliplatin-based therapy 2 weeks prior to this presentation.

Physical Examination

Significant physical examination findings included dry mucous membranes, oropharyngeal candidiasis, tachycardia, clear lungs, hypoactive bowel sounds, nontender, non-distended abdomen, and a right lower abdominal ileostomy bag with semi-formed stool.

Laboratory test results were pertinent for diabetic ketoacidosis (DKA) with an anion gap of 33, lactic acidosis, acute kidney injury (creatinine 2.7 mg/dL from a baseline of 1.0) and blood glucose of 1059 mg/dL. Remainder of complete blood count and complete metabolic panel were unremarkable.

Hospital Course

The patient was treated for oropharyngeal candidiasis with fluconazole, started on an insulin drip and given intravenous fluids (IVFs) with subsequent resolution of DKA. Once the DKA resolved, his diet was advanced to a mechanical soft, moderate calorie, consistent carbohydrate diet (2000 calories allowed daily with all foods chopped, pureed or cooked, and all meals containing nearly equal amounts of carbohydrates). He was also given Boost supplementation 3 times per day, and daily weights were recorded while assessing for fluid losses. However, during his hospital course the patient developed increasing ileostomy output ranging from 2.7 to 6.5 L per day that only improved when he stopped eating by mouth (NPO).

What conditions should be evaluated prior to starting therapy for high-output enterostomy/diarrhea from either functional or structural SBS?

Prior to starting anti-diarrheal and anti-secretory therapy, infectious and metabolic etiologies for high-enterostomy output should be ruled out. Depending on the patient’s risk factors (eg, recent sick contacts, travel) and whether they are immunocompetent versus immunosuppressed, infectious studies should be obtained. In this patient, Clostridium difficile, stool culture, Giardia antigen, stool ova and parasites were all negative. Additional metabolic labs including thyroid-stimulating hormone, fecal elastase, and fecal fat were obtained and were all within normal limits. In this particular scenario, fecal fat was obtained while he was NPO. Testing for fat malabsorption and pancreatic insufficiency in a patient that is consuming less than 100 grams of fat per day can result in a false-negative outcome, however, and was not an appropriate test in this patient.

Hospital Course Continued

Once infectious etiologies were ruled out, the patient was started on anti-diarrheal medication consisting of loperamide 2 mg every 6 hours and oral pantoprazole 40 mg once per day. The primary internal medicine team speculated that the Boost supplementation may be contributing to the diarrhea because of its hyperosmolar concentration and wanted to discontinue it, but because the patient had protein-calorie malnutrition the dietician recommended continuing Boost supplementation. The primary internal medicine team also encouraged the patient to drink Gatorade with each meal with the approval from the dietician.

What are key dietary recommendations to help reduce high-output enterostomy/diarrhea?

Dietary recommendations are often quite variable depending on the intestinal anatomy (specifically, whether the colon is intact or absent), comorbidities such as renal disease, and severity of fluid and nutrient loses. This patient has the majority of his colon remaining; however, fluid and nutrients are being diverted away from his colon because he has a loop ileostomy. To reduce enterostomy output, it is generally recommended that liquids be consumed separately from solids, and that oral rehydration solutions (ORS) should replace most hyperosmolar and hypoosmolar liquids. Although these recommendations are commonly used, there is sparse data to suggest separating liquids from solids in a medically stable patient with SBS is indeed necessary [6]. In our patient, however, because he has not yet reached medical stability, it would be reasonable to separate the consumption of liquids from solids. The solid component of a SBS diet should consist mainly of protein and carbohydrates, with limited intake of simple sugars and sugar alcohols. If the colon remains intact, it is particularly important to limit fats to less than 30% of the daily caloric intake, to consume a low-oxalate diet, supplement with oral calcium to reduce the risk of calcium-oxalate nephrolithiasis, and increase dietary fiber intake as tolerated. Soluble fiber is fermented by colonic bacteria into short-chain fatty acids (SCFAs) and serve as an additional energy source [7,8]. Medium-chain triglycerides (MCTs) are good sources of fat because the body is able to absorb them into the bloodstream without the use of intestinal lymphatics, which may be damaged or absent in those with intestinal failure. For this particular patient, he would have benefitted from initiation of ORS and counseled to sip on it throughout the day while limiting liquid consumption during meals. He should have also been advised to limit plain Gatorade and Boost as they are both hyperosmolar liquid formulations and can worsen diarrhea. If the patient was unable to tolerate the taste of standard ORS formulations, or the hospital did not have any ORS on formulary, sugar, salt and water at specific amounts may be added to create a homemade ORS. In summary, this patient would have likely tolerated protein in solid form better than liquid protein supplementation.

Hospital Course Continued

The patient continued to have greater than 5 L of output from the ileostomy per day, so the following day the primary team increased the loperamide from 2 mg every 6 hours to 4 mg every 6 hours, added 2 tabs of diphenoxylate-atropine every 8 hours, and made the patient NPO. He continued to require IVFs and frequent electrolyte repletion because of the significant ongoing gastrointestinal losses.

What is the recommended first-line medical therapy for high-output enterostomy/diarrhea?

Anti-diarrheal medications are commonly used in high-output states because they work by reducing the rate of bowel translocation thereby allowing for longer time for nutrient and fluid absorption in the small and large intestine. Loperamide in particular also improves fecal incontinence because it effects the recto-anal inhibitory reflex and increases internal anal sphincter tone [9]. Four RCTs showed that loperamide lead to a significant reduction in enterostomy output compared to placebo with enterostomy output reductions ranging from 22% to 45%; varying dosages of loperamide were used, and ranged from 6 mg per day to 16 total mg per day [10–12]. King et al compared loperamide and codeine to placebo and found that both medications led to reductions in enterostomy output with a greater reduction and better side effect profile in those that received loperamide or combination therapy with loperamide and codeine [13,14]. The majority of studies used a maximum dose of 16 mg per day of loperamide, and this is the maxium daily dose approved by the US Food and Drug Administration (FDA). Interestingly however, loperamide circulates through the enterohepatic circulation which is severely disrupted in SBS, so titrating up to a maximum dose of 32 mg per day while closely monitoring for side effects is also practiced by experts in intestinal failure [15]. It is also important to note that anti-diarrheal medications are most effective when administered 20 to 30 minutes prior to meals and not scheduled every 4 to 6 hours if the patient is eating by mouth. If intestinal transit is so rapid such that undigested anti-diarrheal tablets or capsules are visualized in the stool or stoma, medications can be crushed or opened and mixed with liquids or solids to enhance digestion and absorption.

Hospital Course Continued

The patient continued to have greater than 3 L of ileostomy output per day despite being on scheduled loperamide, diphenoxylate-atropine, and a proton pump inhibitory (PPI), although improved from greater than 5 L per day. He was subsequently started on opium tincture 6 mg every 6 hours, psyllium 3 times per day, the dose of diphenoxylate-atropine was increased from 2 tablets every 8 hours to 2 tablets every 6 hours, and he was encouraged to drink water in between meals. As mentioned previously, the introduction of dietary fiber should be carefully monitored, as this patient population is commonly intolerant of high dietary fiber intake, and hypoosmolar liquids like water should actually be minimized. Within a 48-hour time period, the surgical team recommended increasing the loperamide from 4 mg every 6 hours (16 mg total daily dose) to 12 mg every 6 hours (48 mg total daily dose), increased opium tincture from 6 mg every 6 hours (24 mg total daily dose) to 10 mg every 6 hours (40 mg total daily dose), and increased oral pantoprazole from 40 mg once per day to twice per day.

What are important considerations with regard to dose changes?

Evidence is lacking to suggest an adequate time period to monitor for response to therapy in regards to improvement in diarrheal output. In this scenario, it may have been prudent to wait 24 to 48 hours after each medication change instead of making drastic dose changes in several medications simultaneously. PPIs irreversibly inhibit gastrointestinal acid secretion as do histamine-2 receptor antagonists (H2RAs) but to a lesser degree, and thus reduce high-output enterostomy [16]. Reduction in pH related to elevated gastrin levels after intestinal resection is associated with pancreatic enzyme denaturation and downstream bile salt dysfunction, which can further lead to malabsorption [17]. Gastrin hypersecretion is most prominent within the first 6 months after intestinal resection such that the use of high- dose PPIs for reduction in gastric acid secretion are most efficacious within that time period [18,19]. Jeppesen et al demonstrated that both omeprazole 40 mg oral twice per day and ranitidine 150 mg IV once per day were effective in reducing enterostomy output, although greater reductions were seen with omeprazole [20]. Three studies using cimetidine (both oral and IV formulations) with dosages varying from 200 mg to 800 mg per day showed significant reductions in enterostomy output as well [21–23].

Hospital Course Continued

Despite the previously mentioned interventions, the patient’s ileostomy output remained greater than 3 L per day. Loperamide was increased from 12 mg every 6 hours to 16 mg every 6 hours (64 mg total daily dose) hours and opium tincture was increased from 10 mg to 16 mg every 6 hours (64 mg total daily dose). Despite these changes, no significant reduction in output was noted, so the following day, 4 grams of cholestyramine light was added twice per day.

If the patient continues to have high-output enterostomy/diarrhea, what are additional treatment options?

Bile acid binding resins like cholestyramine, colestipol, and colesevelam are occasionally used if there is a high suspicion for bile acid diarrhea. Bile salt diarrhea typically occurs because of alterations in the enterohepatic circulation of bile salts, which leads to an increased level of bile salts in the colon and stimulation of electrolyte and water secretion and watery diarrhea [24]. Optimal candidates for bile acid binding therapy are those with an intact colon and less than 100 cm of resected ileum. Patients with little to no remaining or functional ileum have a depleted bile salt pool, therefore the addition of bile acid resin binders may actually lead to worsening diarrhea secondary to bile acid deficiency and fat malabsorption. Bile-acid resin binders can also decrease oxalate absorption and precipitate oxalate stone formation in the kidneys. Caution should also be taken to ensure that these medications are administered separately from the remainder of the patient’s medications to limit medication binding.

If the patient exhibits hemodynamic stability, alpha-2 receptor agonists are occasionally used as adjunctive therapy in reducing enterostomy output, although strong evidence to support its use is lacking. The mechanism of action involves stimulation of alpha-2 adrenergic receptors on enteric neurons, which theoretically causes a reduction in gastric and colonic motility and decreases fluid secretion. Buchman et al showed that the effects of a clonidine patch versus placebo did not in fact lead to a significant reduction in enterostomy output; however, a single case report suggested that the combination of 1200 mcg of clonidine per day and somatostatin resulted in decreased enterostomy output via alpha 2-receptor inhibition of adenylate cyclase [25,26].

Hospital Course Continued

The patient’s ileostomy output remained greater than 3 L per day, so loperamide was increased from 14 mg every 6 hours to 20 mg every 6 hours (80 mg total daily dose), cholestyramine was discontinued because of metabolic derangements, and the patient was initiated on 100 mcg of subcutaneous octreotide 3 times per day. Colorectal surgery was consulted for ileostomy takedown given persistently high-output, but surgery was deferred. After a 16-day hospitalization, the patient was eventually discharged home. At the time of discharge, he was having 2–3 L of ileostomy output per day and plans for future chemotherapy were discontinued because of this.

Does hormonal therapy have a role in the management of high-output enterostomy or entero-cutaneous fistulas?

Somatostatin analogues are growth-hormone inhibiting factors that have been used in the treatment of SBS and gastrointestinal fistulas. These medications reduce intestinal and pancreatic fluid secretion, slow intestinal motility, and inhibit the secretion of several hormones including gastrin, vasoactive intestinal peptide, cholecystokinin, and other key intestinal hormones. There is conflicting evidence for the role of these medications in reducing enterostomy output when first-line treatments have failed. Several previous studies using octreotide or somatostatin showed significant reductions in enterostomy output using variable dosages [27–30]. One study using the long-acting release depot octreotide preparation in 8 TPN-dependent patients with SBS showed a significant increase in small bowel transit time, however there was no significant improvement in the following parameters: body weight, stool weight, fecal fat excretion, stool electrolyte excretion, or gastric emptying [31]. Other studies evaluating enterostomy output from gastrointestinal and pancreatic fistulas comparing combined therapy with octreotide and TPN to placebo and TPN failed to show a significant difference in output and spontaneous fistula closure within 20 days of treatment initiation [32]. Because these studies use highly variable somatostatin analogue dosages and routes of administration, the most optimal dosing and route of administration (SQ versus IV) are unknown. In patients with difficult to control blood sugars, initiation of somatostatin analogues should be cautioned since these medications can lead to blood sugar alterations [33]. Additional unintended effects include impairment in intestinal adaptation and an increased risk in gallstone formation [8].

