1-Minute Consult

Yes, measuring the levels of certain natriuretic peptides can help diagnose decompensated heart failure and predict the risk of death and cardiac hospitalization in patients across a wide spectrum of renal function.

However, at this time, it is unclear whether routinely measuring natriuretic peptides will result in any change in the management of patients with chronic kidney disease. Additionally, using these peptides to monitor volume status in dialysis patients has not yet been deemed useful, although it may be complementary to echocardiography in evaluating cardiac risk in patients with end-stage renal disease.

A BRIEF REVIEW OF NATRIURETIC PEPTIDES

Natriuretic peptides include atrial natriuretic peptide, brain natriuretic peptide (BNP), C-type natriuretic peptide, and urodilantin.

BNP, which is homologous to atrial natriuretic peptide, is present in the brain and the heart. The circulating concentration of BNP is less than 20% of the atrial natriuretic peptide level in healthy people, but equals or exceeds that of atrial natriuretic peptide in patients with congestive heart failure.

BNP starts as a precursor protein. This is modified within the cell into a prohormone, proBNP, which is secreted from the left ventricle in response to myocardial wall stress. In the circulation, proBNP is cleaved into a biologically active C-terminal fragment—BNP—and a biologically inactive N-terminal fragment (NT-proBNP).¹ NT-proBNP is primarily cleared by the kidney. BNP is cleared by receptor-mediated binding and removed by neutral endopeptidase, as well as by the kidney.

Both BNP and NT-proBNP have been investigated as diagnostic markers of suspected heart disease.

PEPTIDE LEVELS ARE HIGH IN CHRONIC KIDNEY DISEASE AND HEART FAILURE

An estimated 8.3 million people in the United States have stage 3, 4, or 5 chronic kidney disease,² defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m². Approximately 50% of patients with heart failure have chronic kidney disease, and almost 60% of patients with chronic kidney disease have some abnormality in ventricular function.

A few years ago, researchers began investigating the benefits and limitations of using natriuretic peptides to diagnose cardiac dysfunction (left ventricular structural and functional abnormalities) in patients with chronic kidney disease.

One important study³ was conducted in almost 3,000 patients from the Dallas Heart Study who were between the ages of 30 and 65 years—a relatively young, mostly healthy population. The authors found that natriuretic peptide levels did not vary as long as the estimated glomerular filtration rate was within the normal range. However, when the estimated glomerular filtration rate dropped below a threshold of 90 mL/min/1.73 m², the concentrations of both NT-proBNP and BNP increased exponentially. NT-proBNP levels rose more than BNP levels, as NT-proBNP is primarily cleared by the kidney.

More recent studies found that the high levels of NT-proBNP in patients with chronic kidney disease do not simply reflect the reduced clearance of this peptide; they also reflect compromised ventricular function.^2,4 This relationship was supported by studies of the fractional renal excretion of NT-proBNP and BNP in several populations with and without renal impairment.⁵ Interestingly, fractional excretion of both peptides remained equivalent across a wide spectrum of renal function. Seemingly, cardiac disease drove the increase in values rather than the degree of renal impairment.

HIGH PEPTIDE LEVELS PREDICT DEATH, HOSPITALIZATION

Both BNP and NT-proBNP are strong predictors of death and cardiac hospitalization in kidney patients.^1,4,6

In patients with end-stage renal disease, the risk of cardiovascular disease and death is significantly higher than that in the general population, and BNP has been found to be a valuable prognostic indicator of cardiac disease.⁷

Multiple studies showed that high levels of natriuretic peptides are associated with a higher risk of death in patients with acute coronary syndrome, independent of traditional cardiovascular risk factors such as electrocardiographic changes and levels of other biomarkers. However, these data were derived from patients with mild renal impairment.²

Apple et al⁸ compared the prognostic value of NT-proBNP with that of cardiac troponin T in hemodialysis patients who had no symptoms and found that NT-proBNP was more strongly associated with left ventricular systolic dysfunction and subsequent cardiovascular death.

PEPTIDE LEVELS ARE HIGHER IN ANEMIA

A significant number of patients with congestive heart failure have renal insufficiency and low hemoglobin levels, which may increase natriuretic peptide levels. It is unclear why anemia is associated with elevated levels of natriuretic peptides, even in the absence of clinical heart failure and independent of other cardiovascular risk factors.⁹ Nevertheless, anemia should be taken into consideration and treated effectively when evaluating patients with renal impairment and possible congestive heart failure.

PEPTIDES COMPLEMENT CARDIAC ECHO IN END-STAGE RENAL DISEASE

Numerous studies have found a close association between BNP and NT-proBNP levels and left ventricular mass and systolic function in patients with end-stage renal disease.^10,11 Data from the Cardiovascular Risk Extended Evaluation in Dialysis Patients study¹² suggest that BNP measurement can be reliably applied in end-stage renal disease to rule out systolic dysfunction and to detect left ventricular hypertrophy, but it has a very low negative predictive value for left ventricular hypertrophy in this patient population: someone with a normal BNP level can still have left ventricular hypertrophy.

In addition, volume status is harder to assess with BNP alone than with echocardiography, and an elevated BNP value is not very specific.¹³

In essence, both BNP and NT-proBNP can be used to complement echocardiography in evaluating cardiac risk in patients with end-stage renal disease. With additional data, it may be possible in the future to use them as substitutes for echocardiography when managing ventricular abnormalities in patients with end-stage renal disease.

USING SPECIFIC CUT POINTS IN RENAL DISEASE

When evaluating a patient with acute dyspnea and either chronic kidney disease or end-stage renal disease who is receiving dialysis, both BNP and NT-proBNP are affected similarly and necessitate a higher level of interpretation to diagnose decompensated heart failure. Currently, researchers disagree about specific cut points for natriuretic peptides. However, deFilippi and colleagues⁴ suggested the following cut points for NT-proBNP for diagnosing heart failure in patients of different ages with or without renal impairment:

• Younger than 50 years—450 ng/L
• Age 50 to 75 years—900 ng/L
• Older than 75 years—1,800 ng/L.

A BNP cutoff point of 225 pg/mL can be used for patients with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m², based on data from the Breathing Not Properly multinational study.¹⁴

There is no set cut-point for either BNP or NT-proBNP for predicting death and cardiac hospitalization in renal patients, but abnormally high levels should signal the need to optimize medical management and to monitor more closely.

Yes, measuring the levels of certain natriuretic peptides can help diagnose decompensated heart failure and predict the risk of death and cardiac hospitalization in patients across a wide spectrum of renal function.

However, at this time, it is unclear whether routinely measuring natriuretic peptides will result in any change in the management of patients with chronic kidney disease. Additionally, using these peptides to monitor volume status in dialysis patients has not yet been deemed useful, although it may be complementary to echocardiography in evaluating cardiac risk in patients with end-stage renal disease.

A BRIEF REVIEW OF NATRIURETIC PEPTIDES

Natriuretic peptides include atrial natriuretic peptide, brain natriuretic peptide (BNP), C-type natriuretic peptide, and urodilantin.

BNP, which is homologous to atrial natriuretic peptide, is present in the brain and the heart. The circulating concentration of BNP is less than 20% of the atrial natriuretic peptide level in healthy people, but equals or exceeds that of atrial natriuretic peptide in patients with congestive heart failure.

BNP starts as a precursor protein. This is modified within the cell into a prohormone, proBNP, which is secreted from the left ventricle in response to myocardial wall stress. In the circulation, proBNP is cleaved into a biologically active C-terminal fragment—BNP—and a biologically inactive N-terminal fragment (NT-proBNP).¹ NT-proBNP is primarily cleared by the kidney. BNP is cleared by receptor-mediated binding and removed by neutral endopeptidase, as well as by the kidney.

Both BNP and NT-proBNP have been investigated as diagnostic markers of suspected heart disease.

PEPTIDE LEVELS ARE HIGH IN CHRONIC KIDNEY DISEASE AND HEART FAILURE

An estimated 8.3 million people in the United States have stage 3, 4, or 5 chronic kidney disease,² defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m². Approximately 50% of patients with heart failure have chronic kidney disease, and almost 60% of patients with chronic kidney disease have some abnormality in ventricular function.

A few years ago, researchers began investigating the benefits and limitations of using natriuretic peptides to diagnose cardiac dysfunction (left ventricular structural and functional abnormalities) in patients with chronic kidney disease.

One important study³ was conducted in almost 3,000 patients from the Dallas Heart Study who were between the ages of 30 and 65 years—a relatively young, mostly healthy population. The authors found that natriuretic peptide levels did not vary as long as the estimated glomerular filtration rate was within the normal range. However, when the estimated glomerular filtration rate dropped below a threshold of 90 mL/min/1.73 m², the concentrations of both NT-proBNP and BNP increased exponentially. NT-proBNP levels rose more than BNP levels, as NT-proBNP is primarily cleared by the kidney.

More recent studies found that the high levels of NT-proBNP in patients with chronic kidney disease do not simply reflect the reduced clearance of this peptide; they also reflect compromised ventricular function.^2,4 This relationship was supported by studies of the fractional renal excretion of NT-proBNP and BNP in several populations with and without renal impairment.⁵ Interestingly, fractional excretion of both peptides remained equivalent across a wide spectrum of renal function. Seemingly, cardiac disease drove the increase in values rather than the degree of renal impairment.

HIGH PEPTIDE LEVELS PREDICT DEATH, HOSPITALIZATION

Both BNP and NT-proBNP are strong predictors of death and cardiac hospitalization in kidney patients.^1,4,6

In patients with end-stage renal disease, the risk of cardiovascular disease and death is significantly higher than that in the general population, and BNP has been found to be a valuable prognostic indicator of cardiac disease.⁷

Multiple studies showed that high levels of natriuretic peptides are associated with a higher risk of death in patients with acute coronary syndrome, independent of traditional cardiovascular risk factors such as electrocardiographic changes and levels of other biomarkers. However, these data were derived from patients with mild renal impairment.²

Apple et al⁸ compared the prognostic value of NT-proBNP with that of cardiac troponin T in hemodialysis patients who had no symptoms and found that NT-proBNP was more strongly associated with left ventricular systolic dysfunction and subsequent cardiovascular death.

PEPTIDE LEVELS ARE HIGHER IN ANEMIA

A significant number of patients with congestive heart failure have renal insufficiency and low hemoglobin levels, which may increase natriuretic peptide levels. It is unclear why anemia is associated with elevated levels of natriuretic peptides, even in the absence of clinical heart failure and independent of other cardiovascular risk factors.⁹ Nevertheless, anemia should be taken into consideration and treated effectively when evaluating patients with renal impairment and possible congestive heart failure.

PEPTIDES COMPLEMENT CARDIAC ECHO IN END-STAGE RENAL DISEASE

Numerous studies have found a close association between BNP and NT-proBNP levels and left ventricular mass and systolic function in patients with end-stage renal disease.^10,11 Data from the Cardiovascular Risk Extended Evaluation in Dialysis Patients study¹² suggest that BNP measurement can be reliably applied in end-stage renal disease to rule out systolic dysfunction and to detect left ventricular hypertrophy, but it has a very low negative predictive value for left ventricular hypertrophy in this patient population: someone with a normal BNP level can still have left ventricular hypertrophy.

In addition, volume status is harder to assess with BNP alone than with echocardiography, and an elevated BNP value is not very specific.¹³

In essence, both BNP and NT-proBNP can be used to complement echocardiography in evaluating cardiac risk in patients with end-stage renal disease. With additional data, it may be possible in the future to use them as substitutes for echocardiography when managing ventricular abnormalities in patients with end-stage renal disease.

USING SPECIFIC CUT POINTS IN RENAL DISEASE

When evaluating a patient with acute dyspnea and either chronic kidney disease or end-stage renal disease who is receiving dialysis, both BNP and NT-proBNP are affected similarly and necessitate a higher level of interpretation to diagnose decompensated heart failure. Currently, researchers disagree about specific cut points for natriuretic peptides. However, deFilippi and colleagues⁴ suggested the following cut points for NT-proBNP for diagnosing heart failure in patients of different ages with or without renal impairment:

• Younger than 50 years—450 ng/L
• Age 50 to 75 years—900 ng/L
• Older than 75 years—1,800 ng/L.

A BNP cutoff point of 225 pg/mL can be used for patients with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m², based on data from the Breathing Not Properly multinational study.¹⁴

There is no set cut-point for either BNP or NT-proBNP for predicting death and cardiac hospitalization in renal patients, but abnormally high levels should signal the need to optimize medical management and to monitor more closely.

Yes, measuring the levels of certain natriuretic peptides can help diagnose decompensated heart failure and predict the risk of death and cardiac hospitalization in patients across a wide spectrum of renal function.

However, at this time, it is unclear whether routinely measuring natriuretic peptides will result in any change in the management of patients with chronic kidney disease. Additionally, using these peptides to monitor volume status in dialysis patients has not yet been deemed useful, although it may be complementary to echocardiography in evaluating cardiac risk in patients with end-stage renal disease.

A BRIEF REVIEW OF NATRIURETIC PEPTIDES

Natriuretic peptides include atrial natriuretic peptide, brain natriuretic peptide (BNP), C-type natriuretic peptide, and urodilantin.

BNP, which is homologous to atrial natriuretic peptide, is present in the brain and the heart. The circulating concentration of BNP is less than 20% of the atrial natriuretic peptide level in healthy people, but equals or exceeds that of atrial natriuretic peptide in patients with congestive heart failure.

BNP starts as a precursor protein. This is modified within the cell into a prohormone, proBNP, which is secreted from the left ventricle in response to myocardial wall stress. In the circulation, proBNP is cleaved into a biologically active C-terminal fragment—BNP—and a biologically inactive N-terminal fragment (NT-proBNP).¹ NT-proBNP is primarily cleared by the kidney. BNP is cleared by receptor-mediated binding and removed by neutral endopeptidase, as well as by the kidney.