The most recent medical advances in SBS management include gut hormones. Glucagon-like peptide 2 (GLP-2) analogues improve structural and functional intestinal adaptation following intestinal resection by decreasing gastric emptying, decreasing gastric acid secretion, increasing intestinal blood flow, and enhancing nutrient and fluid absorption. Teduglutide, a GLP-2 analog, was successful in reducing fecal energy losses and increasing intestinal wet weight absorption, and reducing the need for PN support in SBS patients [1].

Whose problem is it anyway?

Not only is there variation in management strategies among subspecialties, but recommendations amongst societies within the same subspecialty differ, and thus make management perplexing.

Gastroenterology Guidelines

Several major gastroenterology societies have published guidelines on the management of diarrhea in patients with intestinal failure. The British Society of Gastroenterology (BSG) published guidelines on the management of SBS in 2006 and recommended the following first-line therapy for diarrhea-related complications: start loperamide at 2–8 mg thirty minutes prior to meals, taken up to 4 times per day, and the addition of codeine phosphate 30–60 mg thirty minutes before meals if output remains above goal on loperamide monotherapy. Cholestyramine may be added for those with 100 cm or less of resected terminal ileum to assist with bile-salt-induced diarrhea, though no specific dosage recommendations were reported. In regards to anti-secretory medications, the BSG recommends cimetidine (400 mg oral or IV 4 times per day), ranitidine (300 mg oral twice per day), or omeprazole (40 mg oral once per day or IV twice per day) to reduce jejunostomy output particularly in patients with greater than 2 L of output per day [15,34]. If diarrhea or enterostomy output continues to remain above goal, the guidelines suggest initiating octreotide and/or growth factors (although dosing and duration of therapy is not discussed in detail), and considering evaluation for intestinal transplant once the patient develops complications related to long-term TPN.

The American Gastroenterology Association (AGA) published guidelines and a position statement in 2003 for the management of high-gastric output and fluid losses. For postoperative patients, the AGA recommends the use of PPIs and H2RAs for the first 6 months following bowel resection when hyper-gastrinemia most commonly occurs. The guidelines do not specify which PPI or H2RA is preferred or recommended dosages. For long-term management of diarrhea or excess fluid losses, the guidelines suggest using loperamide or diphenoxylate (4-16 mg per day) first, followed by codeine sulfate 15–60 mg two to three times per day or opium tincture (dosages not specified). The use of octreotide (100 mcg SQ 3 times per day, 30 minutes prior to meals) is recommended only as a last resort if IVF requirements are greater than 3 L per day [8].

Surgical Guidelines

The Cleveland Clinic published institutional guidelines for the management of intestinal failure in 2010 with updated recommendations in 2016. Dietary recommendations include the liberal use of salt, sipping on 1–2 L of ORS between meals, and a slow reintroduction of soluble fiber from foods and/or supplements as tolerated. The guidelines also suggest considering placement of a nasogastric feeding tube or percutaneous gastrostomy tube (PEG) for continuous enteral feeding in addition to oral intake to enhance nutrient absorption [35]. If dietary manipulation is inadequate and medical therapy is required, the following medications are recommended in no particular order: loperamide 4 times per day (maximum dosage of 16 mg), diphenoxylate-atropine 4 times per day (maximum dosage of 20 mg per day), codeine 4 times per day (maximum dosage 240 mg per day), paregoric 5 mL (containing 2 mg of anhydrous morphine) 4 times per day, and opium tincture 0.5 mL (10 mg/mL) 4 times per day. H2RAs and PPIs are recommended for postoperative high-output states, although no dosage recommendations or routes of administration were discussed. 

Nutrition Guidelines

Villafranca et al published a protocol for the management of high-output stomas in 2015 that was shown to be effective in reducing high-enterostomy output. The protocol recommended initial treatment with loperamide 2 mg orally up to 4 times per day. If enterostomy output did not improve, the protocol recommended increasing loperamide to 4 mg four times per day, adding omeprazole 20 mg orally or cholestyramine 4 g twice per day before lunch and dinner if fat malabsorption or steatorrhea is suspected, and lastly the addition of codeine 15–60 mg up to 4 times per day and octreotide 200 mcg per day only if symptoms had not improved after 2 weeks [37].

The American Society for Parenteral and Enteral Nutrition (ASPEN) does not have published guidelines for the management of SBS. In 2016 however, the European Society for Clinical Nutrition and Metabolism (ESPEN) published guidelines on the management of chronic intestinal failure in adults. In patients with an intact colon, ESPEN strongly recommends a diet rich in complex carbohydrates and low in fat and using H2RAs or PPIs to treat hyper-gastrinemia within the first 6 months after intestinal resection particularly in those with greater than 2 L per day of fecal output. The ESPEN guidelines do not include whether to start a PPI or H2RA first, which particular drug in each class to try, or dosage recommendations but state that IV soluble formulations should be considered in those that do not seem to respond to tablets. ESPEN does not recommend the addition of soluble fiber to enhance intestinal absorption or probiotics and glutamine to aid in intestinal rehabilitation. For diarrhea and excessive fecal fluid, the guidelines recommend 4 mg of oral loperamide 30–60 minutes prior to meals, 3 to 4 times per day, as first-line treatment in comparison to codeine phosphate or opium tincture given the risks of dependence and sedation with the latter agents. They report, however, that dosages up to 12–24 mg at one time of loperamide are used in patients with terminal ileum resection and persistently high-output enterostomy [38].

Case Conclusion

The services that were closely involved in this patient’s care were general internal medicine, general surgery, colorectal surgery, and ancillary services, including dietary and wound care. Interestingly, despite persistent high ileostomy output during the patient’s 16-day hospital admission, the gastroenterology service was never consulted. This case illustrates the importance of having a multidisciplinary approach to the care of these complicated patients to ensure that the appropriate medications are ordered based on the individual’s anatomy and that medications are ordered at appropriate dosages and timing intervals to maximize drug efficacy. It is also critical to ensure that nursing staff accurately documents all intake and output so that necessary changes can be made after adequate time is given to assess for a true response. There should be close communication between the primary medical or surgical service with the dietician to ensure the patient is counseled on appropriate dietary intake to help minimize diarrhea and fluid losses.

Conclusion

In conclusion, intestinal failure is a heterogenous group of disease states that often occurs after major intestinal resection and is commonly associated with malabsorption and high output states. High-output enterostomy and diarrhea are the most common etiologies leading to hospital re-admission following enterostomy creation or intestinal resection. These patients have high morbidity and mortality rates, and their conditions are costly to the health care system. Lack of high-quality evidence from RCTs and numerous societal guidelines without clear medication and dietary algorithms and low prevalence of these conditions makes management of these patients by general medical and surgical teams challenging. The proper management of intestinal failure and related complications requires a multidisciplinary approach with involvement from medical, surgical, and ancillary services. We propose a multidisciplinary approach with involvement from medical, surgical, and ancillary services in designed and implementing a protocol using electronic medical record based order sets to simplify and improve the management of these patients in the inpatient setting.

Corresponding author: Jake Hutto, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, [email protected].

Financial disclosures: None.

From the University of Texas Southwestern, Department of Internal Medicine, Dallas, TX.

Abstract

• Objective: To define intestinal failure and associated diseases that often lead to diarrhea and high-output states, and to provide a literature review on the current evidence and practice guidelines for the management of these conditions in the context of a clinical case.
• Methods: Database search on dietary and medical interventions as well as major societal guidelines for the management of intestinal failure and associated conditions.
• Results: Although major societal guidelines exist, the guidelines vary greatly amongst various specialties and are not supported by strong evidence from large randomized controlled trials. The majority of the guidelines recommend consideration of several drug classes, but do not specify medications within the drug class, optimal dose, frequency, mode of administration, and how long to trial a regimen before considering it a failure and adding additional medical therapies.
• Conclusions: Intestinal failure and high-output states affect a very heterogenous population with high morbidity and mortality. This subset of patients should be managed using a multidisciplinary approach involving surgery, gastroenterology, dietetics, internal medicine and ancillary services that include but are not limited to ostomy nurses and home health care. Implementation of a standardized protocol in the electronic medical record including both medical and nutritional therapies may be useful to help optimize efficacy of medications, aid in nutrient absorption, decrease cost, reduce hospital length of stay, and decrease hospital readmissions.

Key words: short bowel syndrome; high-output ostomy; entero-cutaneous fistula; diarrhea; malnutrition.

Intestinal failure includes but is not limited to short bowel syndrome (SBS), high-output enterostomy, and high-output related to entero-cutaneous fistulas (ECF). These conditions are unfortunate complications after major abdominal surgery requiring extensive intestinal resection leading to structural SBS. Absorption of macronutrients and micronutrients is most dependent on the length and specific segment of remaining intact small intestine [1]. The normal small intestine length varies greatly but ranges from 300 to 800 cm, while in those with structural SBS the typical length is 200 cm or less [2,3]. Certain malabsorptive enteropathies and severe intestinal dysmotility conditions may manifest as functional SBS as well. Factors that influence whether an individual will develop functional SBS despite having sufficient small intestinal absorptive area include the degree of jejunal absorptive efficacy and the ability to overcompensate with enough oral caloric intake despite high fecal energy losses, also known as hyperphagia [4].

Pathophysiology

Maintenance of normal bodily functions and homeostasis is dependent on sufficient intestinal absorption of essential macronutrients, micronutrients, and fluids. The hallmark of intestinal failure is based on the presence of decreased small bowel absorptive surface area and subsequent increased losses of key solutes and fluids [1]. Intestinal failure is a broad term that is comprised of 3 distinct phenotypes. The 3 functional classifications of intestinal failure include the following:

• Type 1. Acute intestinal failure is generally self-limiting, occurs after abdominal surgery, and typically lasts less than 28 days.
• Type 2. Subacute intestinal failure frequently occurs in septic, stressed, or metabolically unstable patients and may last up to several months.
• Type 3. Chronic intestinal failure occurs due to a chronic condition that generally requires indefinite parenteral nutrition (PN) [1,3,4].

SBS and enterostomy formation are often associated with excessive diarrhea, such that it is the most common etiology for postoperative readmissions. The definition of “high-output” varies amongst studies, but output is generally considered to be abnormally high if it is greater than 500 mL per 24 hours in ECFs and greater than 1500 mL per 24 hours for enterostomies. There is significant variability from patient to patient, as output largely depends on length of remaining bowel [2,4].

Epidemiology

SBS, high-output enterostomy, and high-output from ECFs comprise a wide spectrum of underlying disease states, including but not limited to inflammatory bowel disease, post-surgical fistula formation, intestinal ischemia, intestinal atresia, radiation enteritis, abdominal trauma, and intussusception [5]. Due to the absence of a United States registry of patients with intestinal failure, the prevalence of these conditions is difficult to ascertain. Most estimations are made using registries for patients on total parenteral nutrition (TPN). The Crohns and Colitis Foundation of America estimates 10,000 to 20,000 people suffer from SBS in the United States. This heterogenous patient population has significant morbidity and mortality for dehydration related to these high-output states. While these conditions are considered rare, they are relatively costly to the health care system. These patients are commonly managed by numerous medical and surgical services, including internal medicine, gastroenterology, surgery, dietitians, wound care nurses, and home health agencies. Management strategies differ amongst these specialties and between professional societies, which makes treatment strategies highly variable and perplexing to providers taking care of this patient population. Furthermore, most of the published guidelines are based on expert opinion and lack high-quality clinical evidence from randomized controlled trials (RCTs). Effectively treating SBS and reducing excess enterostomy output leads to reduced rates of dehydration, electrolyte imbalances, initiation of PN, weight loss and ultimately a reduction in malnutrition. Developing hospital-wide management protocols in the electronic medical record for this heterogenous condition may lead to less complications, fewer hospitalizations, and an improved quality of life for these patients.

Case Study

Initial Presentation

A 72-year-old man with history of rectal adenocarcinoma stage T4bN2 status post low anterior resection (LAR) with diverting loop ileostomy and neoadjuvant chemoradiation presented to the hospital with a 3-day history of nausea, vomiting, fatigue, and productive cough.

Additional History

On further questioning, the patient also reported odynophagia and dysphagia related to thrush. Because of his decreased oral intake, he stopped taking his usual insulin regimen prior to admission. His cancer treatment course was notable for a LAR with diverting loop ileostomy which was performed 5 months prior. He had also completed 3 out of 8 cycles of capecitabine and oxaliplatin-based therapy 2 weeks prior to this presentation.

Physical Examination

Significant physical examination findings included dry mucous membranes, oropharyngeal candidiasis, tachycardia, clear lungs, hypoactive bowel sounds, nontender, non-distended abdomen, and a right lower abdominal ileostomy bag with semi-formed stool.

Laboratory test results were pertinent for diabetic ketoacidosis (DKA) with an anion gap of 33, lactic acidosis, acute kidney injury (creatinine 2.7 mg/dL from a baseline of 1.0) and blood glucose of 1059 mg/dL. Remainder of complete blood count and complete metabolic panel were unremarkable.