Both BNP and NT-proBNP have been investigated as diagnostic markers of suspected heart disease.

PEPTIDE LEVELS ARE HIGH IN CHRONIC KIDNEY DISEASE AND HEART FAILURE

An estimated 8.3 million people in the United States have stage 3, 4, or 5 chronic kidney disease,² defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m². Approximately 50% of patients with heart failure have chronic kidney disease, and almost 60% of patients with chronic kidney disease have some abnormality in ventricular function.

A few years ago, researchers began investigating the benefits and limitations of using natriuretic peptides to diagnose cardiac dysfunction (left ventricular structural and functional abnormalities) in patients with chronic kidney disease.

One important study³ was conducted in almost 3,000 patients from the Dallas Heart Study who were between the ages of 30 and 65 years—a relatively young, mostly healthy population. The authors found that natriuretic peptide levels did not vary as long as the estimated glomerular filtration rate was within the normal range. However, when the estimated glomerular filtration rate dropped below a threshold of 90 mL/min/1.73 m², the concentrations of both NT-proBNP and BNP increased exponentially. NT-proBNP levels rose more than BNP levels, as NT-proBNP is primarily cleared by the kidney.

More recent studies found that the high levels of NT-proBNP in patients with chronic kidney disease do not simply reflect the reduced clearance of this peptide; they also reflect compromised ventricular function.^2,4 This relationship was supported by studies of the fractional renal excretion of NT-proBNP and BNP in several populations with and without renal impairment.⁵ Interestingly, fractional excretion of both peptides remained equivalent across a wide spectrum of renal function. Seemingly, cardiac disease drove the increase in values rather than the degree of renal impairment.

HIGH PEPTIDE LEVELS PREDICT DEATH, HOSPITALIZATION

Both BNP and NT-proBNP are strong predictors of death and cardiac hospitalization in kidney patients.^1,4,6

In patients with end-stage renal disease, the risk of cardiovascular disease and death is significantly higher than that in the general population, and BNP has been found to be a valuable prognostic indicator of cardiac disease.⁷

Multiple studies showed that high levels of natriuretic peptides are associated with a higher risk of death in patients with acute coronary syndrome, independent of traditional cardiovascular risk factors such as electrocardiographic changes and levels of other biomarkers. However, these data were derived from patients with mild renal impairment.²

Apple et al⁸ compared the prognostic value of NT-proBNP with that of cardiac troponin T in hemodialysis patients who had no symptoms and found that NT-proBNP was more strongly associated with left ventricular systolic dysfunction and subsequent cardiovascular death.

PEPTIDE LEVELS ARE HIGHER IN ANEMIA

A significant number of patients with congestive heart failure have renal insufficiency and low hemoglobin levels, which may increase natriuretic peptide levels. It is unclear why anemia is associated with elevated levels of natriuretic peptides, even in the absence of clinical heart failure and independent of other cardiovascular risk factors.⁹ Nevertheless, anemia should be taken into consideration and treated effectively when evaluating patients with renal impairment and possible congestive heart failure.

PEPTIDES COMPLEMENT CARDIAC ECHO IN END-STAGE RENAL DISEASE

Numerous studies have found a close association between BNP and NT-proBNP levels and left ventricular mass and systolic function in patients with end-stage renal disease.^10,11 Data from the Cardiovascular Risk Extended Evaluation in Dialysis Patients study¹² suggest that BNP measurement can be reliably applied in end-stage renal disease to rule out systolic dysfunction and to detect left ventricular hypertrophy, but it has a very low negative predictive value for left ventricular hypertrophy in this patient population: someone with a normal BNP level can still have left ventricular hypertrophy.

In addition, volume status is harder to assess with BNP alone than with echocardiography, and an elevated BNP value is not very specific.¹³

In essence, both BNP and NT-proBNP can be used to complement echocardiography in evaluating cardiac risk in patients with end-stage renal disease. With additional data, it may be possible in the future to use them as substitutes for echocardiography when managing ventricular abnormalities in patients with end-stage renal disease.

USING SPECIFIC CUT POINTS IN RENAL DISEASE

When evaluating a patient with acute dyspnea and either chronic kidney disease or end-stage renal disease who is receiving dialysis, both BNP and NT-proBNP are affected similarly and necessitate a higher level of interpretation to diagnose decompensated heart failure. Currently, researchers disagree about specific cut points for natriuretic peptides. However, deFilippi and colleagues⁴ suggested the following cut points for NT-proBNP for diagnosing heart failure in patients of different ages with or without renal impairment:

• Younger than 50 years—450 ng/L
• Age 50 to 75 years—900 ng/L
• Older than 75 years—1,800 ng/L.

A BNP cutoff point of 225 pg/mL can be used for patients with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m², based on data from the Breathing Not Properly multinational study.¹⁴

There is no set cut-point for either BNP or NT-proBNP for predicting death and cardiac hospitalization in renal patients, but abnormally high levels should signal the need to optimize medical management and to monitor more closely.

Overall, the evidence does not support using probiotics to treat Clostridium difficile-associated diarrhea (CDAD). More studies are needed to determine if they are helpful and, if so, which ones and at what dosages.

WHAT ARE PROBIOTICS?

Probiotics are live bacteria or fungi that carry health benefits when ingested. There is great interest in using these agents to treat and prevent gastrointestinal disorders, as they have been said to inhibit the growth or invasion of pathogenic bacteria, enhance the intestinal barrier, and augment the immune system by regulating cytokines. Their proposed use in treating and preventing CDAD is based on their presumed mechanisms of action and effectiveness in other disorders of the gastrointestinal tract. Given that these readily available bacteria and fungi appear to be safe and well tolerated, their potential use in CDAD is of substantial interest.

LIMITED STUDIES AVAILABLE

Few clinical trials have tested probiotics in CDAD. Two recent systematic reviews did not find a clear benefit to adding probiotics to antibiotics to treat CDAD.^1,2 Six trials of various probiotics were included in a 2006 meta-analysis.³ Overall, the analysis did find a benefit, but this was mostly derived from two trials of Saccharomyces boulardii.^4,5 This yeast has a mechanism other probiotics do not have: a protease that it produces can degrade the exotoxins produced by C difficile.⁶

McFarland et al⁴ gave either S boulardii or placebo to 124 patients who were having either a first episode or a recurrence of CDAD. All patients also received either vancomycin (Vancocin) or metronidazole (Flagyl) in doses chosen by their physician. Patients taking S boulardii were more likely to have their diarrhea resolve and not recur, though post hoc analysis found that this benefit was limited to those with recurrent CDAD.⁴

Surawicz et al⁵ gave either S boulardii or placebo to 168 patients with recurrent CDAD who were also participating in a trial comparing vancomycin in a high dose, vancomycin in a low dose, and metronidazole. The probiotic was beneficial, but only in patients on high-dose vancomycin (2 g/day). These patients tended to have a more severe form of CDAD with colitis.

YOGURT, OVER-THE-COUNTER PRODUCTS MAY NOT CONTAIN ACTIVE BACTERIA

The efficacy of over-the-counter probiotic preparations and probiotic-containing foods, such as yogurt, is difficult to determine. For example, in the case of yogurts with “live and active cultures,” the inocula must remain stable from the factory to the grocery store shelf to the table and then through the gastrointestinal tract to the colon. The number of bacteria that survive this long journey is variable.

Another issue is whether probiotic products contain the species and quantities of organisms listed on their labels. In studies that have attempted to examine this issue, many of the products contained species not listed on the label. Most products that did contain viable cells of the stated therapeutic agent did so at a lower number than listed.^7,8 The contents and dosages of these over-the-counter products are not regulated and may vary even within the same brand.

The US Food and Drug Administration (FDA) classifies these products as dietary supplements and therefore does not test them for efficacy or safety, though it does have the ability to remove them from the market if they are proven harmful.

FEW ADVERSE EFFECTS

Adverse effects seem to be uncommon with probiotics. Untoward symptoms include flatulence, bloating, and thirst. There are reports of invasive disease, including Lactobacillus bacteremia and Saccharomyces fungemia, occurring after these probiotics were given to patients with severe comorbidities.^9,10,11

BENIGN STRAINS OF C DIFFICILE MAY PROTECT AGAINST CDAD

Interestingly, C difficile itself may serve as a probiotic, preventing future episodes of CDAD. Several studies in hamsters showed that colonization with nontoxigenic strains of C difficile can prevent infection with toxigenic strains. In these studies, hamsters receiving clindamycin (Cleocin) or cefoxitin (Mefoxin) were given nontoxigenic strains of C difficile that were either susceptible or resistant to the antibiotic, followed by a toxigenic strain. Those given resistant nontoxigenic strains were significantly less likely to develop CDAD. One study, for example, found that 100% of hamsters given a clindamycin-resistant, nontoxigenic strain of C difficile were protected from CDAD.¹²

INFECTION CONTROL IS KEY

Novel treatments for CDAD and ways to prevent it are constantly being sought as C difficile has reemerged in hospitals across North America and Europe. However, CDAD is fundamentally a hospital-acquired infection transmitted from patient to patient via the hands of health care workers. The most common predisposing factor is antibiotic use. While new therapeutic advances would be welcome, hand hygiene, basic infection control practice, and judicious use of antimicrobials are essential to decreasing the incidence of this disease.

Overall, the evidence does not support using probiotics to treat Clostridium difficile-associated diarrhea (CDAD). More studies are needed to determine if they are helpful and, if so, which ones and at what dosages.

WHAT ARE PROBIOTICS?

Probiotics are live bacteria or fungi that carry health benefits when ingested. There is great interest in using these agents to treat and prevent gastrointestinal disorders, as they have been said to inhibit the growth or invasion of pathogenic bacteria, enhance the intestinal barrier, and augment the immune system by regulating cytokines. Their proposed use in treating and preventing CDAD is based on their presumed mechanisms of action and effectiveness in other disorders of the gastrointestinal tract. Given that these readily available bacteria and fungi appear to be safe and well tolerated, their potential use in CDAD is of substantial interest.

LIMITED STUDIES AVAILABLE

Few clinical trials have tested probiotics in CDAD. Two recent systematic reviews did not find a clear benefit to adding probiotics to antibiotics to treat CDAD.^1,2 Six trials of various probiotics were included in a 2006 meta-analysis.³ Overall, the analysis did find a benefit, but this was mostly derived from two trials of Saccharomyces boulardii.^4,5 This yeast has a mechanism other probiotics do not have: a protease that it produces can degrade the exotoxins produced by C difficile.⁶

McFarland et al⁴ gave either S boulardii or placebo to 124 patients who were having either a first episode or a recurrence of CDAD. All patients also received either vancomycin (Vancocin) or metronidazole (Flagyl) in doses chosen by their physician. Patients taking S boulardii were more likely to have their diarrhea resolve and not recur, though post hoc analysis found that this benefit was limited to those with recurrent CDAD.⁴

Surawicz et al⁵ gave either S boulardii or placebo to 168 patients with recurrent CDAD who were also participating in a trial comparing vancomycin in a high dose, vancomycin in a low dose, and metronidazole. The probiotic was beneficial, but only in patients on high-dose vancomycin (2 g/day). These patients tended to have a more severe form of CDAD with colitis.

YOGURT, OVER-THE-COUNTER PRODUCTS MAY NOT CONTAIN ACTIVE BACTERIA

The efficacy of over-the-counter probiotic preparations and probiotic-containing foods, such as yogurt, is difficult to determine. For example, in the case of yogurts with “live and active cultures,” the inocula must remain stable from the factory to the grocery store shelf to the table and then through the gastrointestinal tract to the colon. The number of bacteria that survive this long journey is variable.

Another issue is whether probiotic products contain the species and quantities of organisms listed on their labels. In studies that have attempted to examine this issue, many of the products contained species not listed on the label. Most products that did contain viable cells of the stated therapeutic agent did so at a lower number than listed.^7,8 The contents and dosages of these over-the-counter products are not regulated and may vary even within the same brand.

The US Food and Drug Administration (FDA) classifies these products as dietary supplements and therefore does not test them for efficacy or safety, though it does have the ability to remove them from the market if they are proven harmful.

FEW ADVERSE EFFECTS

Adverse effects seem to be uncommon with probiotics. Untoward symptoms include flatulence, bloating, and thirst. There are reports of invasive disease, including Lactobacillus bacteremia and Saccharomyces fungemia, occurring after these probiotics were given to patients with severe comorbidities.^9,10,11

BENIGN STRAINS OF C DIFFICILE MAY PROTECT AGAINST CDAD

Interestingly, C difficile itself may serve as a probiotic, preventing future episodes of CDAD. Several studies in hamsters showed that colonization with nontoxigenic strains of C difficile can prevent infection with toxigenic strains. In these studies, hamsters receiving clindamycin (Cleocin) or cefoxitin (Mefoxin) were given nontoxigenic strains of C difficile that were either susceptible or resistant to the antibiotic, followed by a toxigenic strain. Those given resistant nontoxigenic strains were significantly less likely to develop CDAD. One study, for example, found that 100% of hamsters given a clindamycin-resistant, nontoxigenic strain of C difficile were protected from CDAD.¹²

INFECTION CONTROL IS KEY

Novel treatments for CDAD and ways to prevent it are constantly being sought as C difficile has reemerged in hospitals across North America and Europe. However, CDAD is fundamentally a hospital-acquired infection transmitted from patient to patient via the hands of health care workers. The most common predisposing factor is antibiotic use. While new therapeutic advances would be welcome, hand hygiene, basic infection control practice, and judicious use of antimicrobials are essential to decreasing the incidence of this disease.

Overall, the evidence does not support using probiotics to treat Clostridium difficile-associated diarrhea (CDAD). More studies are needed to determine if they are helpful and, if so, which ones and at what dosages.

WHAT ARE PROBIOTICS?

Probiotics are live bacteria or fungi that carry health benefits when ingested. There is great interest in using these agents to treat and prevent gastrointestinal disorders, as they have been said to inhibit the growth or invasion of pathogenic bacteria, enhance the intestinal barrier, and augment the immune system by regulating cytokines. Their proposed use in treating and preventing CDAD is based on their presumed mechanisms of action and effectiveness in other disorders of the gastrointestinal tract. Given that these readily available bacteria and fungi appear to be safe and well tolerated, their potential use in CDAD is of substantial interest.

LIMITED STUDIES AVAILABLE

Few clinical trials have tested probiotics in CDAD. Two recent systematic reviews did not find a clear benefit to adding probiotics to antibiotics to treat CDAD.^1,2 Six trials of various probiotics were included in a 2006 meta-analysis.³ Overall, the analysis did find a benefit, but this was mostly derived from two trials of Saccharomyces boulardii.^4,5 This yeast has a mechanism other probiotics do not have: a protease that it produces can degrade the exotoxins produced by C difficile.⁶

McFarland et al⁴ gave either S boulardii or placebo to 124 patients who were having either a first episode or a recurrence of CDAD. All patients also received either vancomycin (Vancocin) or metronidazole (Flagyl) in doses chosen by their physician. Patients taking S boulardii were more likely to have their diarrhea resolve and not recur, though post hoc analysis found that this benefit was limited to those with recurrent CDAD.⁴

Surawicz et al⁵ gave either S boulardii or placebo to 168 patients with recurrent CDAD who were also participating in a trial comparing vancomycin in a high dose, vancomycin in a low dose, and metronidazole. The probiotic was beneficial, but only in patients on high-dose vancomycin (2 g/day). These patients tended to have a more severe form of CDAD with colitis.

YOGURT, OVER-THE-COUNTER PRODUCTS MAY NOT CONTAIN ACTIVE BACTERIA

The efficacy of over-the-counter probiotic preparations and probiotic-containing foods, such as yogurt, is difficult to determine. For example, in the case of yogurts with “live and active cultures,” the inocula must remain stable from the factory to the grocery store shelf to the table and then through the gastrointestinal tract to the colon. The number of bacteria that survive this long journey is variable.

Another issue is whether probiotic products contain the species and quantities of organisms listed on their labels. In studies that have attempted to examine this issue, many of the products contained species not listed on the label. Most products that did contain viable cells of the stated therapeutic agent did so at a lower number than listed.^7,8 The contents and dosages of these over-the-counter products are not regulated and may vary even within the same brand.

The US Food and Drug Administration (FDA) classifies these products as dietary supplements and therefore does not test them for efficacy or safety, though it does have the ability to remove them from the market if they are proven harmful.

FEW ADVERSE EFFECTS

Adverse effects seem to be uncommon with probiotics. Untoward symptoms include flatulence, bloating, and thirst. There are reports of invasive disease, including Lactobacillus bacteremia and Saccharomyces fungemia, occurring after these probiotics were given to patients with severe comorbidities.^9,10,11

BENIGN STRAINS OF C DIFFICILE MAY PROTECT AGAINST CDAD

Interestingly, C difficile itself may serve as a probiotic, preventing future episodes of CDAD. Several studies in hamsters showed that colonization with nontoxigenic strains of C difficile can prevent infection with toxigenic strains. In these studies, hamsters receiving clindamycin (Cleocin) or cefoxitin (Mefoxin) were given nontoxigenic strains of C difficile that were either susceptible or resistant to the antibiotic, followed by a toxigenic strain. Those given resistant nontoxigenic strains were significantly less likely to develop CDAD. One study, for example, found that 100% of hamsters given a clindamycin-resistant, nontoxigenic strain of C difficile were protected from CDAD.¹²

INFECTION CONTROL IS KEY

Novel treatments for CDAD and ways to prevent it are constantly being sought as C difficile has reemerged in hospitals across North America and Europe. However, CDAD is fundamentally a hospital-acquired infection transmitted from patient to patient via the hands of health care workers. The most common predisposing factor is antibiotic use. While new therapeutic advances would be welcome, hand hygiene, basic infection control practice, and judicious use of antimicrobials are essential to decreasing the incidence of this disease.

If you already know that the patient with altered mental status has decompensated liver disease, measuring the arterial or venous ammonia level has little utility. In these patients, one’s clinical suspicion is the main guide to diagnosing hepatic encephalopathy, and a normal or modestly elevated blood ammonia level does not rule out the diagnosis.

On the other hand, provided that it is appropriately performed, blood ammonia testing may be helpful if there is no clear evidence of underlying chronic liver disease. In these cases, an elevated blood ammonia level may have significant prognostic value (as in acute liver failure) or may prompt you to initiate further evaluation for uncommon but significant meta bolic disorders such as urea cycle disorders.

WHEN AMMONIA LEVELS RISE

Ammonia levels are elevated in several conditions in which its production is increased (eg, in convulsive seizures with increased muscle production) or its clearance is impaired (eg, in hepatocellular dysfunction, portosystemic shunting, or both, with subsequent impaired hepatic detoxification of ammonia).

Because the blood-brain barrier is highly permeable to ammonia, the brain is exposed to excessive concentrations of it in these circumstances. In the brain, ammonia is thought to cause both functional and structural abnormalities that could explain neuropsychiatric dysfunction, often manifested as an altered mental status of variable degree.^1–3

DOES THE PATIENT HAVE DECOMPENSATED LIVER DISEASE?

Physicians often measure the venous (and less often, the arterial) ammonia level while evaluating patients presenting with altered mental status. However, in many cases, this test result may be of uncertain utility—it may not have a significant impact on a specific patient’s management and, worse, it can confuse the physician regarding diagnosis. Also, the test itself is a needless expense. Therefore, we need to carefully consider whether to obtain a blood ammonia test and how to interpret the results in patients with altered mental status.

The key initial question in such patients is whether the patient is known to have decompensated liver disease with a typical clinical picture of hepatic encephalopathy.

Hepatic encephalopathy is a common complication of end-stage liver disease and is also one of the diagnostic markers of acute liver failure. An accepted factor in its pathophysiology is that the liver fails to clear toxic products of bacterial metabolism brought via the portal venous system from the gut, owing to low detoxifying capacity, portosystemic shunts, or both.⁴ Although the exact neurotoxins involved remain poorly defined, ammonia is thought to play a central role.^5–7

If the patient is known to have chronic liver disease, we usually do not need to measure the blood ammonia level because normal levels in these patients do not rule out hepatic encephalopathy. Multiple studies have shown that the ammonia level correlates to some extent with the severity of hepatic encephalopathy,⁸ but ammonia levels substantially overlap among patients with differing clinical grades of hepatic encephalopathy. Moreover, 69% of patients with no evidence of encephalopathy had ammonia levels higher than normal in a study by Ong et al.⁸

Therefore, hyperammonemia is neither sensitive nor specific for the presence or the degree of hepatic encephalopathy. In this respect, three related issues should be emphasized:

Altered mental status in cirrhotic patients does not always equal hepatic encephalopathy. Regardless of the degree of blood ammonia elevation, other relevant causes of altered mental status should be excluded on the basis of the clinical presentation.

Computed tomography of the head is usually obtained in cirrhotic patients:

• Who have changes in mental status but whose presentation is not typical of hepatic encephalopathy (such as those with focal neurologic signs);
• In cases of severe hepatic encephalopathy, suspected head trauma (especially given the commonly associated coagulopathy in cirrhotic patients), and hepatic encephalopathy resistant to standard therapy; and
• Without clear precipitating factors for hepatic encephalopathy, such as infection (eg, spontaneous bacterial peritonitis) and renal insufficiency.

Similarly, in alcoholic patients who present with altered mental status, we should always consider Wernicke encephalopathy.

In patients with established hepatic encephalopathy, monitoring the ammonia level during therapy is not as useful as ongoing clinical assessment.

In patients with acute liver failure, a blood ammonia level may have a special prognostic value. In hyperammonemic states that subsequently lead to elevated ammonia in the brain, astrocytes convert ammonia to glutamine. Glutamine is not toxic, but it is osmotically active, and as it accumulates, it leads to astrocyte swelling and brain edema. This pathologic process is very prominent in acute hyperammonemic states in which astrocytes do not have time to adapt osmotically by pumping in myoinositol.⁹ Clemmesen et al¹⁰ have shown that arterial ammonia levels higher than 200 μg/dL are strongly associated with cerebral herniation in patients with acute liver failure.

If the patient is not known to have chronic liver disease

Occasionally, the blood ammonia level is found to be high in a patient who presents with altered mental status but who does not have known liver disease. In these patients, undiagnosed or new-onset decompensated cirrhosis is still possible, and the possibility should be explored. Acute liver failure is another possibility, but it is usually obvious, with associated coagulopathy, hyperbilirubinemia, and other clinical and laboratory features.

The main diagnostic challenge is in patients who have altered mental status and hyperammonemia but no features to suggest the above possibilities. In this setting, three tasks should be approached simultaneously:

• Look for and aggressively manage cerebral edema and increased intracranial pressure with ammonia-lowering measures such as lactulose, renal replacement therapy, and other specific therapeutic agents if a urea cycle disorder is suspected.¹¹
• Search for causes of elevated ammonia other than hepatic dysfunction. These causes can be classified into two major categories¹¹: 1) causes of increased ammonia production such as total parenteral nutrition, gastrointestinal hemorrhage, and steroid use, and 2) causes of decreased ammonia excretion such as portosystemic shunts, medications that decrease ammonia metabolism, and inborn errors of metabolism such as urea cycle disorders. Portosystemic shunts have been well documented in patients with no underlying liver disease.¹²

Several drugs, such as glycine (used during transurethral prostate resection), salicylates, and valproate raise the ammonia level by altering the urea cycle.¹¹ Although most severe inborn errors of metabolism become evident early in childhood, certain urea cycle disorders, especially ornithine transcarbamylase deficiency, may manifest later during adulthood when a precipitating event occurs, such as an increase in protein intake (eg, with total parenteral nutrition), use of certain medications, or infection.

• Explore concomitant or alternative causes of altered mental status based on the clinical setting, such as a cerebrovascular accident, infectious meningoencephalitis, drug intoxication, or other metabolic or systemic disorders.

IN AMMONIA TESTING, TECHNIQUE MATTERS

To obtain an accurate measurement, the blood sample for ammonia testing must be obtained and handled properly. Prolonged application of a tourniquet or fist-clenching while obtaining the blood sample or improper specimen handling can result in a falsely elevated blood ammonia level, which can lead you down the wrong diagnostic pathway.

Venous blood, if appropriately collected, transported in ice, and handled quickly for analysis, has been shown to be as useful as arterial blood in ammonia measurement.⁸

If you already know that the patient with altered mental status has decompensated liver disease, measuring the arterial or venous ammonia level has little utility. In these patients, one’s clinical suspicion is the main guide to diagnosing hepatic encephalopathy, and a normal or modestly elevated blood ammonia level does not rule out the diagnosis.

On the other hand, provided that it is appropriately performed, blood ammonia testing may be helpful if there is no clear evidence of underlying chronic liver disease. In these cases, an elevated blood ammonia level may have significant prognostic value (as in acute liver failure) or may prompt you to initiate further evaluation for uncommon but significant meta bolic disorders such as urea cycle disorders.

WHEN AMMONIA LEVELS RISE

Ammonia levels are elevated in several conditions in which its production is increased (eg, in convulsive seizures with increased muscle production) or its clearance is impaired (eg, in hepatocellular dysfunction, portosystemic shunting, or both, with subsequent impaired hepatic detoxification of ammonia).

Because the blood-brain barrier is highly permeable to ammonia, the brain is exposed to excessive concentrations of it in these circumstances. In the brain, ammonia is thought to cause both functional and structural abnormalities that could explain neuropsychiatric dysfunction, often manifested as an altered mental status of variable degree.^1–3

DOES THE PATIENT HAVE DECOMPENSATED LIVER DISEASE?

Physicians often measure the venous (and less often, the arterial) ammonia level while evaluating patients presenting with altered mental status. However, in many cases, this test result may be of uncertain utility—it may not have a significant impact on a specific patient’s management and, worse, it can confuse the physician regarding diagnosis. Also, the test itself is a needless expense. Therefore, we need to carefully consider whether to obtain a blood ammonia test and how to interpret the results in patients with altered mental status.

The key initial question in such patients is whether the patient is known to have decompensated liver disease with a typical clinical picture of hepatic encephalopathy.

Hepatic encephalopathy is a common complication of end-stage liver disease and is also one of the diagnostic markers of acute liver failure. An accepted factor in its pathophysiology is that the liver fails to clear toxic products of bacterial metabolism brought via the portal venous system from the gut, owing to low detoxifying capacity, portosystemic shunts, or both.⁴ Although the exact neurotoxins involved remain poorly defined, ammonia is thought to play a central role.^5–7

If the patient is known to have chronic liver disease, we usually do not need to measure the blood ammonia level because normal levels in these patients do not rule out hepatic encephalopathy. Multiple studies have shown that the ammonia level correlates to some extent with the severity of hepatic encephalopathy,⁸ but ammonia levels substantially overlap among patients with differing clinical grades of hepatic encephalopathy. Moreover, 69% of patients with no evidence of encephalopathy had ammonia levels higher than normal in a study by Ong et al.⁸

Therefore, hyperammonemia is neither sensitive nor specific for the presence or the degree of hepatic encephalopathy. In this respect, three related issues should be emphasized:

Altered mental status in cirrhotic patients does not always equal hepatic encephalopathy. Regardless of the degree of blood ammonia elevation, other relevant causes of altered mental status should be excluded on the basis of the clinical presentation.