Hospital Course

The patient was treated for oropharyngeal candidiasis with fluconazole, started on an insulin drip and given intravenous fluids (IVFs) with subsequent resolution of DKA. Once the DKA resolved, his diet was advanced to a mechanical soft, moderate calorie, consistent carbohydrate diet (2000 calories allowed daily with all foods chopped, pureed or cooked, and all meals containing nearly equal amounts of carbohydrates). He was also given Boost supplementation 3 times per day, and daily weights were recorded while assessing for fluid losses. However, during his hospital course the patient developed increasing ileostomy output ranging from 2.7 to 6.5 L per day that only improved when he stopped eating by mouth (NPO).

What conditions should be evaluated prior to starting therapy for high-output enterostomy/diarrhea from either functional or structural SBS?

Prior to starting anti-diarrheal and anti-secretory therapy, infectious and metabolic etiologies for high-enterostomy output should be ruled out. Depending on the patient’s risk factors (eg, recent sick contacts, travel) and whether they are immunocompetent versus immunosuppressed, infectious studies should be obtained. In this patient, Clostridium difficile, stool culture, Giardia antigen, stool ova and parasites were all negative. Additional metabolic labs including thyroid-stimulating hormone, fecal elastase, and fecal fat were obtained and were all within normal limits. In this particular scenario, fecal fat was obtained while he was NPO. Testing for fat malabsorption and pancreatic insufficiency in a patient that is consuming less than 100 grams of fat per day can result in a false-negative outcome, however, and was not an appropriate test in this patient.

Hospital Course Continued

Once infectious etiologies were ruled out, the patient was started on anti-diarrheal medication consisting of loperamide 2 mg every 6 hours and oral pantoprazole 40 mg once per day. The primary internal medicine team speculated that the Boost supplementation may be contributing to the diarrhea because of its hyperosmolar concentration and wanted to discontinue it, but because the patient had protein-calorie malnutrition the dietician recommended continuing Boost supplementation. The primary internal medicine team also encouraged the patient to drink Gatorade with each meal with the approval from the dietician.

What are key dietary recommendations to help reduce high-output enterostomy/diarrhea?

Dietary recommendations are often quite variable depending on the intestinal anatomy (specifically, whether the colon is intact or absent), comorbidities such as renal disease, and severity of fluid and nutrient loses. This patient has the majority of his colon remaining; however, fluid and nutrients are being diverted away from his colon because he has a loop ileostomy. To reduce enterostomy output, it is generally recommended that liquids be consumed separately from solids, and that oral rehydration solutions (ORS) should replace most hyperosmolar and hypoosmolar liquids. Although these recommendations are commonly used, there is sparse data to suggest separating liquids from solids in a medically stable patient with SBS is indeed necessary [6]. In our patient, however, because he has not yet reached medical stability, it would be reasonable to separate the consumption of liquids from solids. The solid component of a SBS diet should consist mainly of protein and carbohydrates, with limited intake of simple sugars and sugar alcohols. If the colon remains intact, it is particularly important to limit fats to less than 30% of the daily caloric intake, to consume a low-oxalate diet, supplement with oral calcium to reduce the risk of calcium-oxalate nephrolithiasis, and increase dietary fiber intake as tolerated. Soluble fiber is fermented by colonic bacteria into short-chain fatty acids (SCFAs) and serve as an additional energy source [7,8]. Medium-chain triglycerides (MCTs) are good sources of fat because the body is able to absorb them into the bloodstream without the use of intestinal lymphatics, which may be damaged or absent in those with intestinal failure. For this particular patient, he would have benefitted from initiation of ORS and counseled to sip on it throughout the day while limiting liquid consumption during meals. He should have also been advised to limit plain Gatorade and Boost as they are both hyperosmolar liquid formulations and can worsen diarrhea. If the patient was unable to tolerate the taste of standard ORS formulations, or the hospital did not have any ORS on formulary, sugar, salt and water at specific amounts may be added to create a homemade ORS. In summary, this patient would have likely tolerated protein in solid form better than liquid protein supplementation.

Hospital Course Continued

The patient continued to have greater than 5 L of output from the ileostomy per day, so the following day the primary team increased the loperamide from 2 mg every 6 hours to 4 mg every 6 hours, added 2 tabs of diphenoxylate-atropine every 8 hours, and made the patient NPO. He continued to require IVFs and frequent electrolyte repletion because of the significant ongoing gastrointestinal losses.

What is the recommended first-line medical therapy for high-output enterostomy/diarrhea?

Anti-diarrheal medications are commonly used in high-output states because they work by reducing the rate of bowel translocation thereby allowing for longer time for nutrient and fluid absorption in the small and large intestine. Loperamide in particular also improves fecal incontinence because it effects the recto-anal inhibitory reflex and increases internal anal sphincter tone [9]. Four RCTs showed that loperamide lead to a significant reduction in enterostomy output compared to placebo with enterostomy output reductions ranging from 22% to 45%; varying dosages of loperamide were used, and ranged from 6 mg per day to 16 total mg per day [10–12]. King et al compared loperamide and codeine to placebo and found that both medications led to reductions in enterostomy output with a greater reduction and better side effect profile in those that received loperamide or combination therapy with loperamide and codeine [13,14]. The majority of studies used a maximum dose of 16 mg per day of loperamide, and this is the maxium daily dose approved by the US Food and Drug Administration (FDA). Interestingly however, loperamide circulates through the enterohepatic circulation which is severely disrupted in SBS, so titrating up to a maximum dose of 32 mg per day while closely monitoring for side effects is also practiced by experts in intestinal failure [15]. It is also important to note that anti-diarrheal medications are most effective when administered 20 to 30 minutes prior to meals and not scheduled every 4 to 6 hours if the patient is eating by mouth. If intestinal transit is so rapid such that undigested anti-diarrheal tablets or capsules are visualized in the stool or stoma, medications can be crushed or opened and mixed with liquids or solids to enhance digestion and absorption.

Hospital Course Continued

The patient continued to have greater than 3 L of ileostomy output per day despite being on scheduled loperamide, diphenoxylate-atropine, and a proton pump inhibitory (PPI), although improved from greater than 5 L per day. He was subsequently started on opium tincture 6 mg every 6 hours, psyllium 3 times per day, the dose of diphenoxylate-atropine was increased from 2 tablets every 8 hours to 2 tablets every 6 hours, and he was encouraged to drink water in between meals. As mentioned previously, the introduction of dietary fiber should be carefully monitored, as this patient population is commonly intolerant of high dietary fiber intake, and hypoosmolar liquids like water should actually be minimized. Within a 48-hour time period, the surgical team recommended increasing the loperamide from 4 mg every 6 hours (16 mg total daily dose) to 12 mg every 6 hours (48 mg total daily dose), increased opium tincture from 6 mg every 6 hours (24 mg total daily dose) to 10 mg every 6 hours (40 mg total daily dose), and increased oral pantoprazole from 40 mg once per day to twice per day.

What are important considerations with regard to dose changes?

Evidence is lacking to suggest an adequate time period to monitor for response to therapy in regards to improvement in diarrheal output. In this scenario, it may have been prudent to wait 24 to 48 hours after each medication change instead of making drastic dose changes in several medications simultaneously. PPIs irreversibly inhibit gastrointestinal acid secretion as do histamine-2 receptor antagonists (H2RAs) but to a lesser degree, and thus reduce high-output enterostomy [16]. Reduction in pH related to elevated gastrin levels after intestinal resection is associated with pancreatic enzyme denaturation and downstream bile salt dysfunction, which can further lead to malabsorption [17]. Gastrin hypersecretion is most prominent within the first 6 months after intestinal resection such that the use of high- dose PPIs for reduction in gastric acid secretion are most efficacious within that time period [18,19]. Jeppesen et al demonstrated that both omeprazole 40 mg oral twice per day and ranitidine 150 mg IV once per day were effective in reducing enterostomy output, although greater reductions were seen with omeprazole [20]. Three studies using cimetidine (both oral and IV formulations) with dosages varying from 200 mg to 800 mg per day showed significant reductions in enterostomy output as well [21–23].

Hospital Course Continued

Despite the previously mentioned interventions, the patient’s ileostomy output remained greater than 3 L per day. Loperamide was increased from 12 mg every 6 hours to 16 mg every 6 hours (64 mg total daily dose) hours and opium tincture was increased from 10 mg to 16 mg every 6 hours (64 mg total daily dose). Despite these changes, no significant reduction in output was noted, so the following day, 4 grams of cholestyramine light was added twice per day.

If the patient continues to have high-output enterostomy/diarrhea, what are additional treatment options?

Bile acid binding resins like cholestyramine, colestipol, and colesevelam are occasionally used if there is a high suspicion for bile acid diarrhea. Bile salt diarrhea typically occurs because of alterations in the enterohepatic circulation of bile salts, which leads to an increased level of bile salts in the colon and stimulation of electrolyte and water secretion and watery diarrhea [24]. Optimal candidates for bile acid binding therapy are those with an intact colon and less than 100 cm of resected ileum. Patients with little to no remaining or functional ileum have a depleted bile salt pool, therefore the addition of bile acid resin binders may actually lead to worsening diarrhea secondary to bile acid deficiency and fat malabsorption. Bile-acid resin binders can also decrease oxalate absorption and precipitate oxalate stone formation in the kidneys. Caution should also be taken to ensure that these medications are administered separately from the remainder of the patient’s medications to limit medication binding.

If the patient exhibits hemodynamic stability, alpha-2 receptor agonists are occasionally used as adjunctive therapy in reducing enterostomy output, although strong evidence to support its use is lacking. The mechanism of action involves stimulation of alpha-2 adrenergic receptors on enteric neurons, which theoretically causes a reduction in gastric and colonic motility and decreases fluid secretion. Buchman et al showed that the effects of a clonidine patch versus placebo did not in fact lead to a significant reduction in enterostomy output; however, a single case report suggested that the combination of 1200 mcg of clonidine per day and somatostatin resulted in decreased enterostomy output via alpha 2-receptor inhibition of adenylate cyclase [25,26].

Hospital Course Continued

The patient’s ileostomy output remained greater than 3 L per day, so loperamide was increased from 14 mg every 6 hours to 20 mg every 6 hours (80 mg total daily dose), cholestyramine was discontinued because of metabolic derangements, and the patient was initiated on 100 mcg of subcutaneous octreotide 3 times per day. Colorectal surgery was consulted for ileostomy takedown given persistently high-output, but surgery was deferred. After a 16-day hospitalization, the patient was eventually discharged home. At the time of discharge, he was having 2–3 L of ileostomy output per day and plans for future chemotherapy were discontinued because of this.

Does hormonal therapy have a role in the management of high-output enterostomy or entero-cutaneous fistulas?

Somatostatin analogues are growth-hormone inhibiting factors that have been used in the treatment of SBS and gastrointestinal fistulas. These medications reduce intestinal and pancreatic fluid secretion, slow intestinal motility, and inhibit the secretion of several hormones including gastrin, vasoactive intestinal peptide, cholecystokinin, and other key intestinal hormones. There is conflicting evidence for the role of these medications in reducing enterostomy output when first-line treatments have failed. Several previous studies using octreotide or somatostatin showed significant reductions in enterostomy output using variable dosages [27–30]. One study using the long-acting release depot octreotide preparation in 8 TPN-dependent patients with SBS showed a significant increase in small bowel transit time, however there was no significant improvement in the following parameters: body weight, stool weight, fecal fat excretion, stool electrolyte excretion, or gastric emptying [31]. Other studies evaluating enterostomy output from gastrointestinal and pancreatic fistulas comparing combined therapy with octreotide and TPN to placebo and TPN failed to show a significant difference in output and spontaneous fistula closure within 20 days of treatment initiation [32]. Because these studies use highly variable somatostatin analogue dosages and routes of administration, the most optimal dosing and route of administration (SQ versus IV) are unknown. In patients with difficult to control blood sugars, initiation of somatostatin analogues should be cautioned since these medications can lead to blood sugar alterations [33]. Additional unintended effects include impairment in intestinal adaptation and an increased risk in gallstone formation [8].

The most recent medical advances in SBS management include gut hormones. Glucagon-like peptide 2 (GLP-2) analogues improve structural and functional intestinal adaptation following intestinal resection by decreasing gastric emptying, decreasing gastric acid secretion, increasing intestinal blood flow, and enhancing nutrient and fluid absorption. Teduglutide, a GLP-2 analog, was successful in reducing fecal energy losses and increasing intestinal wet weight absorption, and reducing the need for PN support in SBS patients [1].

Whose problem is it anyway?

Not only is there variation in management strategies among subspecialties, but recommendations amongst societies within the same subspecialty differ, and thus make management perplexing.