Computed tomography of the head is usually obtained in cirrhotic patients:

• Who have changes in mental status but whose presentation is not typical of hepatic encephalopathy (such as those with focal neurologic signs);
• In cases of severe hepatic encephalopathy, suspected head trauma (especially given the commonly associated coagulopathy in cirrhotic patients), and hepatic encephalopathy resistant to standard therapy; and
• Without clear precipitating factors for hepatic encephalopathy, such as infection (eg, spontaneous bacterial peritonitis) and renal insufficiency.

Similarly, in alcoholic patients who present with altered mental status, we should always consider Wernicke encephalopathy.

In patients with established hepatic encephalopathy, monitoring the ammonia level during therapy is not as useful as ongoing clinical assessment.

In patients with acute liver failure, a blood ammonia level may have a special prognostic value. In hyperammonemic states that subsequently lead to elevated ammonia in the brain, astrocytes convert ammonia to glutamine. Glutamine is not toxic, but it is osmotically active, and as it accumulates, it leads to astrocyte swelling and brain edema. This pathologic process is very prominent in acute hyperammonemic states in which astrocytes do not have time to adapt osmotically by pumping in myoinositol.⁹ Clemmesen et al¹⁰ have shown that arterial ammonia levels higher than 200 μg/dL are strongly associated with cerebral herniation in patients with acute liver failure.

If the patient is not known to have chronic liver disease

Occasionally, the blood ammonia level is found to be high in a patient who presents with altered mental status but who does not have known liver disease. In these patients, undiagnosed or new-onset decompensated cirrhosis is still possible, and the possibility should be explored. Acute liver failure is another possibility, but it is usually obvious, with associated coagulopathy, hyperbilirubinemia, and other clinical and laboratory features.

The main diagnostic challenge is in patients who have altered mental status and hyperammonemia but no features to suggest the above possibilities. In this setting, three tasks should be approached simultaneously:

• Look for and aggressively manage cerebral edema and increased intracranial pressure with ammonia-lowering measures such as lactulose, renal replacement therapy, and other specific therapeutic agents if a urea cycle disorder is suspected.¹¹
• Search for causes of elevated ammonia other than hepatic dysfunction. These causes can be classified into two major categories¹¹: 1) causes of increased ammonia production such as total parenteral nutrition, gastrointestinal hemorrhage, and steroid use, and 2) causes of decreased ammonia excretion such as portosystemic shunts, medications that decrease ammonia metabolism, and inborn errors of metabolism such as urea cycle disorders. Portosystemic shunts have been well documented in patients with no underlying liver disease.¹²

Several drugs, such as glycine (used during transurethral prostate resection), salicylates, and valproate raise the ammonia level by altering the urea cycle.¹¹ Although most severe inborn errors of metabolism become evident early in childhood, certain urea cycle disorders, especially ornithine transcarbamylase deficiency, may manifest later during adulthood when a precipitating event occurs, such as an increase in protein intake (eg, with total parenteral nutrition), use of certain medications, or infection.

• Explore concomitant or alternative causes of altered mental status based on the clinical setting, such as a cerebrovascular accident, infectious meningoencephalitis, drug intoxication, or other metabolic or systemic disorders.

IN AMMONIA TESTING, TECHNIQUE MATTERS

To obtain an accurate measurement, the blood sample for ammonia testing must be obtained and handled properly. Prolonged application of a tourniquet or fist-clenching while obtaining the blood sample or improper specimen handling can result in a falsely elevated blood ammonia level, which can lead you down the wrong diagnostic pathway.

Venous blood, if appropriately collected, transported in ice, and handled quickly for analysis, has been shown to be as useful as arterial blood in ammonia measurement.⁸

If you already know that the patient with altered mental status has decompensated liver disease, measuring the arterial or venous ammonia level has little utility. In these patients, one’s clinical suspicion is the main guide to diagnosing hepatic encephalopathy, and a normal or modestly elevated blood ammonia level does not rule out the diagnosis.

On the other hand, provided that it is appropriately performed, blood ammonia testing may be helpful if there is no clear evidence of underlying chronic liver disease. In these cases, an elevated blood ammonia level may have significant prognostic value (as in acute liver failure) or may prompt you to initiate further evaluation for uncommon but significant meta bolic disorders such as urea cycle disorders.

WHEN AMMONIA LEVELS RISE

Ammonia levels are elevated in several conditions in which its production is increased (eg, in convulsive seizures with increased muscle production) or its clearance is impaired (eg, in hepatocellular dysfunction, portosystemic shunting, or both, with subsequent impaired hepatic detoxification of ammonia).

Because the blood-brain barrier is highly permeable to ammonia, the brain is exposed to excessive concentrations of it in these circumstances. In the brain, ammonia is thought to cause both functional and structural abnormalities that could explain neuropsychiatric dysfunction, often manifested as an altered mental status of variable degree.^1–3

DOES THE PATIENT HAVE DECOMPENSATED LIVER DISEASE?

Physicians often measure the venous (and less often, the arterial) ammonia level while evaluating patients presenting with altered mental status. However, in many cases, this test result may be of uncertain utility—it may not have a significant impact on a specific patient’s management and, worse, it can confuse the physician regarding diagnosis. Also, the test itself is a needless expense. Therefore, we need to carefully consider whether to obtain a blood ammonia test and how to interpret the results in patients with altered mental status.

The key initial question in such patients is whether the patient is known to have decompensated liver disease with a typical clinical picture of hepatic encephalopathy.

Hepatic encephalopathy is a common complication of end-stage liver disease and is also one of the diagnostic markers of acute liver failure. An accepted factor in its pathophysiology is that the liver fails to clear toxic products of bacterial metabolism brought via the portal venous system from the gut, owing to low detoxifying capacity, portosystemic shunts, or both.⁴ Although the exact neurotoxins involved remain poorly defined, ammonia is thought to play a central role.^5–7

If the patient is known to have chronic liver disease, we usually do not need to measure the blood ammonia level because normal levels in these patients do not rule out hepatic encephalopathy. Multiple studies have shown that the ammonia level correlates to some extent with the severity of hepatic encephalopathy,⁸ but ammonia levels substantially overlap among patients with differing clinical grades of hepatic encephalopathy. Moreover, 69% of patients with no evidence of encephalopathy had ammonia levels higher than normal in a study by Ong et al.⁸

Therefore, hyperammonemia is neither sensitive nor specific for the presence or the degree of hepatic encephalopathy. In this respect, three related issues should be emphasized:

Altered mental status in cirrhotic patients does not always equal hepatic encephalopathy. Regardless of the degree of blood ammonia elevation, other relevant causes of altered mental status should be excluded on the basis of the clinical presentation.

Computed tomography of the head is usually obtained in cirrhotic patients:

• Who have changes in mental status but whose presentation is not typical of hepatic encephalopathy (such as those with focal neurologic signs);
• In cases of severe hepatic encephalopathy, suspected head trauma (especially given the commonly associated coagulopathy in cirrhotic patients), and hepatic encephalopathy resistant to standard therapy; and
• Without clear precipitating factors for hepatic encephalopathy, such as infection (eg, spontaneous bacterial peritonitis) and renal insufficiency.

Similarly, in alcoholic patients who present with altered mental status, we should always consider Wernicke encephalopathy.

In patients with established hepatic encephalopathy, monitoring the ammonia level during therapy is not as useful as ongoing clinical assessment.

In patients with acute liver failure, a blood ammonia level may have a special prognostic value. In hyperammonemic states that subsequently lead to elevated ammonia in the brain, astrocytes convert ammonia to glutamine. Glutamine is not toxic, but it is osmotically active, and as it accumulates, it leads to astrocyte swelling and brain edema. This pathologic process is very prominent in acute hyperammonemic states in which astrocytes do not have time to adapt osmotically by pumping in myoinositol.⁹ Clemmesen et al¹⁰ have shown that arterial ammonia levels higher than 200 μg/dL are strongly associated with cerebral herniation in patients with acute liver failure.

If the patient is not known to have chronic liver disease

Occasionally, the blood ammonia level is found to be high in a patient who presents with altered mental status but who does not have known liver disease. In these patients, undiagnosed or new-onset decompensated cirrhosis is still possible, and the possibility should be explored. Acute liver failure is another possibility, but it is usually obvious, with associated coagulopathy, hyperbilirubinemia, and other clinical and laboratory features.

The main diagnostic challenge is in patients who have altered mental status and hyperammonemia but no features to suggest the above possibilities. In this setting, three tasks should be approached simultaneously:

• Look for and aggressively manage cerebral edema and increased intracranial pressure with ammonia-lowering measures such as lactulose, renal replacement therapy, and other specific therapeutic agents if a urea cycle disorder is suspected.¹¹
• Search for causes of elevated ammonia other than hepatic dysfunction. These causes can be classified into two major categories¹¹: 1) causes of increased ammonia production such as total parenteral nutrition, gastrointestinal hemorrhage, and steroid use, and 2) causes of decreased ammonia excretion such as portosystemic shunts, medications that decrease ammonia metabolism, and inborn errors of metabolism such as urea cycle disorders. Portosystemic shunts have been well documented in patients with no underlying liver disease.¹²

Several drugs, such as glycine (used during transurethral prostate resection), salicylates, and valproate raise the ammonia level by altering the urea cycle.¹¹ Although most severe inborn errors of metabolism become evident early in childhood, certain urea cycle disorders, especially ornithine transcarbamylase deficiency, may manifest later during adulthood when a precipitating event occurs, such as an increase in protein intake (eg, with total parenteral nutrition), use of certain medications, or infection.

• Explore concomitant or alternative causes of altered mental status based on the clinical setting, such as a cerebrovascular accident, infectious meningoencephalitis, drug intoxication, or other metabolic or systemic disorders.

IN AMMONIA TESTING, TECHNIQUE MATTERS

To obtain an accurate measurement, the blood sample for ammonia testing must be obtained and handled properly. Prolonged application of a tourniquet or fist-clenching while obtaining the blood sample or improper specimen handling can result in a falsely elevated blood ammonia level, which can lead you down the wrong diagnostic pathway.

Venous blood, if appropriately collected, transported in ice, and handled quickly for analysis, has been shown to be as useful as arterial blood in ammonia measurement.⁸

The Advisory Committee on Immunization Practices (ACIP) recommends routinely giving a single dose of live zoster vaccine to immunocompetent patients age 60 and older at their first clinical encounter. The vaccine effectively prevents shingles and postherpetic neuralgia and their associated burden of illness. Although not all insurance companies pay for it yet, it should be offered to all patients for whom it is indicated to increase their health-related quality of life.

IMMUNITY WANES WITH AGE

Shingles, also known as zoster or herpes zoster, is caused by retrograde transport of the varicella zoster virus (VZV) from the ganglia to the skin in a host who had a primary varicella infection (chickenpox) in the past.¹ Although shingles is not one of the diseases that must be reported to public health authorities, more than 1 million cases are estimated to occur each year in the United States. From 10% to 30% of people develop shingles during their lifetime.^2,3

The elderly are at particular risk of shingles, because immunity to VZV wanes as a part of normal aging. As many as 50% of people who live to age 85 will have shingles at some point in their life.

Moreover, about 20% of patients with shingles develop postherpetic neuralgia,^3,4 the pain and discomfort of which can be disabling and can diminish quality of life.⁵

Antiviral therapy reduces the severity and duration of an episode of shingles but does not prevent postherpetic neuralgia.^2,6 Steroids provide additional relief of acute zoster pain, but they do not clearly prevent postherpetic neuralgia either and should be used only in combination with antiviral drugs. Preventing zoster and postherpetic neuralgia by routine vaccination should be a goal in our efforts to promote healthy aging, especially with the increasing number of elderly in our country.⁷

THE VACCINE IS EFFECTIVE: THE SHINGLES PREVENTION STUDY

The Shingles Prevention Study was a prospective, double-blind trial in more than 38,000 adults, median age 69 years (range 59–99), who were followed for a mean of 3.13 years (range 1 day to 4.9 years) after receiving the zoster vaccine or placebo.^8–10

The virus in the vaccine did not elicit shingles in any patient. After vaccination, if lesions did occur, they were from the patient’s native strain, not the vaccine strain.⁸

ZOSTAVAX

The US Food and Drug Administration approved the zoster vaccine in May 2006 for prevention of herpes zoster in people age 60 and older. Zostavax, licensed by Merck, is the only vaccine available for this purpose.^11,12 Zoster vaccine is not indicated for treating episodes of shingles or postherpetic neuralgia or for preventing primary varicella infection (chickenpox).

Zostavax does not contain thimerosal, a mercury-based preservative used in other vaccines. Therefore, it must be kept frozen at an average temperature of –15°C (5°F) and should not be used if its temperature rises above –5°C (23°F).^13,14 Just before it is given, the vaccine is reconstituted with the supplied diluents and then injected subcutaneously in the deltoid region.¹²

No booster dose is recommended at present. Also, many cases of herpes zoster occur in people under age 60, for whom there is no recommendation.^11,15 Although the vaccine would probably be safe and effective in this younger group, data are insufficient to recommend vaccinating them.¹⁶

ZOSTER VACCINE (ZOSTAVAX) IS NOT CHICKENPOX VACCINE (VARIVAX)

Both Zostavax and the chickenpox vaccine (Varivax) are live, attenuated vaccines from the same Oka/Merck strain of the virus, but Zostavax is about 14 times more potent than Varivax (Zostavax contains 8,700–60,000 plaque-forming units of virus, whereas Varivax contains 1,350), and they should not be used interchangeably.¹⁴

GIVING ZOSTER VACCINE WITH OTHER VACCINES IN THE ELDERLY

Zostavax can be given either simultaneously with or at any time before or after any inactivated vaccine (such as tetanus toxoid, influenza, pneumococcus). However, each vaccine must be given in a separate syringe at a different anatomic site.¹⁷

VACCINATE EVEN IF THE PATIENT DOESN’T RECALL HAVING CHICKENPOX

Even in people who do not recall ever having chickenpox, the rate of VZV seropositivity is very high (> 95% in those over age 60 in the United States).¹⁸ The ACIP recommends vaccination whether or not the patient reports having had chickenpox. Serologic testing to determine varicella immunity is not needed before vaccination, nor was it required for entry in the Shingles Prevention Study.

Furthermore, in VZV-seronegative adults, giving the zoster vaccine is thought to provide at least partial protection against varicella, and no data indicate any excessive adverse effects in this population.

VACCINATE EVEN IF THE PATIENT HAS HAD SHINGLES

The ACIP says that people with a history of zoster can be vaccinated. Recurrent zoster has been confirmed in immunocompetent patients soon after a previous episode. There is no test to confirm prior zoster episodes, and if the patient is immunocompetent, no different safety concerns are anticipated with vaccination in this group.¹⁶

ADVERSE EFFECTS ARE MILD

No significant safety concerns have been noted with zoster vaccine. Mild local reactions (erythema, swelling, pain, pruritus) and headache are the most common adverse events. There have been no differences in the numbers and types of serious adverse events during the 42 days after receipt of vaccine or placebo.

CONTRAINDICATIONS

Contraindications to zoster vaccine are:

• A history of anaphylactic or anaphylactoid reactions to gelatin, neomycin, or other components of the vaccine
• Acquired or primary immune deficiency states, including AIDS
• Cancer chemotherapy or radiotherapy
• Leukemia
• Lymphoma
• Organ transplantation
• Active untreated tuberculosis
• Pregnancy or breast-feeding.

However, patients with leukemia in remission who have not received chemotherapy (eg, alkylating drugs or antimetabolites) or radiation for at least 3 months can receive zoster vaccine.

Although zoster vaccine is contraindicated in conditions of cellular immune deficiency, patients with humoral immunodeficiency (eg, hypogammaglobulinemia or dysgammaglobulinemia) can receive it.

Diabetes, hypertension, chronic renal failure, coronary artery disease, chronic lung disease, rheumatoid arthritis, and other medical conditions are not considered contraindications to the vaccine.

The ACIP does not recommend any upper age limit for the vaccine, and preventing zoster is particularly important in the oldest elderly because they have the highest incidence of zoster and postherpetic neuralgia.¹⁶

Do not vaccinate during immunosuppressive treatment

If immunosuppressive treatment is planned (eg, with corticosteroids or anti-tumor necrosis factor agents), the vaccine should be given at least 14 days (preferably 1 month) before immunosuppression begins.

The safety and efficacy of zoster vaccine is unknown in patients receiving recombinant human immune mediators and immune modulators, especially anti-tumor necrosis factor agents such as adalimumab (Humira), infliximab (Remicade), or etanercept (Enbrel). These patients should be vaccinated 1 month before starting the treatment or 1 month after stopping it.¹⁶

Patients on corticosteroids in doses equivalent to prednisone 20 mg/day or more for 2 or more weeks should not be vaccinated against zoster unless the steroids have been stopped for at least 1 month.¹¹

Low doses of methotrexate (< 0.4 mg/kg/week), azathioprine (Azasan) (< 3.0 mg/kg/day), or 6-mercaptopurine (Purinethol, 6-MP) (< 1.5 mg/kg/day) for the treatment of rheumatoid arthritis, psoriasis, polymyositis, sarcoidosis, inflammatory bowel disease, and other conditions are not contraindications to zoster vaccination.

Medications against herpes, such as acyclovir (Zovirax), famciclovir (Famvir), or valacyclovir (Valtrex) should be discontinued at least 24 hours before zoster vaccination and should not be started until 14 days afterward.

COSTLY AND EFFECTIVE? OR COST-EFFECTIVE?

The average cost associated with an acute episode of zoster ranges from $112 to $287 if treated on an outpatient basis and $3,221 to $7,206 if the patient is hospitalized (costs in 2006).¹⁹

Although pharmacists are licensed to administer influenza and pneumococcal vaccines, several states do not specifically allow them to administer zoster vaccine. Moreover, one usually cannot provide the vaccine out of the office stock and get reimbursed for it (except by some private insurance companies). Instead, the patient needs to take a prescription to a local pharmacy, where the vaccine is placed on ice and then brought back to the physician’s office for administration.

The Advisory Committee on Immunization Practices (ACIP) recommends routinely giving a single dose of live zoster vaccine to immunocompetent patients age 60 and older at their first clinical encounter. The vaccine effectively prevents shingles and postherpetic neuralgia and their associated burden of illness. Although not all insurance companies pay for it yet, it should be offered to all patients for whom it is indicated to increase their health-related quality of life.

IMMUNITY WANES WITH AGE

Shingles, also known as zoster or herpes zoster, is caused by retrograde transport of the varicella zoster virus (VZV) from the ganglia to the skin in a host who had a primary varicella infection (chickenpox) in the past.¹ Although shingles is not one of the diseases that must be reported to public health authorities, more than 1 million cases are estimated to occur each year in the United States. From 10% to 30% of people develop shingles during their lifetime.^2,3

The elderly are at particular risk of shingles, because immunity to VZV wanes as a part of normal aging. As many as 50% of people who live to age 85 will have shingles at some point in their life.

Moreover, about 20% of patients with shingles develop postherpetic neuralgia,^3,4 the pain and discomfort of which can be disabling and can diminish quality of life.⁵

Antiviral therapy reduces the severity and duration of an episode of shingles but does not prevent postherpetic neuralgia.^2,6 Steroids provide additional relief of acute zoster pain, but they do not clearly prevent postherpetic neuralgia either and should be used only in combination with antiviral drugs. Preventing zoster and postherpetic neuralgia by routine vaccination should be a goal in our efforts to promote healthy aging, especially with the increasing number of elderly in our country.⁷

THE VACCINE IS EFFECTIVE: THE SHINGLES PREVENTION STUDY

The Shingles Prevention Study was a prospective, double-blind trial in more than 38,000 adults, median age 69 years (range 59–99), who were followed for a mean of 3.13 years (range 1 day to 4.9 years) after receiving the zoster vaccine or placebo.^8–10

The virus in the vaccine did not elicit shingles in any patient. After vaccination, if lesions did occur, they were from the patient’s native strain, not the vaccine strain.⁸

ZOSTAVAX

The US Food and Drug Administration approved the zoster vaccine in May 2006 for prevention of herpes zoster in people age 60 and older. Zostavax, licensed by Merck, is the only vaccine available for this purpose.^11,12 Zoster vaccine is not indicated for treating episodes of shingles or postherpetic neuralgia or for preventing primary varicella infection (chickenpox).

Zostavax does not contain thimerosal, a mercury-based preservative used in other vaccines. Therefore, it must be kept frozen at an average temperature of –15°C (5°F) and should not be used if its temperature rises above –5°C (23°F).^13,14 Just before it is given, the vaccine is reconstituted with the supplied diluents and then injected subcutaneously in the deltoid region.¹²

No booster dose is recommended at present. Also, many cases of herpes zoster occur in people under age 60, for whom there is no recommendation.^11,15 Although the vaccine would probably be safe and effective in this younger group, data are insufficient to recommend vaccinating them.¹⁶

ZOSTER VACCINE (ZOSTAVAX) IS NOT CHICKENPOX VACCINE (VARIVAX)

Both Zostavax and the chickenpox vaccine (Varivax) are live, attenuated vaccines from the same Oka/Merck strain of the virus, but Zostavax is about 14 times more potent than Varivax (Zostavax contains 8,700–60,000 plaque-forming units of virus, whereas Varivax contains 1,350), and they should not be used interchangeably.¹⁴

GIVING ZOSTER VACCINE WITH OTHER VACCINES IN THE ELDERLY

Zostavax can be given either simultaneously with or at any time before or after any inactivated vaccine (such as tetanus toxoid, influenza, pneumococcus). However, each vaccine must be given in a separate syringe at a different anatomic site.¹⁷

VACCINATE EVEN IF THE PATIENT DOESN’T RECALL HAVING CHICKENPOX

Even in people who do not recall ever having chickenpox, the rate of VZV seropositivity is very high (> 95% in those over age 60 in the United States).¹⁸ The ACIP recommends vaccination whether or not the patient reports having had chickenpox. Serologic testing to determine varicella immunity is not needed before vaccination, nor was it required for entry in the Shingles Prevention Study.

Furthermore, in VZV-seronegative adults, giving the zoster vaccine is thought to provide at least partial protection against varicella, and no data indicate any excessive adverse effects in this population.

VACCINATE EVEN IF THE PATIENT HAS HAD SHINGLES

The ACIP says that people with a history of zoster can be vaccinated. Recurrent zoster has been confirmed in immunocompetent patients soon after a previous episode. There is no test to confirm prior zoster episodes, and if the patient is immunocompetent, no different safety concerns are anticipated with vaccination in this group.¹⁶

ADVERSE EFFECTS ARE MILD

No significant safety concerns have been noted with zoster vaccine. Mild local reactions (erythema, swelling, pain, pruritus) and headache are the most common adverse events. There have been no differences in the numbers and types of serious adverse events during the 42 days after receipt of vaccine or placebo.

CONTRAINDICATIONS

Contraindications to zoster vaccine are:

• A history of anaphylactic or anaphylactoid reactions to gelatin, neomycin, or other components of the vaccine
• Acquired or primary immune deficiency states, including AIDS
• Cancer chemotherapy or radiotherapy
• Leukemia
• Lymphoma
• Organ transplantation
• Active untreated tuberculosis
• Pregnancy or breast-feeding.

However, patients with leukemia in remission who have not received chemotherapy (eg, alkylating drugs or antimetabolites) or radiation for at least 3 months can receive zoster vaccine.

Although zoster vaccine is contraindicated in conditions of cellular immune deficiency, patients with humoral immunodeficiency (eg, hypogammaglobulinemia or dysgammaglobulinemia) can receive it.

Diabetes, hypertension, chronic renal failure, coronary artery disease, chronic lung disease, rheumatoid arthritis, and other medical conditions are not considered contraindications to the vaccine.

The ACIP does not recommend any upper age limit for the vaccine, and preventing zoster is particularly important in the oldest elderly because they have the highest incidence of zoster and postherpetic neuralgia.¹⁶

Do not vaccinate during immunosuppressive treatment

If immunosuppressive treatment is planned (eg, with corticosteroids or anti-tumor necrosis factor agents), the vaccine should be given at least 14 days (preferably 1 month) before immunosuppression begins.

The safety and efficacy of zoster vaccine is unknown in patients receiving recombinant human immune mediators and immune modulators, especially anti-tumor necrosis factor agents such as adalimumab (Humira), infliximab (Remicade), or etanercept (Enbrel). These patients should be vaccinated 1 month before starting the treatment or 1 month after stopping it.¹⁶

Patients on corticosteroids in doses equivalent to prednisone 20 mg/day or more for 2 or more weeks should not be vaccinated against zoster unless the steroids have been stopped for at least 1 month.¹¹

Low doses of methotrexate (< 0.4 mg/kg/week), azathioprine (Azasan) (< 3.0 mg/kg/day), or 6-mercaptopurine (Purinethol, 6-MP) (< 1.5 mg/kg/day) for the treatment of rheumatoid arthritis, psoriasis, polymyositis, sarcoidosis, inflammatory bowel disease, and other conditions are not contraindications to zoster vaccination.

Medications against herpes, such as acyclovir (Zovirax), famciclovir (Famvir), or valacyclovir (Valtrex) should be discontinued at least 24 hours before zoster vaccination and should not be started until 14 days afterward.

COSTLY AND EFFECTIVE? OR COST-EFFECTIVE?

The average cost associated with an acute episode of zoster ranges from $112 to $287 if treated on an outpatient basis and $3,221 to $7,206 if the patient is hospitalized (costs in 2006).¹⁹

Although pharmacists are licensed to administer influenza and pneumococcal vaccines, several states do not specifically allow them to administer zoster vaccine. Moreover, one usually cannot provide the vaccine out of the office stock and get reimbursed for it (except by some private insurance companies). Instead, the patient needs to take a prescription to a local pharmacy, where the vaccine is placed on ice and then brought back to the physician’s office for administration.

The Advisory Committee on Immunization Practices (ACIP) recommends routinely giving a single dose of live zoster vaccine to immunocompetent patients age 60 and older at their first clinical encounter. The vaccine effectively prevents shingles and postherpetic neuralgia and their associated burden of illness. Although not all insurance companies pay for it yet, it should be offered to all patients for whom it is indicated to increase their health-related quality of life.

IMMUNITY WANES WITH AGE

Shingles, also known as zoster or herpes zoster, is caused by retrograde transport of the varicella zoster virus (VZV) from the ganglia to the skin in a host who had a primary varicella infection (chickenpox) in the past.¹ Although shingles is not one of the diseases that must be reported to public health authorities, more than 1 million cases are estimated to occur each year in the United States. From 10% to 30% of people develop shingles during their lifetime.^2,3

The elderly are at particular risk of shingles, because immunity to VZV wanes as a part of normal aging. As many as 50% of people who live to age 85 will have shingles at some point in their life.