Gastroenterology Guidelines

Several major gastroenterology societies have published guidelines on the management of diarrhea in patients with intestinal failure. The British Society of Gastroenterology (BSG) published guidelines on the management of SBS in 2006 and recommended the following first-line therapy for diarrhea-related complications: start loperamide at 2–8 mg thirty minutes prior to meals, taken up to 4 times per day, and the addition of codeine phosphate 30–60 mg thirty minutes before meals if output remains above goal on loperamide monotherapy. Cholestyramine may be added for those with 100 cm or less of resected terminal ileum to assist with bile-salt-induced diarrhea, though no specific dosage recommendations were reported. In regards to anti-secretory medications, the BSG recommends cimetidine (400 mg oral or IV 4 times per day), ranitidine (300 mg oral twice per day), or omeprazole (40 mg oral once per day or IV twice per day) to reduce jejunostomy output particularly in patients with greater than 2 L of output per day [15,34]. If diarrhea or enterostomy output continues to remain above goal, the guidelines suggest initiating octreotide and/or growth factors (although dosing and duration of therapy is not discussed in detail), and considering evaluation for intestinal transplant once the patient develops complications related to long-term TPN.

The American Gastroenterology Association (AGA) published guidelines and a position statement in 2003 for the management of high-gastric output and fluid losses. For postoperative patients, the AGA recommends the use of PPIs and H2RAs for the first 6 months following bowel resection when hyper-gastrinemia most commonly occurs. The guidelines do not specify which PPI or H2RA is preferred or recommended dosages. For long-term management of diarrhea or excess fluid losses, the guidelines suggest using loperamide or diphenoxylate (4-16 mg per day) first, followed by codeine sulfate 15–60 mg two to three times per day or opium tincture (dosages not specified). The use of octreotide (100 mcg SQ 3 times per day, 30 minutes prior to meals) is recommended only as a last resort if IVF requirements are greater than 3 L per day [8].

Surgical Guidelines

The Cleveland Clinic published institutional guidelines for the management of intestinal failure in 2010 with updated recommendations in 2016. Dietary recommendations include the liberal use of salt, sipping on 1–2 L of ORS between meals, and a slow reintroduction of soluble fiber from foods and/or supplements as tolerated. The guidelines also suggest considering placement of a nasogastric feeding tube or percutaneous gastrostomy tube (PEG) for continuous enteral feeding in addition to oral intake to enhance nutrient absorption [35]. If dietary manipulation is inadequate and medical therapy is required, the following medications are recommended in no particular order: loperamide 4 times per day (maximum dosage of 16 mg), diphenoxylate-atropine 4 times per day (maximum dosage of 20 mg per day), codeine 4 times per day (maximum dosage 240 mg per day), paregoric 5 mL (containing 2 mg of anhydrous morphine) 4 times per day, and opium tincture 0.5 mL (10 mg/mL) 4 times per day. H2RAs and PPIs are recommended for postoperative high-output states, although no dosage recommendations or routes of administration were discussed. 

Nutrition Guidelines

Villafranca et al published a protocol for the management of high-output stomas in 2015 that was shown to be effective in reducing high-enterostomy output. The protocol recommended initial treatment with loperamide 2 mg orally up to 4 times per day. If enterostomy output did not improve, the protocol recommended increasing loperamide to 4 mg four times per day, adding omeprazole 20 mg orally or cholestyramine 4 g twice per day before lunch and dinner if fat malabsorption or steatorrhea is suspected, and lastly the addition of codeine 15–60 mg up to 4 times per day and octreotide 200 mcg per day only if symptoms had not improved after 2 weeks [37].

The American Society for Parenteral and Enteral Nutrition (ASPEN) does not have published guidelines for the management of SBS. In 2016 however, the European Society for Clinical Nutrition and Metabolism (ESPEN) published guidelines on the management of chronic intestinal failure in adults. In patients with an intact colon, ESPEN strongly recommends a diet rich in complex carbohydrates and low in fat and using H2RAs or PPIs to treat hyper-gastrinemia within the first 6 months after intestinal resection particularly in those with greater than 2 L per day of fecal output. The ESPEN guidelines do not include whether to start a PPI or H2RA first, which particular drug in each class to try, or dosage recommendations but state that IV soluble formulations should be considered in those that do not seem to respond to tablets. ESPEN does not recommend the addition of soluble fiber to enhance intestinal absorption or probiotics and glutamine to aid in intestinal rehabilitation. For diarrhea and excessive fecal fluid, the guidelines recommend 4 mg of oral loperamide 30–60 minutes prior to meals, 3 to 4 times per day, as first-line treatment in comparison to codeine phosphate or opium tincture given the risks of dependence and sedation with the latter agents. They report, however, that dosages up to 12–24 mg at one time of loperamide are used in patients with terminal ileum resection and persistently high-output enterostomy [38].

Case Conclusion

The services that were closely involved in this patient’s care were general internal medicine, general surgery, colorectal surgery, and ancillary services, including dietary and wound care. Interestingly, despite persistent high ileostomy output during the patient’s 16-day hospital admission, the gastroenterology service was never consulted. This case illustrates the importance of having a multidisciplinary approach to the care of these complicated patients to ensure that the appropriate medications are ordered based on the individual’s anatomy and that medications are ordered at appropriate dosages and timing intervals to maximize drug efficacy. It is also critical to ensure that nursing staff accurately documents all intake and output so that necessary changes can be made after adequate time is given to assess for a true response. There should be close communication between the primary medical or surgical service with the dietician to ensure the patient is counseled on appropriate dietary intake to help minimize diarrhea and fluid losses.

Conclusion

In conclusion, intestinal failure is a heterogenous group of disease states that often occurs after major intestinal resection and is commonly associated with malabsorption and high output states. High-output enterostomy and diarrhea are the most common etiologies leading to hospital re-admission following enterostomy creation or intestinal resection. These patients have high morbidity and mortality rates, and their conditions are costly to the health care system. Lack of high-quality evidence from RCTs and numerous societal guidelines without clear medication and dietary algorithms and low prevalence of these conditions makes management of these patients by general medical and surgical teams challenging. The proper management of intestinal failure and related complications requires a multidisciplinary approach with involvement from medical, surgical, and ancillary services. We propose a multidisciplinary approach with involvement from medical, surgical, and ancillary services in designed and implementing a protocol using electronic medical record based order sets to simplify and improve the management of these patients in the inpatient setting.

Corresponding author: Jake Hutto, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, [email protected].

Financial disclosures: None.

From the University of Texas Southwestern, Department of Internal Medicine, Dallas, TX.

Abstract

• Objective: To define intestinal failure and associated diseases that often lead to diarrhea and high-output states, and to provide a literature review on the current evidence and practice guidelines for the management of these conditions in the context of a clinical case.
• Methods: Database search on dietary and medical interventions as well as major societal guidelines for the management of intestinal failure and associated conditions.
• Results: Although major societal guidelines exist, the guidelines vary greatly amongst various specialties and are not supported by strong evidence from large randomized controlled trials. The majority of the guidelines recommend consideration of several drug classes, but do not specify medications within the drug class, optimal dose, frequency, mode of administration, and how long to trial a regimen before considering it a failure and adding additional medical therapies.
• Conclusions: Intestinal failure and high-output states affect a very heterogenous population with high morbidity and mortality. This subset of patients should be managed using a multidisciplinary approach involving surgery, gastroenterology, dietetics, internal medicine and ancillary services that include but are not limited to ostomy nurses and home health care. Implementation of a standardized protocol in the electronic medical record including both medical and nutritional therapies may be useful to help optimize efficacy of medications, aid in nutrient absorption, decrease cost, reduce hospital length of stay, and decrease hospital readmissions.

Key words: short bowel syndrome; high-output ostomy; entero-cutaneous fistula; diarrhea; malnutrition.

Intestinal failure includes but is not limited to short bowel syndrome (SBS), high-output enterostomy, and high-output related to entero-cutaneous fistulas (ECF). These conditions are unfortunate complications after major abdominal surgery requiring extensive intestinal resection leading to structural SBS. Absorption of macronutrients and micronutrients is most dependent on the length and specific segment of remaining intact small intestine [1]. The normal small intestine length varies greatly but ranges from 300 to 800 cm, while in those with structural SBS the typical length is 200 cm or less [2,3]. Certain malabsorptive enteropathies and severe intestinal dysmotility conditions may manifest as functional SBS as well. Factors that influence whether an individual will develop functional SBS despite having sufficient small intestinal absorptive area include the degree of jejunal absorptive efficacy and the ability to overcompensate with enough oral caloric intake despite high fecal energy losses, also known as hyperphagia [4].

Pathophysiology

Maintenance of normal bodily functions and homeostasis is dependent on sufficient intestinal absorption of essential macronutrients, micronutrients, and fluids. The hallmark of intestinal failure is based on the presence of decreased small bowel absorptive surface area and subsequent increased losses of key solutes and fluids [1]. Intestinal failure is a broad term that is comprised of 3 distinct phenotypes. The 3 functional classifications of intestinal failure include the following:

• Type 1. Acute intestinal failure is generally self-limiting, occurs after abdominal surgery, and typically lasts less than 28 days.
• Type 2. Subacute intestinal failure frequently occurs in septic, stressed, or metabolically unstable patients and may last up to several months.
• Type 3. Chronic intestinal failure occurs due to a chronic condition that generally requires indefinite parenteral nutrition (PN) [1,3,4].

SBS and enterostomy formation are often associated with excessive diarrhea, such that it is the most common etiology for postoperative readmissions. The definition of “high-output” varies amongst studies, but output is generally considered to be abnormally high if it is greater than 500 mL per 24 hours in ECFs and greater than 1500 mL per 24 hours for enterostomies. There is significant variability from patient to patient, as output largely depends on length of remaining bowel [2,4].

Epidemiology

SBS, high-output enterostomy, and high-output from ECFs comprise a wide spectrum of underlying disease states, including but not limited to inflammatory bowel disease, post-surgical fistula formation, intestinal ischemia, intestinal atresia, radiation enteritis, abdominal trauma, and intussusception [5]. Due to the absence of a United States registry of patients with intestinal failure, the prevalence of these conditions is difficult to ascertain. Most estimations are made using registries for patients on total parenteral nutrition (TPN). The Crohns and Colitis Foundation of America estimates 10,000 to 20,000 people suffer from SBS in the United States. This heterogenous patient population has significant morbidity and mortality for dehydration related to these high-output states. While these conditions are considered rare, they are relatively costly to the health care system. These patients are commonly managed by numerous medical and surgical services, including internal medicine, gastroenterology, surgery, dietitians, wound care nurses, and home health agencies. Management strategies differ amongst these specialties and between professional societies, which makes treatment strategies highly variable and perplexing to providers taking care of this patient population. Furthermore, most of the published guidelines are based on expert opinion and lack high-quality clinical evidence from randomized controlled trials (RCTs). Effectively treating SBS and reducing excess enterostomy output leads to reduced rates of dehydration, electrolyte imbalances, initiation of PN, weight loss and ultimately a reduction in malnutrition. Developing hospital-wide management protocols in the electronic medical record for this heterogenous condition may lead to less complications, fewer hospitalizations, and an improved quality of life for these patients.

Case Study

Initial Presentation

A 72-year-old man with history of rectal adenocarcinoma stage T4bN2 status post low anterior resection (LAR) with diverting loop ileostomy and neoadjuvant chemoradiation presented to the hospital with a 3-day history of nausea, vomiting, fatigue, and productive cough.

Additional History

On further questioning, the patient also reported odynophagia and dysphagia related to thrush. Because of his decreased oral intake, he stopped taking his usual insulin regimen prior to admission. His cancer treatment course was notable for a LAR with diverting loop ileostomy which was performed 5 months prior. He had also completed 3 out of 8 cycles of capecitabine and oxaliplatin-based therapy 2 weeks prior to this presentation.

Physical Examination

Significant physical examination findings included dry mucous membranes, oropharyngeal candidiasis, tachycardia, clear lungs, hypoactive bowel sounds, nontender, non-distended abdomen, and a right lower abdominal ileostomy bag with semi-formed stool.

Laboratory test results were pertinent for diabetic ketoacidosis (DKA) with an anion gap of 33, lactic acidosis, acute kidney injury (creatinine 2.7 mg/dL from a baseline of 1.0) and blood glucose of 1059 mg/dL. Remainder of complete blood count and complete metabolic panel were unremarkable.

Hospital Course

The patient was treated for oropharyngeal candidiasis with fluconazole, started on an insulin drip and given intravenous fluids (IVFs) with subsequent resolution of DKA. Once the DKA resolved, his diet was advanced to a mechanical soft, moderate calorie, consistent carbohydrate diet (2000 calories allowed daily with all foods chopped, pureed or cooked, and all meals containing nearly equal amounts of carbohydrates). He was also given Boost supplementation 3 times per day, and daily weights were recorded while assessing for fluid losses. However, during his hospital course the patient developed increasing ileostomy output ranging from 2.7 to 6.5 L per day that only improved when he stopped eating by mouth (NPO).

What conditions should be evaluated prior to starting therapy for high-output enterostomy/diarrhea from either functional or structural SBS?

Prior to starting anti-diarrheal and anti-secretory therapy, infectious and metabolic etiologies for high-enterostomy output should be ruled out. Depending on the patient’s risk factors (eg, recent sick contacts, travel) and whether they are immunocompetent versus immunosuppressed, infectious studies should be obtained. In this patient, Clostridium difficile, stool culture, Giardia antigen, stool ova and parasites were all negative. Additional metabolic labs including thyroid-stimulating hormone, fecal elastase, and fecal fat were obtained and were all within normal limits. In this particular scenario, fecal fat was obtained while he was NPO. Testing for fat malabsorption and pancreatic insufficiency in a patient that is consuming less than 100 grams of fat per day can result in a false-negative outcome, however, and was not an appropriate test in this patient.

Hospital Course Continued

Once infectious etiologies were ruled out, the patient was started on anti-diarrheal medication consisting of loperamide 2 mg every 6 hours and oral pantoprazole 40 mg once per day. The primary internal medicine team speculated that the Boost supplementation may be contributing to the diarrhea because of its hyperosmolar concentration and wanted to discontinue it, but because the patient had protein-calorie malnutrition the dietician recommended continuing Boost supplementation. The primary internal medicine team also encouraged the patient to drink Gatorade with each meal with the approval from the dietician.

What are key dietary recommendations to help reduce high-output enterostomy/diarrhea?

Dietary recommendations are often quite variable depending on the intestinal anatomy (specifically, whether the colon is intact or absent), comorbidities such as renal disease, and severity of fluid and nutrient loses. This patient has the majority of his colon remaining; however, fluid and nutrients are being diverted away from his colon because he has a loop ileostomy. To reduce enterostomy output, it is generally recommended that liquids be consumed separately from solids, and that oral rehydration solutions (ORS) should replace most hyperosmolar and hypoosmolar liquids. Although these recommendations are commonly used, there is sparse data to suggest separating liquids from solids in a medically stable patient with SBS is indeed necessary [6]. In our patient, however, because he has not yet reached medical stability, it would be reasonable to separate the consumption of liquids from solids. The solid component of a SBS diet should consist mainly of protein and carbohydrates, with limited intake of simple sugars and sugar alcohols. If the colon remains intact, it is particularly important to limit fats to less than 30% of the daily caloric intake, to consume a low-oxalate diet, supplement with oral calcium to reduce the risk of calcium-oxalate nephrolithiasis, and increase dietary fiber intake as tolerated. Soluble fiber is fermented by colonic bacteria into short-chain fatty acids (SCFAs) and serve as an additional energy source [7,8]. Medium-chain triglycerides (MCTs) are good sources of fat because the body is able to absorb them into the bloodstream without the use of intestinal lymphatics, which may be damaged or absent in those with intestinal failure. For this particular patient, he would have benefitted from initiation of ORS and counseled to sip on it throughout the day while limiting liquid consumption during meals. He should have also been advised to limit plain Gatorade and Boost as they are both hyperosmolar liquid formulations and can worsen diarrhea. If the patient was unable to tolerate the taste of standard ORS formulations, or the hospital did not have any ORS on formulary, sugar, salt and water at specific amounts may be added to create a homemade ORS. In summary, this patient would have likely tolerated protein in solid form better than liquid protein supplementation.

Hospital Course Continued

The patient continued to have greater than 5 L of output from the ileostomy per day, so the following day the primary team increased the loperamide from 2 mg every 6 hours to 4 mg every 6 hours, added 2 tabs of diphenoxylate-atropine every 8 hours, and made the patient NPO. He continued to require IVFs and frequent electrolyte repletion because of the significant ongoing gastrointestinal losses.

What is the recommended first-line medical therapy for high-output enterostomy/diarrhea?

Anti-diarrheal medications are commonly used in high-output states because they work by reducing the rate of bowel translocation thereby allowing for longer time for nutrient and fluid absorption in the small and large intestine. Loperamide in particular also improves fecal incontinence because it effects the recto-anal inhibitory reflex and increases internal anal sphincter tone [9]. Four RCTs showed that loperamide lead to a significant reduction in enterostomy output compared to placebo with enterostomy output reductions ranging from 22% to 45%; varying dosages of loperamide were used, and ranged from 6 mg per day to 16 total mg per day [10–12]. King et al compared loperamide and codeine to placebo and found that both medications led to reductions in enterostomy output with a greater reduction and better side effect profile in those that received loperamide or combination therapy with loperamide and codeine [13,14]. The majority of studies used a maximum dose of 16 mg per day of loperamide, and this is the maxium daily dose approved by the US Food and Drug Administration (FDA). Interestingly however, loperamide circulates through the enterohepatic circulation which is severely disrupted in SBS, so titrating up to a maximum dose of 32 mg per day while closely monitoring for side effects is also practiced by experts in intestinal failure [15]. It is also important to note that anti-diarrheal medications are most effective when administered 20 to 30 minutes prior to meals and not scheduled every 4 to 6 hours if the patient is eating by mouth. If intestinal transit is so rapid such that undigested anti-diarrheal tablets or capsules are visualized in the stool or stoma, medications can be crushed or opened and mixed with liquids or solids to enhance digestion and absorption.

Hospital Course Continued

The patient continued to have greater than 3 L of ileostomy output per day despite being on scheduled loperamide, diphenoxylate-atropine, and a proton pump inhibitory (PPI), although improved from greater than 5 L per day. He was subsequently started on opium tincture 6 mg every 6 hours, psyllium 3 times per day, the dose of diphenoxylate-atropine was increased from 2 tablets every 8 hours to 2 tablets every 6 hours, and he was encouraged to drink water in between meals. As mentioned previously, the introduction of dietary fiber should be carefully monitored, as this patient population is commonly intolerant of high dietary fiber intake, and hypoosmolar liquids like water should actually be minimized. Within a 48-hour time period, the surgical team recommended increasing the loperamide from 4 mg every 6 hours (16 mg total daily dose) to 12 mg every 6 hours (48 mg total daily dose), increased opium tincture from 6 mg every 6 hours (24 mg total daily dose) to 10 mg every 6 hours (40 mg total daily dose), and increased oral pantoprazole from 40 mg once per day to twice per day.

What are important considerations with regard to dose changes?

Evidence is lacking to suggest an adequate time period to monitor for response to therapy in regards to improvement in diarrheal output. In this scenario, it may have been prudent to wait 24 to 48 hours after each medication change instead of making drastic dose changes in several medications simultaneously. PPIs irreversibly inhibit gastrointestinal acid secretion as do histamine-2 receptor antagonists (H2RAs) but to a lesser degree, and thus reduce high-output enterostomy [16]. Reduction in pH related to elevated gastrin levels after intestinal resection is associated with pancreatic enzyme denaturation and downstream bile salt dysfunction, which can further lead to malabsorption [17]. Gastrin hypersecretion is most prominent within the first 6 months after intestinal resection such that the use of high- dose PPIs for reduction in gastric acid secretion are most efficacious within that time period [18,19]. Jeppesen et al demonstrated that both omeprazole 40 mg oral twice per day and ranitidine 150 mg IV once per day were effective in reducing enterostomy output, although greater reductions were seen with omeprazole [20]. Three studies using cimetidine (both oral and IV formulations) with dosages varying from 200 mg to 800 mg per day showed significant reductions in enterostomy output as well [21–23].

Hospital Course Continued

Despite the previously mentioned interventions, the patient’s ileostomy output remained greater than 3 L per day. Loperamide was increased from 12 mg every 6 hours to 16 mg every 6 hours (64 mg total daily dose) hours and opium tincture was increased from 10 mg to 16 mg every 6 hours (64 mg total daily dose). Despite these changes, no significant reduction in output was noted, so the following day, 4 grams of cholestyramine light was added twice per day.

If the patient continues to have high-output enterostomy/diarrhea, what are additional treatment options?

Bile acid binding resins like cholestyramine, colestipol, and colesevelam are occasionally used if there is a high suspicion for bile acid diarrhea. Bile salt diarrhea typically occurs because of alterations in the enterohepatic circulation of bile salts, which leads to an increased level of bile salts in the colon and stimulation of electrolyte and water secretion and watery diarrhea [24]. Optimal candidates for bile acid binding therapy are those with an intact colon and less than 100 cm of resected ileum. Patients with little to no remaining or functional ileum have a depleted bile salt pool, therefore the addition of bile acid resin binders may actually lead to worsening diarrhea secondary to bile acid deficiency and fat malabsorption. Bile-acid resin binders can also decrease oxalate absorption and precipitate oxalate stone formation in the kidneys. Caution should also be taken to ensure that these medications are administered separately from the remainder of the patient’s medications to limit medication binding.

If the patient exhibits hemodynamic stability, alpha-2 receptor agonists are occasionally used as adjunctive therapy in reducing enterostomy output, although strong evidence to support its use is lacking. The mechanism of action involves stimulation of alpha-2 adrenergic receptors on enteric neurons, which theoretically causes a reduction in gastric and colonic motility and decreases fluid secretion. Buchman et al showed that the effects of a clonidine patch versus placebo did not in fact lead to a significant reduction in enterostomy output; however, a single case report suggested that the combination of 1200 mcg of clonidine per day and somatostatin resulted in decreased enterostomy output via alpha 2-receptor inhibition of adenylate cyclase [25,26].

Hospital Course Continued

The patient’s ileostomy output remained greater than 3 L per day, so loperamide was increased from 14 mg every 6 hours to 20 mg every 6 hours (80 mg total daily dose), cholestyramine was discontinued because of metabolic derangements, and the patient was initiated on 100 mcg of subcutaneous octreotide 3 times per day. Colorectal surgery was consulted for ileostomy takedown given persistently high-output, but surgery was deferred. After a 16-day hospitalization, the patient was eventually discharged home. At the time of discharge, he was having 2–3 L of ileostomy output per day and plans for future chemotherapy were discontinued because of this.

Does hormonal therapy have a role in the management of high-output enterostomy or entero-cutaneous fistulas?

Somatostatin analogues are growth-hormone inhibiting factors that have been used in the treatment of SBS and gastrointestinal fistulas. These medications reduce intestinal and pancreatic fluid secretion, slow intestinal motility, and inhibit the secretion of several hormones including gastrin, vasoactive intestinal peptide, cholecystokinin, and other key intestinal hormones. There is conflicting evidence for the role of these medications in reducing enterostomy output when first-line treatments have failed. Several previous studies using octreotide or somatostatin showed significant reductions in enterostomy output using variable dosages [27–30]. One study using the long-acting release depot octreotide preparation in 8 TPN-dependent patients with SBS showed a significant increase in small bowel transit time, however there was no significant improvement in the following parameters: body weight, stool weight, fecal fat excretion, stool electrolyte excretion, or gastric emptying [31]. Other studies evaluating enterostomy output from gastrointestinal and pancreatic fistulas comparing combined therapy with octreotide and TPN to placebo and TPN failed to show a significant difference in output and spontaneous fistula closure within 20 days of treatment initiation [32]. Because these studies use highly variable somatostatin analogue dosages and routes of administration, the most optimal dosing and route of administration (SQ versus IV) are unknown. In patients with difficult to control blood sugars, initiation of somatostatin analogues should be cautioned since these medications can lead to blood sugar alterations [33]. Additional unintended effects include impairment in intestinal adaptation and an increased risk in gallstone formation [8].

The most recent medical advances in SBS management include gut hormones. Glucagon-like peptide 2 (GLP-2) analogues improve structural and functional intestinal adaptation following intestinal resection by decreasing gastric emptying, decreasing gastric acid secretion, increasing intestinal blood flow, and enhancing nutrient and fluid absorption. Teduglutide, a GLP-2 analog, was successful in reducing fecal energy losses and increasing intestinal wet weight absorption, and reducing the need for PN support in SBS patients [1].

Whose problem is it anyway?

Not only is there variation in management strategies among subspecialties, but recommendations amongst societies within the same subspecialty differ, and thus make management perplexing.

Gastroenterology Guidelines

Several major gastroenterology societies have published guidelines on the management of diarrhea in patients with intestinal failure. The British Society of Gastroenterology (BSG) published guidelines on the management of SBS in 2006 and recommended the following first-line therapy for diarrhea-related complications: start loperamide at 2–8 mg thirty minutes prior to meals, taken up to 4 times per day, and the addition of codeine phosphate 30–60 mg thirty minutes before meals if output remains above goal on loperamide monotherapy. Cholestyramine may be added for those with 100 cm or less of resected terminal ileum to assist with bile-salt-induced diarrhea, though no specific dosage recommendations were reported. In regards to anti-secretory medications, the BSG recommends cimetidine (400 mg oral or IV 4 times per day), ranitidine (300 mg oral twice per day), or omeprazole (40 mg oral once per day or IV twice per day) to reduce jejunostomy output particularly in patients with greater than 2 L of output per day [15,34]. If diarrhea or enterostomy output continues to remain above goal, the guidelines suggest initiating octreotide and/or growth factors (although dosing and duration of therapy is not discussed in detail), and considering evaluation for intestinal transplant once the patient develops complications related to long-term TPN.