Moreover, about 20% of patients with shingles develop postherpetic neuralgia,^3,4 the pain and discomfort of which can be disabling and can diminish quality of life.⁵

Antiviral therapy reduces the severity and duration of an episode of shingles but does not prevent postherpetic neuralgia.^2,6 Steroids provide additional relief of acute zoster pain, but they do not clearly prevent postherpetic neuralgia either and should be used only in combination with antiviral drugs. Preventing zoster and postherpetic neuralgia by routine vaccination should be a goal in our efforts to promote healthy aging, especially with the increasing number of elderly in our country.⁷

THE VACCINE IS EFFECTIVE: THE SHINGLES PREVENTION STUDY

The Shingles Prevention Study was a prospective, double-blind trial in more than 38,000 adults, median age 69 years (range 59–99), who were followed for a mean of 3.13 years (range 1 day to 4.9 years) after receiving the zoster vaccine or placebo.^8–10

The virus in the vaccine did not elicit shingles in any patient. After vaccination, if lesions did occur, they were from the patient’s native strain, not the vaccine strain.⁸

ZOSTAVAX

The US Food and Drug Administration approved the zoster vaccine in May 2006 for prevention of herpes zoster in people age 60 and older. Zostavax, licensed by Merck, is the only vaccine available for this purpose.^11,12 Zoster vaccine is not indicated for treating episodes of shingles or postherpetic neuralgia or for preventing primary varicella infection (chickenpox).

Zostavax does not contain thimerosal, a mercury-based preservative used in other vaccines. Therefore, it must be kept frozen at an average temperature of –15°C (5°F) and should not be used if its temperature rises above –5°C (23°F).^13,14 Just before it is given, the vaccine is reconstituted with the supplied diluents and then injected subcutaneously in the deltoid region.¹²

No booster dose is recommended at present. Also, many cases of herpes zoster occur in people under age 60, for whom there is no recommendation.^11,15 Although the vaccine would probably be safe and effective in this younger group, data are insufficient to recommend vaccinating them.¹⁶

ZOSTER VACCINE (ZOSTAVAX) IS NOT CHICKENPOX VACCINE (VARIVAX)

Both Zostavax and the chickenpox vaccine (Varivax) are live, attenuated vaccines from the same Oka/Merck strain of the virus, but Zostavax is about 14 times more potent than Varivax (Zostavax contains 8,700–60,000 plaque-forming units of virus, whereas Varivax contains 1,350), and they should not be used interchangeably.¹⁴

GIVING ZOSTER VACCINE WITH OTHER VACCINES IN THE ELDERLY

Zostavax can be given either simultaneously with or at any time before or after any inactivated vaccine (such as tetanus toxoid, influenza, pneumococcus). However, each vaccine must be given in a separate syringe at a different anatomic site.¹⁷

VACCINATE EVEN IF THE PATIENT DOESN’T RECALL HAVING CHICKENPOX

Even in people who do not recall ever having chickenpox, the rate of VZV seropositivity is very high (> 95% in those over age 60 in the United States).¹⁸ The ACIP recommends vaccination whether or not the patient reports having had chickenpox. Serologic testing to determine varicella immunity is not needed before vaccination, nor was it required for entry in the Shingles Prevention Study.

Furthermore, in VZV-seronegative adults, giving the zoster vaccine is thought to provide at least partial protection against varicella, and no data indicate any excessive adverse effects in this population.

VACCINATE EVEN IF THE PATIENT HAS HAD SHINGLES

The ACIP says that people with a history of zoster can be vaccinated. Recurrent zoster has been confirmed in immunocompetent patients soon after a previous episode. There is no test to confirm prior zoster episodes, and if the patient is immunocompetent, no different safety concerns are anticipated with vaccination in this group.¹⁶

ADVERSE EFFECTS ARE MILD

No significant safety concerns have been noted with zoster vaccine. Mild local reactions (erythema, swelling, pain, pruritus) and headache are the most common adverse events. There have been no differences in the numbers and types of serious adverse events during the 42 days after receipt of vaccine or placebo.

CONTRAINDICATIONS

Contraindications to zoster vaccine are:

• A history of anaphylactic or anaphylactoid reactions to gelatin, neomycin, or other components of the vaccine
• Acquired or primary immune deficiency states, including AIDS
• Cancer chemotherapy or radiotherapy
• Leukemia
• Lymphoma
• Organ transplantation
• Active untreated tuberculosis
• Pregnancy or breast-feeding.

However, patients with leukemia in remission who have not received chemotherapy (eg, alkylating drugs or antimetabolites) or radiation for at least 3 months can receive zoster vaccine.

Although zoster vaccine is contraindicated in conditions of cellular immune deficiency, patients with humoral immunodeficiency (eg, hypogammaglobulinemia or dysgammaglobulinemia) can receive it.

Diabetes, hypertension, chronic renal failure, coronary artery disease, chronic lung disease, rheumatoid arthritis, and other medical conditions are not considered contraindications to the vaccine.

The ACIP does not recommend any upper age limit for the vaccine, and preventing zoster is particularly important in the oldest elderly because they have the highest incidence of zoster and postherpetic neuralgia.¹⁶

Do not vaccinate during immunosuppressive treatment

If immunosuppressive treatment is planned (eg, with corticosteroids or anti-tumor necrosis factor agents), the vaccine should be given at least 14 days (preferably 1 month) before immunosuppression begins.

The safety and efficacy of zoster vaccine is unknown in patients receiving recombinant human immune mediators and immune modulators, especially anti-tumor necrosis factor agents such as adalimumab (Humira), infliximab (Remicade), or etanercept (Enbrel). These patients should be vaccinated 1 month before starting the treatment or 1 month after stopping it.¹⁶

Patients on corticosteroids in doses equivalent to prednisone 20 mg/day or more for 2 or more weeks should not be vaccinated against zoster unless the steroids have been stopped for at least 1 month.¹¹

Low doses of methotrexate (< 0.4 mg/kg/week), azathioprine (Azasan) (< 3.0 mg/kg/day), or 6-mercaptopurine (Purinethol, 6-MP) (< 1.5 mg/kg/day) for the treatment of rheumatoid arthritis, psoriasis, polymyositis, sarcoidosis, inflammatory bowel disease, and other conditions are not contraindications to zoster vaccination.

Medications against herpes, such as acyclovir (Zovirax), famciclovir (Famvir), or valacyclovir (Valtrex) should be discontinued at least 24 hours before zoster vaccination and should not be started until 14 days afterward.

COSTLY AND EFFECTIVE? OR COST-EFFECTIVE?

The average cost associated with an acute episode of zoster ranges from $112 to $287 if treated on an outpatient basis and $3,221 to $7,206 if the patient is hospitalized (costs in 2006).¹⁹

Although pharmacists are licensed to administer influenza and pneumococcal vaccines, several states do not specifically allow them to administer zoster vaccine. Moreover, one usually cannot provide the vaccine out of the office stock and get reimbursed for it (except by some private insurance companies). Instead, the patient needs to take a prescription to a local pharmacy, where the vaccine is placed on ice and then brought back to the physician’s office for administration.

Yes. In selected patients with hypercapnic respiratory failure due to an acute exacerbation of chronic obstructive pulmonary disease (COPD), noninvasive positive pressure ventilation (NIPPV) is an effective adjunct to usual medical therapy. In controlled trials, it reduced the need for endotracheal intubation, the length of hospital stay, and the risk of death.

Acute COPD exacerbations are responsible for more than 500,000 hospitalizations yearly in the United States, and 6% to 34% of patients die.¹

Many patients need invasive ventilatory assistance via an endotracheal tube, but such therapy puts the patient at risk of ventilator-associated pneumonia, pneumothorax, and tracheal stenosis.

WHAT IS NONINVASIVE POSITIVE PRESSURE VENTILATION?

WHY IS IT BENEFICIAL?

Several mechanisms may explain why noninvasive positive pressure ventilation is beneficial in acute exacerbations of COPD.

Patients with decompensated respiratory failure lack sufficient alveolar ventilation, owing to abnormal respiratory mechanics and inspiratory muscle fatigue.¹⁰ For these patients, breathing faster does not fully compensate. Noninvasive positive pressure ventilation partially counteracts these factors by providing a larger tidal volume with the same inspiratory effort.^10,11

Additionally, this treatment can decrease the work of breathing by partially overcoming auto-PEEP (positive end-expiratory pressure) in certain situations.² Auto-PEEP is pressure greater than the atmospheric pressure remaining in the alveoli at the end of exhalation.¹² This condition is related to limited expiratory flow and is common in those with severe COPD. Noninvasive positive pressure ventilation decreases the pressure difference between the atmosphere and the alveoli, thereby reducing the inspiratory force needed for initiation of inspiratory effort, which may reduce the work of breathing. However, caution should be used when using this therapy in tachypneic patients, in whom NIPPV may not fully overcome the auto-PEEP.

WHAT STUDIES SHOWED

Several randomized trials have shown NIPPV to be beneficial in acute hypercapnic COPD exacerbations. A recent meta-analysis of eight studies¹³ showed that, compared with usual care alone, this therapy was associated with:

• A lower mortality rate (relative risk 0.41; 95% confidence interval [CI] 0.26–0.64)
• Less need for endotracheal intubation (relative risk 0.42; 95% CI 0.31–0.59)
• A lower rate of treatment failure (relative risk 0.51; 95% CI 0.38–0.67)
• Greater improvements in the 1-hour post-treatment pH and PaCO₂ levels
• A lower respiratory rate
• A shorter length of stay in the hospital.

WHICH PATIENTS SHOULD RECEIVE IT?

NIPPV is not suitable for all patients with hypercapnic respiratory failure. It should not be substituted for endotracheal intubation and mechanical ventilation if they are indicated, eg, in patients who are medically unstable because of hypotension, sepsis, hypoxia, or other life-threatening systemic illness. In addition, those who cannot protect the airway, who have had a worsening in mental status, or who have excessive secretions should not undergo NIPPV because they have a high risk of aspiration. Factors that predict that this therapy will fail include an Acute Physiology and Chronic Health Evaluation (APACHE) score of 29 or higher, a respiratory rate of 30 or higher, and a pH lower than 7.25 after 2 hours of this therapy.¹⁵

GENERAL WARD OR INTENSIVE CARE UNIT?

Mild to moderate COPD exacerbations (in which the pH is 7.30 or higher) can be effectively treated with NIPPV in a general ward if the staff has appropriate expertise.^5,18 Keeping the patient in a general ward reduces cost and provides a favorable outcome in selected patients.^5,19 However, if the patient’s hemodynamic or mental status deteriorates or if gas exchange, pH, respiratory rate, or dyspnea fail to improve, he or she should be transferred to an intensive care unit and endotracheal intubation should be considered.¹⁸ The use of NIPPV in general wards should always be approached with caution and should never be attempted without adequate patient supervision and an experienced respiratory therapy team.

TAKE-HOME MESSAGE

NIPPV has been shown to be an effective adjunct in the treatment of acute hypercapnic respiratory failure secondary to a COPD exacerbation, reducing the need for endotracheal intubation, the length of hospital stay, and the mortality rate. On the basis of controlled trials, NIPPV is now considered the ventilatory therapy of choice in selected patients with this condition. However, it should not be used as a substitute for intubation and mechanical ventilation if these are needed or if the patient is at risk of aspiration.

Yes. In selected patients with hypercapnic respiratory failure due to an acute exacerbation of chronic obstructive pulmonary disease (COPD), noninvasive positive pressure ventilation (NIPPV) is an effective adjunct to usual medical therapy. In controlled trials, it reduced the need for endotracheal intubation, the length of hospital stay, and the risk of death.

Acute COPD exacerbations are responsible for more than 500,000 hospitalizations yearly in the United States, and 6% to 34% of patients die.¹

Many patients need invasive ventilatory assistance via an endotracheal tube, but such therapy puts the patient at risk of ventilator-associated pneumonia, pneumothorax, and tracheal stenosis.

WHAT IS NONINVASIVE POSITIVE PRESSURE VENTILATION?

WHY IS IT BENEFICIAL?

Several mechanisms may explain why noninvasive positive pressure ventilation is beneficial in acute exacerbations of COPD.

Patients with decompensated respiratory failure lack sufficient alveolar ventilation, owing to abnormal respiratory mechanics and inspiratory muscle fatigue.¹⁰ For these patients, breathing faster does not fully compensate. Noninvasive positive pressure ventilation partially counteracts these factors by providing a larger tidal volume with the same inspiratory effort.^10,11

Additionally, this treatment can decrease the work of breathing by partially overcoming auto-PEEP (positive end-expiratory pressure) in certain situations.² Auto-PEEP is pressure greater than the atmospheric pressure remaining in the alveoli at the end of exhalation.¹² This condition is related to limited expiratory flow and is common in those with severe COPD. Noninvasive positive pressure ventilation decreases the pressure difference between the atmosphere and the alveoli, thereby reducing the inspiratory force needed for initiation of inspiratory effort, which may reduce the work of breathing. However, caution should be used when using this therapy in tachypneic patients, in whom NIPPV may not fully overcome the auto-PEEP.

WHAT STUDIES SHOWED

Several randomized trials have shown NIPPV to be beneficial in acute hypercapnic COPD exacerbations. A recent meta-analysis of eight studies¹³ showed that, compared with usual care alone, this therapy was associated with:

• A lower mortality rate (relative risk 0.41; 95% confidence interval [CI] 0.26–0.64)
• Less need for endotracheal intubation (relative risk 0.42; 95% CI 0.31–0.59)
• A lower rate of treatment failure (relative risk 0.51; 95% CI 0.38–0.67)
• Greater improvements in the 1-hour post-treatment pH and PaCO₂ levels
• A lower respiratory rate
• A shorter length of stay in the hospital.

WHICH PATIENTS SHOULD RECEIVE IT?