The American Gastroenterology Association (AGA) published guidelines and a position statement in 2003 for the management of high-gastric output and fluid losses. For postoperative patients, the AGA recommends the use of PPIs and H2RAs for the first 6 months following bowel resection when hyper-gastrinemia most commonly occurs. The guidelines do not specify which PPI or H2RA is preferred or recommended dosages. For long-term management of diarrhea or excess fluid losses, the guidelines suggest using loperamide or diphenoxylate (4-16 mg per day) first, followed by codeine sulfate 15–60 mg two to three times per day or opium tincture (dosages not specified). The use of octreotide (100 mcg SQ 3 times per day, 30 minutes prior to meals) is recommended only as a last resort if IVF requirements are greater than 3 L per day [8].

Surgical Guidelines

The Cleveland Clinic published institutional guidelines for the management of intestinal failure in 2010 with updated recommendations in 2016. Dietary recommendations include the liberal use of salt, sipping on 1–2 L of ORS between meals, and a slow reintroduction of soluble fiber from foods and/or supplements as tolerated. The guidelines also suggest considering placement of a nasogastric feeding tube or percutaneous gastrostomy tube (PEG) for continuous enteral feeding in addition to oral intake to enhance nutrient absorption [35]. If dietary manipulation is inadequate and medical therapy is required, the following medications are recommended in no particular order: loperamide 4 times per day (maximum dosage of 16 mg), diphenoxylate-atropine 4 times per day (maximum dosage of 20 mg per day), codeine 4 times per day (maximum dosage 240 mg per day), paregoric 5 mL (containing 2 mg of anhydrous morphine) 4 times per day, and opium tincture 0.5 mL (10 mg/mL) 4 times per day. H2RAs and PPIs are recommended for postoperative high-output states, although no dosage recommendations or routes of administration were discussed. 

Nutrition Guidelines

Villafranca et al published a protocol for the management of high-output stomas in 2015 that was shown to be effective in reducing high-enterostomy output. The protocol recommended initial treatment with loperamide 2 mg orally up to 4 times per day. If enterostomy output did not improve, the protocol recommended increasing loperamide to 4 mg four times per day, adding omeprazole 20 mg orally or cholestyramine 4 g twice per day before lunch and dinner if fat malabsorption or steatorrhea is suspected, and lastly the addition of codeine 15–60 mg up to 4 times per day and octreotide 200 mcg per day only if symptoms had not improved after 2 weeks [37].

The American Society for Parenteral and Enteral Nutrition (ASPEN) does not have published guidelines for the management of SBS. In 2016 however, the European Society for Clinical Nutrition and Metabolism (ESPEN) published guidelines on the management of chronic intestinal failure in adults. In patients with an intact colon, ESPEN strongly recommends a diet rich in complex carbohydrates and low in fat and using H2RAs or PPIs to treat hyper-gastrinemia within the first 6 months after intestinal resection particularly in those with greater than 2 L per day of fecal output. The ESPEN guidelines do not include whether to start a PPI or H2RA first, which particular drug in each class to try, or dosage recommendations but state that IV soluble formulations should be considered in those that do not seem to respond to tablets. ESPEN does not recommend the addition of soluble fiber to enhance intestinal absorption or probiotics and glutamine to aid in intestinal rehabilitation. For diarrhea and excessive fecal fluid, the guidelines recommend 4 mg of oral loperamide 30–60 minutes prior to meals, 3 to 4 times per day, as first-line treatment in comparison to codeine phosphate or opium tincture given the risks of dependence and sedation with the latter agents. They report, however, that dosages up to 12–24 mg at one time of loperamide are used in patients with terminal ileum resection and persistently high-output enterostomy [38].

Case Conclusion

The services that were closely involved in this patient’s care were general internal medicine, general surgery, colorectal surgery, and ancillary services, including dietary and wound care. Interestingly, despite persistent high ileostomy output during the patient’s 16-day hospital admission, the gastroenterology service was never consulted. This case illustrates the importance of having a multidisciplinary approach to the care of these complicated patients to ensure that the appropriate medications are ordered based on the individual’s anatomy and that medications are ordered at appropriate dosages and timing intervals to maximize drug efficacy. It is also critical to ensure that nursing staff accurately documents all intake and output so that necessary changes can be made after adequate time is given to assess for a true response. There should be close communication between the primary medical or surgical service with the dietician to ensure the patient is counseled on appropriate dietary intake to help minimize diarrhea and fluid losses.

Conclusion

In conclusion, intestinal failure is a heterogenous group of disease states that often occurs after major intestinal resection and is commonly associated with malabsorption and high output states. High-output enterostomy and diarrhea are the most common etiologies leading to hospital re-admission following enterostomy creation or intestinal resection. These patients have high morbidity and mortality rates, and their conditions are costly to the health care system. Lack of high-quality evidence from RCTs and numerous societal guidelines without clear medication and dietary algorithms and low prevalence of these conditions makes management of these patients by general medical and surgical teams challenging. The proper management of intestinal failure and related complications requires a multidisciplinary approach with involvement from medical, surgical, and ancillary services. We propose a multidisciplinary approach with involvement from medical, surgical, and ancillary services in designed and implementing a protocol using electronic medical record based order sets to simplify and improve the management of these patients in the inpatient setting.

Corresponding author: Jake Hutto, 5323 Harry Hines Blvd, Dallas, TX 75390-9030, [email protected].

Financial disclosures: None.

Division of Infectious Diseases, Department of Internal Medicine, VA Ann Arbor Healthcare System and University of Michigan Health System, Ann Arbor, MI.

Abstract

• Objective: To review prevention of central line–associated bloodstream infection (CLABSI).
• Method: Review of the literature.
• Results: Evidence-based prevention practices include ensuring hand hygiene before the procedure, using maximal sterile barrier precautions, cleaning the skin with alcoholic chlorhexidine before central line insertion, avoiding the femoral site for insertion, and removing unneeded catheters.
• Conclusion: For continued success in CLABSI prevention, best practices should be followed and patient safety should be emphasized.

Health care–associated infections (HAIs) are a preventable cause of morbidity and mortality in the United States and internationally. A Centers for Disease Control and Prevention (CDC) report estimates that in acute care hospitals, 1 in 25 patients end up with at least one HAI during their hospital stay [1]. HAIs can also be costly; in the United States, the indirect and direct cost has been estimated to be between $96 to $147 billion dollars [2]. National initiatives to prevent these types of infections have included efforts from the Department of Health and Human Services (HHS), the Institute of Medicine (IOM), the Institute for Healthcare Improvement (IHI) and the Centers for Medicare and Medicaid Services (CMS). This work has led to particular success in preventing central line–associated bloodstream infection (CLABSI).

CLABSI can lead to considerable mortality, morbidity, and cost. An estimated 250,000 CLABSIs occur in patients yearly, and about 80,000 of those are estimated to occur in the intensive care unit (ICU) setting [3]. Since central venous catheters (CVCs), or central lines, are most often used in the ICU setting, much of the work on prevention and management of CLABSI has been within the ICU population [4,5]. The increased use of peripherally inserted central catheters (PICCs) in the non-ICU setting and recognition of CLABSI in non-ICU settings has led to new efforts to understand the best way to prevent CLABSI in the non-ICU setting [4,6]. Regardless of setting, the annual cost of these infections has been estimated to be as high as $2.3 billion [7]. One episode is estimated to cost a hospital up to $46,485 per episode with components of excess length of stay, antibiotic cost, and cost of care [8]. In this review, selected best practices in CLABSI prevention are identified and described.

Elements of CLABSI Prevention

One of the key papers in the CLABSI literature was the Keystone ICU project in Michigan [9]. This state-wide effort grew out of a successful pilot patient-safety program that was trialed at Johns Hopkins Medical Institutions to reduce CLABSI in the ICU setting. In 2003, the Agency for Healthcare Research and Quality (AHRQ) funded a study to examine the intervention in ICUs in the state of Michigan. A total of 108 ICUs from 67 individual hospitals participated in the pre-intervention/post-intervention study [9]. A combination of technical and socio-adaptive interventions to prevent CLABSI included clinician education on best practices in insertion of central lines, having a central-line cart in each ICU, an insertion checklist of best practices, empowering nursing staff to stop the procedure if best practices were not being followed, discussing removal of catheters daily, and providing feedback to units regarding rates of CLABSI [10]. Executive administration of each hospital was also involved and there were monthly phone calls for hospital teams to share successes and barriers.

In the pre-intervention phase, the median catheter- related bloodstream infection rate was 2.7 infections per 1000 catheter days for the sum of hospitals. After the interventions were put in place, the median rate of catheter related bloodstream infections was down to 0.34 at 18 months. The study showed that results from a relatively inexpensive and straightforward intervention could be effective and could last in the long term. This study led to many other single center and multicenter studies, nationally and internationally, to replicate results in efforts to decrease CLABSI in ICU populations [5]. The CDC and AHRQ have continued to partner with regional, state and national efforts to focus on CLABSI prevention.

The Bundle Approach

A number of interventions have been proven to be effective at preventing CLABSI. Combining more than one intervention can often have additive effects. This effect has been recognized in numerous quality improvement studies on CLABSI and has been termed using the “bundle” approach. 

Hand Hygiene

Poor hand hygiene by health care workers is generally thought to be the most common cause of HAIs [12]. Guidelines recommend an alcohol-based waterless product or antiseptic soap and water prior to catheter insertion [13]. The most common underlying etiology of CLABSI is through microorganisms introduced at time of insertion of catheter. This can be extraluminally mediated via skin flora of the patient, or due to lack of hand washing on the inserter’s part and can lead to CLABSI [14]. While a randomized controlled trial would be unethical, several studies have shown when targeted hand hygiene campaigns are held, CLABSI rates tend to decrease [15–17].

Maximal Barrier Precautions

The use of maximal sterile barrier precautions has been associated with less mortality, decreasing catheter colonization, incidence of HAI and cost savings [18–20]. Like most components of the bundle, maximal sterile barrier precautions have rarely been studied alone, but are often a part of a “bundle” or number of interventions [21]. Like hand hygiene, while regularly a part of many hospital’s checklist or bundle process, compliance with this key part of infection prevention can be deficient; one study noted measured maximal sterile barriers compliance to be 44% [22].

Chlorhexidine Skin Antisepsis

Chlorhexidine skin preparation decreases bacterial burden at site of insertion and is thought to reduce infection from this mechanism. Chlorhexidine-alcohol skin preparation has been proven in randomized controlled trials to outperform povidone iodine-alcohol in preventing CLABSI [23,24]. Chlorhexidine skin preparation is considered a technical element of checklists and is thought to be a straightforward and easily implementable action [25]. If a hospital supplies only alcoholic chlorhexidine and doesn’t provide povidone-iodine for skin preparation, then clinicians can be “nudged” towards performing this part of the bundle.

Optimal Catheter Site Selection

For all sites of insertion of CVC, the risk of mechanical and infectious complications depends on the skill and proficiency of operators, the clinical situation, and the availability of ultrasound to help guide placement. These factors are important in determining which anatomical site is best for each patient [26]. The femoral site has been associated with a greater risk of catheter-related infection and catheter-related thrombosis and is not recommended as the initial choice for non-emergent CVC insertion according to national guidelines [13,27]. The internal jugular vein site is associated with a lower risk of severe mechanical complications such as pneumothorax when compared to subclavian vein site [27]. The subclavian vein site is associated with a lower risk of catheter-related blood stream infection and lower rate of thrombosis, but this greatly depends on experience of operator. Experts have proposed that the subclavian site has a lower burden of colonization by bacteria than other sites and is anatomically more protected by catheter dressing; also the subcutaneous course of the central line itself is longer for the subclavian site than other sites and these reasons could contribute to the lower risk of infection [28]. The subclavian site is, however, associated with a higher risk of mechanical complications that can be serious for ICU patients. In general, the femoral vein site should be avoided in non-emergent line placement situations, particularly if the patient is an obese adult [13]. Using ultrasound as a guidance for catheter insertion has also been shown to reduce risk of CLABSI and other mechanical complications and is recommended [29,30].

Daily Review of Line Necessity

Removing unnecessary catheters as soon as possible decreases catheter dwell time and risk of infection. Few studies have concentrated on this step alone in CLABSI prevention, but the studies that have focused on catheter removal usually implement electronic reminders or multidisciplinary catheter rounds (where need for catheter is incorporated into daily rounds or discussed separately by a multidisciplinary group) [5,31].

Additional Considerations

Other basic practices that all hospitals should adopt include the above strategies and providing all inclusive catheter carts or kits, disinfecting hubs in maintenance care of catheters, covering the CVC site with sterile dressings, having recurrent educational interventions and using checklists to assure adherence to the evidence-based bundle (Table) [4,13]. As prevalence of non-ICU central lines has also grown, maintenance care is particularly important in reducing CLABSI. Maintenance bundles that highlight best practices such as aseptic technique, correct hand hygiene, chlorhexidine skin disinfection scrub, antimicrobial bandage application, and catheter hub disinfection have been used with success [32]. Specialized CVC insertion teams with trained personnel have also been recommended [4]. When these basic evidence-based practices are still unable to bring down CLABSI rates for select populations or during an outbreak, supplemental strategies can be tried to reduce CLABSI. These include antimicrobial-impregnated catheters, chlorhexidine-impregnated dressings, and chlorhexidine bathing, which is increasingly being used in the ICU setting [5,13,33].

Epidemiology/Risk Factors

At-risk Populations

ICU patients are at risk for CLABSI because of frequent use of multiple catheters, and the comorbidities and acuity of care that these patients have. ICU patients also tend to have lots of manipulation of their catheters and often these catheters are placed in emergent situations [13]. Patients in the non-ICU and outpatient setting are also at risk for CLABSI when they have a central venous catheter. Long courses of antibiotics for disease states such as osteomyelitis and endocarditis often entail central venous catheters. Recent work has shown that PICCs carry as high of a CLABSI risk as short-term CVCs in hospitalized patients [34]. Patients with end-stage renal disease, especially those undergoing maintenance hemodialysis via a tunneled dialysis catheter are particularly vulnerable to CLABSI [13,35].

Risk Factors for CLABSI

A number of studies have reviewed risk factors and epidemiology of CLABSI in the adult and pediatric population. Factors that have been associated with risk of CLABSI in more than one study include prolonged hospitalization before placement of the central line, prolonged duration of the central line, heavy microbial colonization at the site of insertion, heavy microbial colonization of the catheter hub, multiple lumens, internal jugular site catheterization, femoral vein site catheterization, neutropenia of the patient, a reduced nurse to patient ratio in the ICU setting, presence of total parenteral nutrition, and poor maintenance care of the catheter [4,13,36–40]. One study [41] that calculated a score to help predict risk of PICC-CLABSI found that previous CLABSI (within 3 months of PICC insertion) significantly increases risk of repeat CLABSI.

Conclusion

CLABSI is an important cause of morbidity, mortality and cost. There has been remarkable success in prevention of these infections in recent years due to focused efforts on patient safety. As efforts have multiplied to put into place interventions to decrease CLABSI nationally, the CDC published a Vital Signs report discussing the impact of these efforts [42]. It was estimated that over one decade, infection prevention efforts had avoided 25,000 CLABSIs in U.S. ICUs, a 58% reduction in this infection [42]. CLABSI has served as the best example of using evidence-based interventions through an infection prevention bundle or framework to reduce HAIs. Similar approaches are being used to try to reduce catheter-associated urinary tract infection, Clostridium difficile infection, surgical site infection, and ventilator-associated pneumonia, but there have been less distinct successes nationally and internationally for these other HAIs.

The literature emphasizes that there are several evidence-based measures that can prevent CLABSI. These include hand hygiene, using alcoholic chlorhexidine for skin preparation prior to insertion, maximal sterile barrier precautions, avoiding the femoral site for CVC insertion, and removing unnecessary catheters as soon as possible. Support from administration in emphasizing patient safety and HAI prevention along with following evidence-based practice could lead to long-term improvement in CLABSI prevention across hospital systems.

Corresponding author: Payal K. Patel, MD, MPH, Div of Infectious Diseases, Dept of Internal Medicine, VA Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, [email protected].

Financial disclosures: None.

Division of Infectious Diseases, Department of Internal Medicine, VA Ann Arbor Healthcare System and University of Michigan Health System, Ann Arbor, MI.

Abstract

• Objective: To review prevention of central line–associated bloodstream infection (CLABSI).
• Method: Review of the literature.
• Results: Evidence-based prevention practices include ensuring hand hygiene before the procedure, using maximal sterile barrier precautions, cleaning the skin with alcoholic chlorhexidine before central line insertion, avoiding the femoral site for insertion, and removing unneeded catheters.
• Conclusion: For continued success in CLABSI prevention, best practices should be followed and patient safety should be emphasized.

Health care–associated infections (HAIs) are a preventable cause of morbidity and mortality in the United States and internationally. A Centers for Disease Control and Prevention (CDC) report estimates that in acute care hospitals, 1 in 25 patients end up with at least one HAI during their hospital stay [1]. HAIs can also be costly; in the United States, the indirect and direct cost has been estimated to be between $96 to $147 billion dollars [2]. National initiatives to prevent these types of infections have included efforts from the Department of Health and Human Services (HHS), the Institute of Medicine (IOM), the Institute for Healthcare Improvement (IHI) and the Centers for Medicare and Medicaid Services (CMS). This work has led to particular success in preventing central line–associated bloodstream infection (CLABSI).

CLABSI can lead to considerable mortality, morbidity, and cost. An estimated 250,000 CLABSIs occur in patients yearly, and about 80,000 of those are estimated to occur in the intensive care unit (ICU) setting [3]. Since central venous catheters (CVCs), or central lines, are most often used in the ICU setting, much of the work on prevention and management of CLABSI has been within the ICU population [4,5]. The increased use of peripherally inserted central catheters (PICCs) in the non-ICU setting and recognition of CLABSI in non-ICU settings has led to new efforts to understand the best way to prevent CLABSI in the non-ICU setting [4,6]. Regardless of setting, the annual cost of these infections has been estimated to be as high as $2.3 billion [7]. One episode is estimated to cost a hospital up to $46,485 per episode with components of excess length of stay, antibiotic cost, and cost of care [8]. In this review, selected best practices in CLABSI prevention are identified and described.

Elements of CLABSI Prevention

One of the key papers in the CLABSI literature was the Keystone ICU project in Michigan [9]. This state-wide effort grew out of a successful pilot patient-safety program that was trialed at Johns Hopkins Medical Institutions to reduce CLABSI in the ICU setting. In 2003, the Agency for Healthcare Research and Quality (AHRQ) funded a study to examine the intervention in ICUs in the state of Michigan. A total of 108 ICUs from 67 individual hospitals participated in the pre-intervention/post-intervention study [9]. A combination of technical and socio-adaptive interventions to prevent CLABSI included clinician education on best practices in insertion of central lines, having a central-line cart in each ICU, an insertion checklist of best practices, empowering nursing staff to stop the procedure if best practices were not being followed, discussing removal of catheters daily, and providing feedback to units regarding rates of CLABSI [10]. Executive administration of each hospital was also involved and there were monthly phone calls for hospital teams to share successes and barriers.

In the pre-intervention phase, the median catheter- related bloodstream infection rate was 2.7 infections per 1000 catheter days for the sum of hospitals. After the interventions were put in place, the median rate of catheter related bloodstream infections was down to 0.34 at 18 months. The study showed that results from a relatively inexpensive and straightforward intervention could be effective and could last in the long term. This study led to many other single center and multicenter studies, nationally and internationally, to replicate results in efforts to decrease CLABSI in ICU populations [5]. The CDC and AHRQ have continued to partner with regional, state and national efforts to focus on CLABSI prevention.

The Bundle Approach

A number of interventions have been proven to be effective at preventing CLABSI. Combining more than one intervention can often have additive effects. This effect has been recognized in numerous quality improvement studies on CLABSI and has been termed using the “bundle” approach. 

Hand Hygiene

Poor hand hygiene by health care workers is generally thought to be the most common cause of HAIs [12]. Guidelines recommend an alcohol-based waterless product or antiseptic soap and water prior to catheter insertion [13]. The most common underlying etiology of CLABSI is through microorganisms introduced at time of insertion of catheter. This can be extraluminally mediated via skin flora of the patient, or due to lack of hand washing on the inserter’s part and can lead to CLABSI [14]. While a randomized controlled trial would be unethical, several studies have shown when targeted hand hygiene campaigns are held, CLABSI rates tend to decrease [15–17].

Maximal Barrier Precautions

The use of maximal sterile barrier precautions has been associated with less mortality, decreasing catheter colonization, incidence of HAI and cost savings [18–20]. Like most components of the bundle, maximal sterile barrier precautions have rarely been studied alone, but are often a part of a “bundle” or number of interventions [21]. Like hand hygiene, while regularly a part of many hospital’s checklist or bundle process, compliance with this key part of infection prevention can be deficient; one study noted measured maximal sterile barriers compliance to be 44% [22].

Chlorhexidine Skin Antisepsis

Chlorhexidine skin preparation decreases bacterial burden at site of insertion and is thought to reduce infection from this mechanism. Chlorhexidine-alcohol skin preparation has been proven in randomized controlled trials to outperform povidone iodine-alcohol in preventing CLABSI [23,24]. Chlorhexidine skin preparation is considered a technical element of checklists and is thought to be a straightforward and easily implementable action [25]. If a hospital supplies only alcoholic chlorhexidine and doesn’t provide povidone-iodine for skin preparation, then clinicians can be “nudged” towards performing this part of the bundle.

Optimal Catheter Site Selection

For all sites of insertion of CVC, the risk of mechanical and infectious complications depends on the skill and proficiency of operators, the clinical situation, and the availability of ultrasound to help guide placement. These factors are important in determining which anatomical site is best for each patient [26]. The femoral site has been associated with a greater risk of catheter-related infection and catheter-related thrombosis and is not recommended as the initial choice for non-emergent CVC insertion according to national guidelines [13,27]. The internal jugular vein site is associated with a lower risk of severe mechanical complications such as pneumothorax when compared to subclavian vein site [27]. The subclavian vein site is associated with a lower risk of catheter-related blood stream infection and lower rate of thrombosis, but this greatly depends on experience of operator. Experts have proposed that the subclavian site has a lower burden of colonization by bacteria than other sites and is anatomically more protected by catheter dressing; also the subcutaneous course of the central line itself is longer for the subclavian site than other sites and these reasons could contribute to the lower risk of infection [28]. The subclavian site is, however, associated with a higher risk of mechanical complications that can be serious for ICU patients. In general, the femoral vein site should be avoided in non-emergent line placement situations, particularly if the patient is an obese adult [13]. Using ultrasound as a guidance for catheter insertion has also been shown to reduce risk of CLABSI and other mechanical complications and is recommended [29,30].

Daily Review of Line Necessity

Removing unnecessary catheters as soon as possible decreases catheter dwell time and risk of infection. Few studies have concentrated on this step alone in CLABSI prevention, but the studies that have focused on catheter removal usually implement electronic reminders or multidisciplinary catheter rounds (where need for catheter is incorporated into daily rounds or discussed separately by a multidisciplinary group) [5,31].

Additional Considerations

Other basic practices that all hospitals should adopt include the above strategies and providing all inclusive catheter carts or kits, disinfecting hubs in maintenance care of catheters, covering the CVC site with sterile dressings, having recurrent educational interventions and using checklists to assure adherence to the evidence-based bundle (Table) [4,13]. As prevalence of non-ICU central lines has also grown, maintenance care is particularly important in reducing CLABSI. Maintenance bundles that highlight best practices such as aseptic technique, correct hand hygiene, chlorhexidine skin disinfection scrub, antimicrobial bandage application, and catheter hub disinfection have been used with success [32]. Specialized CVC insertion teams with trained personnel have also been recommended [4]. When these basic evidence-based practices are still unable to bring down CLABSI rates for select populations or during an outbreak, supplemental strategies can be tried to reduce CLABSI. These include antimicrobial-impregnated catheters, chlorhexidine-impregnated dressings, and chlorhexidine bathing, which is increasingly being used in the ICU setting [5,13,33].

Epidemiology/Risk Factors

At-risk Populations

ICU patients are at risk for CLABSI because of frequent use of multiple catheters, and the comorbidities and acuity of care that these patients have. ICU patients also tend to have lots of manipulation of their catheters and often these catheters are placed in emergent situations [13]. Patients in the non-ICU and outpatient setting are also at risk for CLABSI when they have a central venous catheter. Long courses of antibiotics for disease states such as osteomyelitis and endocarditis often entail central venous catheters. Recent work has shown that PICCs carry as high of a CLABSI risk as short-term CVCs in hospitalized patients [34]. Patients with end-stage renal disease, especially those undergoing maintenance hemodialysis via a tunneled dialysis catheter are particularly vulnerable to CLABSI [13,35].