NIPPV is not suitable for all patients with hypercapnic respiratory failure. It should not be substituted for endotracheal intubation and mechanical ventilation if they are indicated, eg, in patients who are medically unstable because of hypotension, sepsis, hypoxia, or other life-threatening systemic illness. In addition, those who cannot protect the airway, who have had a worsening in mental status, or who have excessive secretions should not undergo NIPPV because they have a high risk of aspiration. Factors that predict that this therapy will fail include an Acute Physiology and Chronic Health Evaluation (APACHE) score of 29 or higher, a respiratory rate of 30 or higher, and a pH lower than 7.25 after 2 hours of this therapy.¹⁵

GENERAL WARD OR INTENSIVE CARE UNIT?

Mild to moderate COPD exacerbations (in which the pH is 7.30 or higher) can be effectively treated with NIPPV in a general ward if the staff has appropriate expertise.^5,18 Keeping the patient in a general ward reduces cost and provides a favorable outcome in selected patients.^5,19 However, if the patient’s hemodynamic or mental status deteriorates or if gas exchange, pH, respiratory rate, or dyspnea fail to improve, he or she should be transferred to an intensive care unit and endotracheal intubation should be considered.¹⁸ The use of NIPPV in general wards should always be approached with caution and should never be attempted without adequate patient supervision and an experienced respiratory therapy team.

TAKE-HOME MESSAGE

NIPPV has been shown to be an effective adjunct in the treatment of acute hypercapnic respiratory failure secondary to a COPD exacerbation, reducing the need for endotracheal intubation, the length of hospital stay, and the mortality rate. On the basis of controlled trials, NIPPV is now considered the ventilatory therapy of choice in selected patients with this condition. However, it should not be used as a substitute for intubation and mechanical ventilation if these are needed or if the patient is at risk of aspiration.

Yes. In selected patients with hypercapnic respiratory failure due to an acute exacerbation of chronic obstructive pulmonary disease (COPD), noninvasive positive pressure ventilation (NIPPV) is an effective adjunct to usual medical therapy. In controlled trials, it reduced the need for endotracheal intubation, the length of hospital stay, and the risk of death.

Acute COPD exacerbations are responsible for more than 500,000 hospitalizations yearly in the United States, and 6% to 34% of patients die.¹

Many patients need invasive ventilatory assistance via an endotracheal tube, but such therapy puts the patient at risk of ventilator-associated pneumonia, pneumothorax, and tracheal stenosis.

WHAT IS NONINVASIVE POSITIVE PRESSURE VENTILATION?

WHY IS IT BENEFICIAL?

Several mechanisms may explain why noninvasive positive pressure ventilation is beneficial in acute exacerbations of COPD.

Patients with decompensated respiratory failure lack sufficient alveolar ventilation, owing to abnormal respiratory mechanics and inspiratory muscle fatigue.¹⁰ For these patients, breathing faster does not fully compensate. Noninvasive positive pressure ventilation partially counteracts these factors by providing a larger tidal volume with the same inspiratory effort.^10,11

Additionally, this treatment can decrease the work of breathing by partially overcoming auto-PEEP (positive end-expiratory pressure) in certain situations.² Auto-PEEP is pressure greater than the atmospheric pressure remaining in the alveoli at the end of exhalation.¹² This condition is related to limited expiratory flow and is common in those with severe COPD. Noninvasive positive pressure ventilation decreases the pressure difference between the atmosphere and the alveoli, thereby reducing the inspiratory force needed for initiation of inspiratory effort, which may reduce the work of breathing. However, caution should be used when using this therapy in tachypneic patients, in whom NIPPV may not fully overcome the auto-PEEP.

WHAT STUDIES SHOWED

Several randomized trials have shown NIPPV to be beneficial in acute hypercapnic COPD exacerbations. A recent meta-analysis of eight studies¹³ showed that, compared with usual care alone, this therapy was associated with:

• A lower mortality rate (relative risk 0.41; 95% confidence interval [CI] 0.26–0.64)
• Less need for endotracheal intubation (relative risk 0.42; 95% CI 0.31–0.59)
• A lower rate of treatment failure (relative risk 0.51; 95% CI 0.38–0.67)
• Greater improvements in the 1-hour post-treatment pH and PaCO₂ levels
• A lower respiratory rate
• A shorter length of stay in the hospital.

WHICH PATIENTS SHOULD RECEIVE IT?

NIPPV is not suitable for all patients with hypercapnic respiratory failure. It should not be substituted for endotracheal intubation and mechanical ventilation if they are indicated, eg, in patients who are medically unstable because of hypotension, sepsis, hypoxia, or other life-threatening systemic illness. In addition, those who cannot protect the airway, who have had a worsening in mental status, or who have excessive secretions should not undergo NIPPV because they have a high risk of aspiration. Factors that predict that this therapy will fail include an Acute Physiology and Chronic Health Evaluation (APACHE) score of 29 or higher, a respiratory rate of 30 or higher, and a pH lower than 7.25 after 2 hours of this therapy.¹⁵

GENERAL WARD OR INTENSIVE CARE UNIT?

Mild to moderate COPD exacerbations (in which the pH is 7.30 or higher) can be effectively treated with NIPPV in a general ward if the staff has appropriate expertise.^5,18 Keeping the patient in a general ward reduces cost and provides a favorable outcome in selected patients.^5,19 However, if the patient’s hemodynamic or mental status deteriorates or if gas exchange, pH, respiratory rate, or dyspnea fail to improve, he or she should be transferred to an intensive care unit and endotracheal intubation should be considered.¹⁸ The use of NIPPV in general wards should always be approached with caution and should never be attempted without adequate patient supervision and an experienced respiratory therapy team.

TAKE-HOME MESSAGE

NIPPV has been shown to be an effective adjunct in the treatment of acute hypercapnic respiratory failure secondary to a COPD exacerbation, reducing the need for endotracheal intubation, the length of hospital stay, and the mortality rate. On the basis of controlled trials, NIPPV is now considered the ventilatory therapy of choice in selected patients with this condition. However, it should not be used as a substitute for intubation and mechanical ventilation if these are needed or if the patient is at risk of aspiration.

Sodium phosphate (NaP) agents were introduced to provide a gentler alternative to polyethylene glycol (PEG) bowel preparations, which require patients to drink up to 4 liters of fluid over a few hours.

However, in May 2006 the US Food and Drug Administration (FDA) issued an alert that NaP products for bowel cleansing may, in some patients, pose a risk of acute phosphate nephropathy, a rare form of acute renal failure.

Although NaP preparations are generally safe and well tolerated, they can cause significant fluid shifts and electrolyte abnormalities. As such, they should not be used in patients with baseline electrolyte imbalances, renal or hepatic dysfunction, or a number of other comorbidities.

CURRENT BOWEL-CLEANSING OPTIONS

For many years the standard preparation for bowel cleansing was a 4-liter or a 2-liter PEG electrolyte solution plus a laxative (eg, magnesium citrate, bisacodyl, or senna).^1–3 The most frequent complaint heard from patients was that “the preparation is worse than the colonoscopy,” attributable to the taste and volume of the fluid they had to consume. Thus, compliance was often a significant issue with patients presenting for colonoscopy. In fact, inadequate bowel preparation is one of the most common reasons polyps are missed during colonoscopy.

Aqueous and tablet forms of NaP (sometimes with a laxative) have become a widely used alternative to PEG solutions because they require much less volume and as a result are more palatable, thereby improving compliance.^4,5

NaP agents cleanse the colon by osmotically drawing plasma water into the bowel lumen. The patient must drink significant amounts of water or other oral solutions to prevent dehydration.

NaP-based bowel-cleansing agents are available in two forms: aqueous solution and tablet. Aqueous NaP (such as Fleet Phospho-soda) is a low-volume hyperosmotic solution containing 48 g of monobasic NaP and 18 g of dibasic NaP per 100 mL.⁶ An oral tablet form (such as Visicol and OsmoPrep) was developed to improve patient tolerance.⁷ Each 2-g tablet of Visicol contains 1,500 mg of active ingredients (monobasic and dibasic NaP) and 460 mg of microcrystalline cellulose, an inert polymer. Each OsmoPrep tablet contains 1,500 mg of the same active ingredients as Visicol, but the inert ingredients include PEG and magnesium stearate.

At first, the regimen was 40 tablets such as Visicol to be taken with water and bisacodyl. Subsequent regimens such as OsmoPrep with fewer tablets have been shown to be as effective and better tolerated.⁸ Microcrystalline cellulose in the tablet can produce a residue that may obscure the bowel mucosa. Newer preparations contain lower amounts of this inert ingredient, allowing for improved visualization of the colonic mucosa during colonoscopy.⁹

ADVANTAGES OF SODIUM PHOSPHATE BOWEL CLEANSERS

In a recent review article, Burke and Church¹⁰ noted that NaP cleansing regimens have been shown to be superior to PEG-electrolyte lavage solution with respect to tolerability and acceptance by patients, improved quality of bowel preparation, better mucosal visualization, and more efficient endoscopic examination. In addition, the volume of the preparation may also help decrease the risk of aspiration in some patients.^2,3

DISADVANTAGES OF SODIUM PHOSPHATE AGENTS

Despite their comparable or better efficacy and their better tolerability, NaP agents have certain disadvantages.

Effects on the colonic mucosa

In rare cases NaP agents have been shown to alter the microscopic and macroscopic features of the colonic mucosa, and they can induce aphthoid erosions that may mimic those seen in inflammatory bowel disease and enteropathy or colopathy associated with nonsteroidal anti-inflammatory drugs (NSAIDs).^11–13 Therefore, NaP agents should not be used prior to the initial endoscopic evaluation of patients with suspected inflammatory bowel disease, microscopic colitis, or NSAID-induced colonopathy.

Fluid and electrolyte shifts

Because NaP acts by drawing plasma water into the bowel lumen, significant volume and electrolyte shifts may occur.^14,15 These can cause hypokalemia, hyperphosphatemia, hypocalcemia, hyponatremia or hypernatremia, hypomagnesemia, elevated blood urea nitrogen levels, decreased exercise capacity, increased plasma osmolarity,^15–17 seizures,¹⁸ and acute renal failure with or without nephrocalcinosis.^17,19–21

Thus, patients with significant comorbidities—such as a recent history of myocardial infarction, renal or hepatic insufficiency, or malnutrition—should not use NaP agents.²²

Pivotal study of adverse events

In May 2006, the FDA issued an alert outlining the concerns of using oral NaP in specific patient populations. Of note were documented cases of acute phosphate nephropathy in 21 patients who used aqueous NaP (Fleet Phospho-Soda or Fleet Accu-Prep), and in 1 patient who used NaP tablets (Visicol).²³ Acute renal injury was not limited to patients with preexisting renal insufficiency. It is uncertain whether this means that otherwise healthy people suffered renal injury or had risk factors besides renal insufficiency, since the data cited by the FDA report do not elucidate the possible risk factors for the development of nephropathy in patients with no preexisting renal insufficiency. So far, no cases of acute phosphate nephropathy or acute renal failure have been reported with OsmoPrep, a NaP tablet bowel preparation recently approved by the FDA.²⁴ The long-term safety of OsmoPrep needs further evaluation.

PROCEED WITH CAUTION

Certain situations such as advanced age and cardiac, renal, and hepatic dysfunction call for extreme caution in the use of NaP bowel preparation agents. Therefore, it is recommended that patients with the following conditions should avoid using NaP agents for colon preparation:

• Hepatic or renal insufficiency (there are no data as to the degree of hepatic or renal insufficiency)
• Congestive heart failure
• Over age 65
• Dehydration or hypercalcemia
• Chronic use of drugs that affect renal perfusion, such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or diuretics for hypertension.

Patients who take diuretics should not take them while they are using NaP for bowel preparation because of the risk of electrolyte abnormalities such as hypokalemia. In patients who have no alternative but to proceed with NaP preparation, our recommendation would be that the patient hold off taking diuretics, ACE inhibitors, and angiotensin receptor blockers while using the NaP prep. Given the importance of these medications in controlling diseases such as hypertension, the physician and the patient should jointly determine whether the benefits of using an NaP agent justify holding these drugs. We believe that patients taking these drugs should try using a PEG solution before considering NaP.

TASK FORCE GUIDELINES

Guidelines for using NaP bowel preparation agents, published by a task force of the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons,²⁵ include the following caveats:

• Aqueous and tablet NaP colonic preparations are an alternative to PEG solutions, except in pediatric populations, patients over age 65, and those with bowel obstruction or other structural intestinal disorder, gut dysmotility, renal or hepatic insufficiency, congestive heart failure, or seizure disorder.
• Dosing should be 45 mL in divided doses, 10 to 12 hours apart, with at least one dose taken on the morning of the procedure.²⁵
• The significant volume contraction and resulting dehydration seen in some patients using NaP preparations may be lessened by encouraging patients to drink fluids liberally during the days leading up to their procedure, and especially during NaP bowel preparation.²⁶
• NaP tablets should be dosed as 32 to 40 tablets. On the evening before the procedure the patient should take 20 tablets and then 12 to 20 tablets approximately 3 to 5 hours before undergoing endoscopy. The tablets should be taken four at a time every 15 minutes with approximately 8 oz of clear liquid.²⁵

Sodium phosphate (NaP) agents were introduced to provide a gentler alternative to polyethylene glycol (PEG) bowel preparations, which require patients to drink up to 4 liters of fluid over a few hours.

However, in May 2006 the US Food and Drug Administration (FDA) issued an alert that NaP products for bowel cleansing may, in some patients, pose a risk of acute phosphate nephropathy, a rare form of acute renal failure.

Although NaP preparations are generally safe and well tolerated, they can cause significant fluid shifts and electrolyte abnormalities. As such, they should not be used in patients with baseline electrolyte imbalances, renal or hepatic dysfunction, or a number of other comorbidities.