Risk Factors for CLABSI

A number of studies have reviewed risk factors and epidemiology of CLABSI in the adult and pediatric population. Factors that have been associated with risk of CLABSI in more than one study include prolonged hospitalization before placement of the central line, prolonged duration of the central line, heavy microbial colonization at the site of insertion, heavy microbial colonization of the catheter hub, multiple lumens, internal jugular site catheterization, femoral vein site catheterization, neutropenia of the patient, a reduced nurse to patient ratio in the ICU setting, presence of total parenteral nutrition, and poor maintenance care of the catheter [4,13,36–40]. One study [41] that calculated a score to help predict risk of PICC-CLABSI found that previous CLABSI (within 3 months of PICC insertion) significantly increases risk of repeat CLABSI.

Conclusion

CLABSI is an important cause of morbidity, mortality and cost. There has been remarkable success in prevention of these infections in recent years due to focused efforts on patient safety. As efforts have multiplied to put into place interventions to decrease CLABSI nationally, the CDC published a Vital Signs report discussing the impact of these efforts [42]. It was estimated that over one decade, infection prevention efforts had avoided 25,000 CLABSIs in U.S. ICUs, a 58% reduction in this infection [42]. CLABSI has served as the best example of using evidence-based interventions through an infection prevention bundle or framework to reduce HAIs. Similar approaches are being used to try to reduce catheter-associated urinary tract infection, Clostridium difficile infection, surgical site infection, and ventilator-associated pneumonia, but there have been less distinct successes nationally and internationally for these other HAIs.

The literature emphasizes that there are several evidence-based measures that can prevent CLABSI. These include hand hygiene, using alcoholic chlorhexidine for skin preparation prior to insertion, maximal sterile barrier precautions, avoiding the femoral site for CVC insertion, and removing unnecessary catheters as soon as possible. Support from administration in emphasizing patient safety and HAI prevention along with following evidence-based practice could lead to long-term improvement in CLABSI prevention across hospital systems.

Corresponding author: Payal K. Patel, MD, MPH, Div of Infectious Diseases, Dept of Internal Medicine, VA Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, [email protected].

Financial disclosures: None.

Division of Infectious Diseases, Department of Internal Medicine, VA Ann Arbor Healthcare System and University of Michigan Health System, Ann Arbor, MI.

Abstract

• Objective: To review prevention of central line–associated bloodstream infection (CLABSI).
• Method: Review of the literature.
• Results: Evidence-based prevention practices include ensuring hand hygiene before the procedure, using maximal sterile barrier precautions, cleaning the skin with alcoholic chlorhexidine before central line insertion, avoiding the femoral site for insertion, and removing unneeded catheters.
• Conclusion: For continued success in CLABSI prevention, best practices should be followed and patient safety should be emphasized.

Health care–associated infections (HAIs) are a preventable cause of morbidity and mortality in the United States and internationally. A Centers for Disease Control and Prevention (CDC) report estimates that in acute care hospitals, 1 in 25 patients end up with at least one HAI during their hospital stay [1]. HAIs can also be costly; in the United States, the indirect and direct cost has been estimated to be between $96 to $147 billion dollars [2]. National initiatives to prevent these types of infections have included efforts from the Department of Health and Human Services (HHS), the Institute of Medicine (IOM), the Institute for Healthcare Improvement (IHI) and the Centers for Medicare and Medicaid Services (CMS). This work has led to particular success in preventing central line–associated bloodstream infection (CLABSI).

CLABSI can lead to considerable mortality, morbidity, and cost. An estimated 250,000 CLABSIs occur in patients yearly, and about 80,000 of those are estimated to occur in the intensive care unit (ICU) setting [3]. Since central venous catheters (CVCs), or central lines, are most often used in the ICU setting, much of the work on prevention and management of CLABSI has been within the ICU population [4,5]. The increased use of peripherally inserted central catheters (PICCs) in the non-ICU setting and recognition of CLABSI in non-ICU settings has led to new efforts to understand the best way to prevent CLABSI in the non-ICU setting [4,6]. Regardless of setting, the annual cost of these infections has been estimated to be as high as $2.3 billion [7]. One episode is estimated to cost a hospital up to $46,485 per episode with components of excess length of stay, antibiotic cost, and cost of care [8]. In this review, selected best practices in CLABSI prevention are identified and described.

Elements of CLABSI Prevention

One of the key papers in the CLABSI literature was the Keystone ICU project in Michigan [9]. This state-wide effort grew out of a successful pilot patient-safety program that was trialed at Johns Hopkins Medical Institutions to reduce CLABSI in the ICU setting. In 2003, the Agency for Healthcare Research and Quality (AHRQ) funded a study to examine the intervention in ICUs in the state of Michigan. A total of 108 ICUs from 67 individual hospitals participated in the pre-intervention/post-intervention study [9]. A combination of technical and socio-adaptive interventions to prevent CLABSI included clinician education on best practices in insertion of central lines, having a central-line cart in each ICU, an insertion checklist of best practices, empowering nursing staff to stop the procedure if best practices were not being followed, discussing removal of catheters daily, and providing feedback to units regarding rates of CLABSI [10]. Executive administration of each hospital was also involved and there were monthly phone calls for hospital teams to share successes and barriers.

In the pre-intervention phase, the median catheter- related bloodstream infection rate was 2.7 infections per 1000 catheter days for the sum of hospitals. After the interventions were put in place, the median rate of catheter related bloodstream infections was down to 0.34 at 18 months. The study showed that results from a relatively inexpensive and straightforward intervention could be effective and could last in the long term. This study led to many other single center and multicenter studies, nationally and internationally, to replicate results in efforts to decrease CLABSI in ICU populations [5]. The CDC and AHRQ have continued to partner with regional, state and national efforts to focus on CLABSI prevention.

The Bundle Approach

A number of interventions have been proven to be effective at preventing CLABSI. Combining more than one intervention can often have additive effects. This effect has been recognized in numerous quality improvement studies on CLABSI and has been termed using the “bundle” approach. 

Hand Hygiene

Poor hand hygiene by health care workers is generally thought to be the most common cause of HAIs [12]. Guidelines recommend an alcohol-based waterless product or antiseptic soap and water prior to catheter insertion [13]. The most common underlying etiology of CLABSI is through microorganisms introduced at time of insertion of catheter. This can be extraluminally mediated via skin flora of the patient, or due to lack of hand washing on the inserter’s part and can lead to CLABSI [14]. While a randomized controlled trial would be unethical, several studies have shown when targeted hand hygiene campaigns are held, CLABSI rates tend to decrease [15–17].

Maximal Barrier Precautions

The use of maximal sterile barrier precautions has been associated with less mortality, decreasing catheter colonization, incidence of HAI and cost savings [18–20]. Like most components of the bundle, maximal sterile barrier precautions have rarely been studied alone, but are often a part of a “bundle” or number of interventions [21]. Like hand hygiene, while regularly a part of many hospital’s checklist or bundle process, compliance with this key part of infection prevention can be deficient; one study noted measured maximal sterile barriers compliance to be 44% [22].

Chlorhexidine Skin Antisepsis

Chlorhexidine skin preparation decreases bacterial burden at site of insertion and is thought to reduce infection from this mechanism. Chlorhexidine-alcohol skin preparation has been proven in randomized controlled trials to outperform povidone iodine-alcohol in preventing CLABSI [23,24]. Chlorhexidine skin preparation is considered a technical element of checklists and is thought to be a straightforward and easily implementable action [25]. If a hospital supplies only alcoholic chlorhexidine and doesn’t provide povidone-iodine for skin preparation, then clinicians can be “nudged” towards performing this part of the bundle.

Optimal Catheter Site Selection

For all sites of insertion of CVC, the risk of mechanical and infectious complications depends on the skill and proficiency of operators, the clinical situation, and the availability of ultrasound to help guide placement. These factors are important in determining which anatomical site is best for each patient [26]. The femoral site has been associated with a greater risk of catheter-related infection and catheter-related thrombosis and is not recommended as the initial choice for non-emergent CVC insertion according to national guidelines [13,27]. The internal jugular vein site is associated with a lower risk of severe mechanical complications such as pneumothorax when compared to subclavian vein site [27]. The subclavian vein site is associated with a lower risk of catheter-related blood stream infection and lower rate of thrombosis, but this greatly depends on experience of operator. Experts have proposed that the subclavian site has a lower burden of colonization by bacteria than other sites and is anatomically more protected by catheter dressing; also the subcutaneous course of the central line itself is longer for the subclavian site than other sites and these reasons could contribute to the lower risk of infection [28]. The subclavian site is, however, associated with a higher risk of mechanical complications that can be serious for ICU patients. In general, the femoral vein site should be avoided in non-emergent line placement situations, particularly if the patient is an obese adult [13]. Using ultrasound as a guidance for catheter insertion has also been shown to reduce risk of CLABSI and other mechanical complications and is recommended [29,30].

Daily Review of Line Necessity

Removing unnecessary catheters as soon as possible decreases catheter dwell time and risk of infection. Few studies have concentrated on this step alone in CLABSI prevention, but the studies that have focused on catheter removal usually implement electronic reminders or multidisciplinary catheter rounds (where need for catheter is incorporated into daily rounds or discussed separately by a multidisciplinary group) [5,31].

Additional Considerations

Other basic practices that all hospitals should adopt include the above strategies and providing all inclusive catheter carts or kits, disinfecting hubs in maintenance care of catheters, covering the CVC site with sterile dressings, having recurrent educational interventions and using checklists to assure adherence to the evidence-based bundle (Table) [4,13]. As prevalence of non-ICU central lines has also grown, maintenance care is particularly important in reducing CLABSI. Maintenance bundles that highlight best practices such as aseptic technique, correct hand hygiene, chlorhexidine skin disinfection scrub, antimicrobial bandage application, and catheter hub disinfection have been used with success [32]. Specialized CVC insertion teams with trained personnel have also been recommended [4]. When these basic evidence-based practices are still unable to bring down CLABSI rates for select populations or during an outbreak, supplemental strategies can be tried to reduce CLABSI. These include antimicrobial-impregnated catheters, chlorhexidine-impregnated dressings, and chlorhexidine bathing, which is increasingly being used in the ICU setting [5,13,33].

Epidemiology/Risk Factors

At-risk Populations

ICU patients are at risk for CLABSI because of frequent use of multiple catheters, and the comorbidities and acuity of care that these patients have. ICU patients also tend to have lots of manipulation of their catheters and often these catheters are placed in emergent situations [13]. Patients in the non-ICU and outpatient setting are also at risk for CLABSI when they have a central venous catheter. Long courses of antibiotics for disease states such as osteomyelitis and endocarditis often entail central venous catheters. Recent work has shown that PICCs carry as high of a CLABSI risk as short-term CVCs in hospitalized patients [34]. Patients with end-stage renal disease, especially those undergoing maintenance hemodialysis via a tunneled dialysis catheter are particularly vulnerable to CLABSI [13,35].

Risk Factors for CLABSI

A number of studies have reviewed risk factors and epidemiology of CLABSI in the adult and pediatric population. Factors that have been associated with risk of CLABSI in more than one study include prolonged hospitalization before placement of the central line, prolonged duration of the central line, heavy microbial colonization at the site of insertion, heavy microbial colonization of the catheter hub, multiple lumens, internal jugular site catheterization, femoral vein site catheterization, neutropenia of the patient, a reduced nurse to patient ratio in the ICU setting, presence of total parenteral nutrition, and poor maintenance care of the catheter [4,13,36–40]. One study [41] that calculated a score to help predict risk of PICC-CLABSI found that previous CLABSI (within 3 months of PICC insertion) significantly increases risk of repeat CLABSI.

Conclusion

CLABSI is an important cause of morbidity, mortality and cost. There has been remarkable success in prevention of these infections in recent years due to focused efforts on patient safety. As efforts have multiplied to put into place interventions to decrease CLABSI nationally, the CDC published a Vital Signs report discussing the impact of these efforts [42]. It was estimated that over one decade, infection prevention efforts had avoided 25,000 CLABSIs in U.S. ICUs, a 58% reduction in this infection [42]. CLABSI has served as the best example of using evidence-based interventions through an infection prevention bundle or framework to reduce HAIs. Similar approaches are being used to try to reduce catheter-associated urinary tract infection, Clostridium difficile infection, surgical site infection, and ventilator-associated pneumonia, but there have been less distinct successes nationally and internationally for these other HAIs.

The literature emphasizes that there are several evidence-based measures that can prevent CLABSI. These include hand hygiene, using alcoholic chlorhexidine for skin preparation prior to insertion, maximal sterile barrier precautions, avoiding the femoral site for CVC insertion, and removing unnecessary catheters as soon as possible. Support from administration in emphasizing patient safety and HAI prevention along with following evidence-based practice could lead to long-term improvement in CLABSI prevention across hospital systems.

Corresponding author: Payal K. Patel, MD, MPH, Div of Infectious Diseases, Dept of Internal Medicine, VA Ann Arbor Healthcare System, 2215 Fuller Rd, Ann Arbor, MI 48105, [email protected].

Financial disclosures: None.