CURRENT BOWEL-CLEANSING OPTIONS

For many years the standard preparation for bowel cleansing was a 4-liter or a 2-liter PEG electrolyte solution plus a laxative (eg, magnesium citrate, bisacodyl, or senna).^1–3 The most frequent complaint heard from patients was that “the preparation is worse than the colonoscopy,” attributable to the taste and volume of the fluid they had to consume. Thus, compliance was often a significant issue with patients presenting for colonoscopy. In fact, inadequate bowel preparation is one of the most common reasons polyps are missed during colonoscopy.

Aqueous and tablet forms of NaP (sometimes with a laxative) have become a widely used alternative to PEG solutions because they require much less volume and as a result are more palatable, thereby improving compliance.^4,5

NaP agents cleanse the colon by osmotically drawing plasma water into the bowel lumen. The patient must drink significant amounts of water or other oral solutions to prevent dehydration.

NaP-based bowel-cleansing agents are available in two forms: aqueous solution and tablet. Aqueous NaP (such as Fleet Phospho-soda) is a low-volume hyperosmotic solution containing 48 g of monobasic NaP and 18 g of dibasic NaP per 100 mL.⁶ An oral tablet form (such as Visicol and OsmoPrep) was developed to improve patient tolerance.⁷ Each 2-g tablet of Visicol contains 1,500 mg of active ingredients (monobasic and dibasic NaP) and 460 mg of microcrystalline cellulose, an inert polymer. Each OsmoPrep tablet contains 1,500 mg of the same active ingredients as Visicol, but the inert ingredients include PEG and magnesium stearate.

At first, the regimen was 40 tablets such as Visicol to be taken with water and bisacodyl. Subsequent regimens such as OsmoPrep with fewer tablets have been shown to be as effective and better tolerated.⁸ Microcrystalline cellulose in the tablet can produce a residue that may obscure the bowel mucosa. Newer preparations contain lower amounts of this inert ingredient, allowing for improved visualization of the colonic mucosa during colonoscopy.⁹

ADVANTAGES OF SODIUM PHOSPHATE BOWEL CLEANSERS

In a recent review article, Burke and Church¹⁰ noted that NaP cleansing regimens have been shown to be superior to PEG-electrolyte lavage solution with respect to tolerability and acceptance by patients, improved quality of bowel preparation, better mucosal visualization, and more efficient endoscopic examination. In addition, the volume of the preparation may also help decrease the risk of aspiration in some patients.^2,3

DISADVANTAGES OF SODIUM PHOSPHATE AGENTS

Despite their comparable or better efficacy and their better tolerability, NaP agents have certain disadvantages.

Effects on the colonic mucosa

In rare cases NaP agents have been shown to alter the microscopic and macroscopic features of the colonic mucosa, and they can induce aphthoid erosions that may mimic those seen in inflammatory bowel disease and enteropathy or colopathy associated with nonsteroidal anti-inflammatory drugs (NSAIDs).^11–13 Therefore, NaP agents should not be used prior to the initial endoscopic evaluation of patients with suspected inflammatory bowel disease, microscopic colitis, or NSAID-induced colonopathy.

Fluid and electrolyte shifts

Because NaP acts by drawing plasma water into the bowel lumen, significant volume and electrolyte shifts may occur.^14,15 These can cause hypokalemia, hyperphosphatemia, hypocalcemia, hyponatremia or hypernatremia, hypomagnesemia, elevated blood urea nitrogen levels, decreased exercise capacity, increased plasma osmolarity,^15–17 seizures,¹⁸ and acute renal failure with or without nephrocalcinosis.^17,19–21

Thus, patients with significant comorbidities—such as a recent history of myocardial infarction, renal or hepatic insufficiency, or malnutrition—should not use NaP agents.²²

Pivotal study of adverse events

In May 2006, the FDA issued an alert outlining the concerns of using oral NaP in specific patient populations. Of note were documented cases of acute phosphate nephropathy in 21 patients who used aqueous NaP (Fleet Phospho-Soda or Fleet Accu-Prep), and in 1 patient who used NaP tablets (Visicol).²³ Acute renal injury was not limited to patients with preexisting renal insufficiency. It is uncertain whether this means that otherwise healthy people suffered renal injury or had risk factors besides renal insufficiency, since the data cited by the FDA report do not elucidate the possible risk factors for the development of nephropathy in patients with no preexisting renal insufficiency. So far, no cases of acute phosphate nephropathy or acute renal failure have been reported with OsmoPrep, a NaP tablet bowel preparation recently approved by the FDA.²⁴ The long-term safety of OsmoPrep needs further evaluation.

PROCEED WITH CAUTION

Certain situations such as advanced age and cardiac, renal, and hepatic dysfunction call for extreme caution in the use of NaP bowel preparation agents. Therefore, it is recommended that patients with the following conditions should avoid using NaP agents for colon preparation:

• Hepatic or renal insufficiency (there are no data as to the degree of hepatic or renal insufficiency)
• Congestive heart failure
• Over age 65
• Dehydration or hypercalcemia
• Chronic use of drugs that affect renal perfusion, such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or diuretics for hypertension.

Patients who take diuretics should not take them while they are using NaP for bowel preparation because of the risk of electrolyte abnormalities such as hypokalemia. In patients who have no alternative but to proceed with NaP preparation, our recommendation would be that the patient hold off taking diuretics, ACE inhibitors, and angiotensin receptor blockers while using the NaP prep. Given the importance of these medications in controlling diseases such as hypertension, the physician and the patient should jointly determine whether the benefits of using an NaP agent justify holding these drugs. We believe that patients taking these drugs should try using a PEG solution before considering NaP.

TASK FORCE GUIDELINES

Guidelines for using NaP bowel preparation agents, published by a task force of the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons,²⁵ include the following caveats:

• Aqueous and tablet NaP colonic preparations are an alternative to PEG solutions, except in pediatric populations, patients over age 65, and those with bowel obstruction or other structural intestinal disorder, gut dysmotility, renal or hepatic insufficiency, congestive heart failure, or seizure disorder.
• Dosing should be 45 mL in divided doses, 10 to 12 hours apart, with at least one dose taken on the morning of the procedure.²⁵
• The significant volume contraction and resulting dehydration seen in some patients using NaP preparations may be lessened by encouraging patients to drink fluids liberally during the days leading up to their procedure, and especially during NaP bowel preparation.²⁶
• NaP tablets should be dosed as 32 to 40 tablets. On the evening before the procedure the patient should take 20 tablets and then 12 to 20 tablets approximately 3 to 5 hours before undergoing endoscopy. The tablets should be taken four at a time every 15 minutes with approximately 8 oz of clear liquid.²⁵

Sodium phosphate (NaP) agents were introduced to provide a gentler alternative to polyethylene glycol (PEG) bowel preparations, which require patients to drink up to 4 liters of fluid over a few hours.

However, in May 2006 the US Food and Drug Administration (FDA) issued an alert that NaP products for bowel cleansing may, in some patients, pose a risk of acute phosphate nephropathy, a rare form of acute renal failure.

Although NaP preparations are generally safe and well tolerated, they can cause significant fluid shifts and electrolyte abnormalities. As such, they should not be used in patients with baseline electrolyte imbalances, renal or hepatic dysfunction, or a number of other comorbidities.

CURRENT BOWEL-CLEANSING OPTIONS

For many years the standard preparation for bowel cleansing was a 4-liter or a 2-liter PEG electrolyte solution plus a laxative (eg, magnesium citrate, bisacodyl, or senna).^1–3 The most frequent complaint heard from patients was that “the preparation is worse than the colonoscopy,” attributable to the taste and volume of the fluid they had to consume. Thus, compliance was often a significant issue with patients presenting for colonoscopy. In fact, inadequate bowel preparation is one of the most common reasons polyps are missed during colonoscopy.

Aqueous and tablet forms of NaP (sometimes with a laxative) have become a widely used alternative to PEG solutions because they require much less volume and as a result are more palatable, thereby improving compliance.^4,5

NaP agents cleanse the colon by osmotically drawing plasma water into the bowel lumen. The patient must drink significant amounts of water or other oral solutions to prevent dehydration.

NaP-based bowel-cleansing agents are available in two forms: aqueous solution and tablet. Aqueous NaP (such as Fleet Phospho-soda) is a low-volume hyperosmotic solution containing 48 g of monobasic NaP and 18 g of dibasic NaP per 100 mL.⁶ An oral tablet form (such as Visicol and OsmoPrep) was developed to improve patient tolerance.⁷ Each 2-g tablet of Visicol contains 1,500 mg of active ingredients (monobasic and dibasic NaP) and 460 mg of microcrystalline cellulose, an inert polymer. Each OsmoPrep tablet contains 1,500 mg of the same active ingredients as Visicol, but the inert ingredients include PEG and magnesium stearate.

At first, the regimen was 40 tablets such as Visicol to be taken with water and bisacodyl. Subsequent regimens such as OsmoPrep with fewer tablets have been shown to be as effective and better tolerated.⁸ Microcrystalline cellulose in the tablet can produce a residue that may obscure the bowel mucosa. Newer preparations contain lower amounts of this inert ingredient, allowing for improved visualization of the colonic mucosa during colonoscopy.⁹

ADVANTAGES OF SODIUM PHOSPHATE BOWEL CLEANSERS

In a recent review article, Burke and Church¹⁰ noted that NaP cleansing regimens have been shown to be superior to PEG-electrolyte lavage solution with respect to tolerability and acceptance by patients, improved quality of bowel preparation, better mucosal visualization, and more efficient endoscopic examination. In addition, the volume of the preparation may also help decrease the risk of aspiration in some patients.^2,3

DISADVANTAGES OF SODIUM PHOSPHATE AGENTS

Despite their comparable or better efficacy and their better tolerability, NaP agents have certain disadvantages.

Effects on the colonic mucosa

In rare cases NaP agents have been shown to alter the microscopic and macroscopic features of the colonic mucosa, and they can induce aphthoid erosions that may mimic those seen in inflammatory bowel disease and enteropathy or colopathy associated with nonsteroidal anti-inflammatory drugs (NSAIDs).^11–13 Therefore, NaP agents should not be used prior to the initial endoscopic evaluation of patients with suspected inflammatory bowel disease, microscopic colitis, or NSAID-induced colonopathy.

Fluid and electrolyte shifts

Because NaP acts by drawing plasma water into the bowel lumen, significant volume and electrolyte shifts may occur.^14,15 These can cause hypokalemia, hyperphosphatemia, hypocalcemia, hyponatremia or hypernatremia, hypomagnesemia, elevated blood urea nitrogen levels, decreased exercise capacity, increased plasma osmolarity,^15–17 seizures,¹⁸ and acute renal failure with or without nephrocalcinosis.^17,19–21

Thus, patients with significant comorbidities—such as a recent history of myocardial infarction, renal or hepatic insufficiency, or malnutrition—should not use NaP agents.²²

Pivotal study of adverse events

In May 2006, the FDA issued an alert outlining the concerns of using oral NaP in specific patient populations. Of note were documented cases of acute phosphate nephropathy in 21 patients who used aqueous NaP (Fleet Phospho-Soda or Fleet Accu-Prep), and in 1 patient who used NaP tablets (Visicol).²³ Acute renal injury was not limited to patients with preexisting renal insufficiency. It is uncertain whether this means that otherwise healthy people suffered renal injury or had risk factors besides renal insufficiency, since the data cited by the FDA report do not elucidate the possible risk factors for the development of nephropathy in patients with no preexisting renal insufficiency. So far, no cases of acute phosphate nephropathy or acute renal failure have been reported with OsmoPrep, a NaP tablet bowel preparation recently approved by the FDA.²⁴ The long-term safety of OsmoPrep needs further evaluation.

PROCEED WITH CAUTION

Certain situations such as advanced age and cardiac, renal, and hepatic dysfunction call for extreme caution in the use of NaP bowel preparation agents. Therefore, it is recommended that patients with the following conditions should avoid using NaP agents for colon preparation:

• Hepatic or renal insufficiency (there are no data as to the degree of hepatic or renal insufficiency)
• Congestive heart failure
• Over age 65
• Dehydration or hypercalcemia
• Chronic use of drugs that affect renal perfusion, such as NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or diuretics for hypertension.

Patients who take diuretics should not take them while they are using NaP for bowel preparation because of the risk of electrolyte abnormalities such as hypokalemia. In patients who have no alternative but to proceed with NaP preparation, our recommendation would be that the patient hold off taking diuretics, ACE inhibitors, and angiotensin receptor blockers while using the NaP prep. Given the importance of these medications in controlling diseases such as hypertension, the physician and the patient should jointly determine whether the benefits of using an NaP agent justify holding these drugs. We believe that patients taking these drugs should try using a PEG solution before considering NaP.

TASK FORCE GUIDELINES

Guidelines for using NaP bowel preparation agents, published by a task force of the American Society of Colon and Rectal Surgeons, the American Society for Gastrointestinal Endoscopy, and the Society of American Gastrointestinal and Endoscopic Surgeons,²⁵ include the following caveats:

• Aqueous and tablet NaP colonic preparations are an alternative to PEG solutions, except in pediatric populations, patients over age 65, and those with bowel obstruction or other structural intestinal disorder, gut dysmotility, renal or hepatic insufficiency, congestive heart failure, or seizure disorder.
• Dosing should be 45 mL in divided doses, 10 to 12 hours apart, with at least one dose taken on the morning of the procedure.²⁵
• The significant volume contraction and resulting dehydration seen in some patients using NaP preparations may be lessened by encouraging patients to drink fluids liberally during the days leading up to their procedure, and especially during NaP bowel preparation.²⁶
• NaP tablets should be dosed as 32 to 40 tablets. On the evening before the procedure the patient should take 20 tablets and then 12 to 20 tablets approximately 3 to 5 hours before undergoing endoscopy. The tablets should be taken four at a time every 15 minutes with approximately 8 oz of clear liquid.²⁵