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Statins for patients with nonalcoholic fatty liver?
Treat patients with hyperlipidemia and presumed nonalcoholic fatty liver disease with atorvastatin to reduce the risk of cardiovascular events.1
STRENGTH OF RECOMMENDATION
B: Based on a single prospective randomized controlled trial (RCT).
Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analysis. Lancet. 2010; 376:1916-1922.
ILLUSTRATIVE CASE
An obese 58-year-old man with type 2 diabetes comes to your office for follow-up. His low-density lipoprotein cholesterol (LDL-C) is 130 mg/dL; triglycerides, 300 mg/dL; alanine transaminase (ALT), 110 units/L; and aspartate transaminase (AST), 120 units/L. The patient’s work-up for chronic hepatitis B and C, autoimmune hepatitis, hemochromatosis, and Wilson’s disease are negative, and you rule out alcohol misuse based on his medical history. An ultrasound of the patient’s liver reveals hepatic steatosis, and you diagnose nonalcoholic fatty liver disease (NAFLD). Should you start him on a statin?
Patients with central obesity, diabetes, hypertension, hyperlipidemia, and metabolic syndrome are at high risk of developing NAFLD. These conditions have increased in prevalence, and NAFLD is now the most common cause of liver disease in the United States.2 In Western industrialized countries, approximately 30% of the general population and 70% to 90% of patients with diabetes will develop NAFLD.3 Although most patients are asymptomatic, their liver enzymes are elevated. To diagnose NAFLD, it is necessary to rule out alcoholic hepatitis with a medical history, and viral hepatitis, hereditary hemochromatosis, Wilson’s disease, and autoimmune hepatitis with laboratory testing. Ultrasound reveals fat accumulation in the liver.
Treatment for NAFLD has little evidence of benefit
Patients with NAFLD have a much higher mortality rate than that of the general public, primarily because of cardiovascular disease.4-6 Increased physical activity and weight loss is the only therapy that has solid evidence of a benefit,7 although other treatments, such as insulin-sensitizing drugs (metformin or pioglitazone), may be beneficial.8 Surprisingly, atorvastatin has been found to reduce aminotransferase levels in patients with NAFLD,9,10 but clinicians are often concerned about prescribing a statin for patients with elevated liver enzymes. In one study, 50% of primary care physicians said they would not prescribe statins for patients whose liver enzymes are 1.5× the upper limit of normal (ULN).11
STUDY SUMMARY: Statins lower risk of cardiovascular morbidity and mortality
The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study was a randomized, prospective open-label, intention-to-treat trial involving 1600 patients. All had established coronary heart disease (CHD), were younger than 75 years, and had triglycerides <400 mg/dL and LDL-C >100 mg/dL. The study reviewed here—evaluating the risk-to-benefit ratio of using a statin to treat hyperlipidemia in patients with NAFLD—was a post hoc analysis of the GREACE study.1
Participants were randomized to either usual care or structured care with atorvastatin, starting at 10 mg/d and adjusted to 80 mg/d to bring the LDL-C level below 100 mg/dL. In the usual care group, treatment included lifestyle changes plus necessary drug treatments (only 30% of those in the usual care group received hyperlipidemia drugs). Patients were followed after medication dose titration, then every 6 months for 3 years. Serum ALT and AST were measured at baseline, at 6 weeks, and every 6 months.
At baseline, mild-to-moderate increases (<3× ULN) in ALT/AST were noted in 437 of the 1600 patients. For these patients, alcoholic hepatitis, chronic hepatitis B and C, Wilson’s disease, and autoimmune hepatitis were excluded by history, laboratory tests, and ultrasound, and the elevated liver enzymes were attributed to NAFLD.
The primary endpoints were the first occurrence of any cardiovascular event, including nonfatal myocardial infarction, revascularization, unstable angina, heart failure, and stroke; all-cause mortality; and CHD mortality. The relative risk (RR) for such events was calculated for the 437 patients with elevated liver enzymes, compared with that of patients without abnormal liver tests. Elevated liver enzymes and liver-related adverse events were secondary endpoints.
A cardiovascular event occurred in 10% (22/227) of the patients with elevated liver enzymes who received a statin, and 30% (63/210) of patients who had elevated liver enzymes but did not receive a statin.
There were 3.2 events per 100 patient-years in the atorvastatin group, compared with 10 events per 100 patient-years in those not on atorvastatin, a 68% reduction in RR (P<.0001) and an NNT of 15 per year to prevent one cardiovascular event. The risk reduction in cardiovascular events was greater in patients with NAFLD (68%) than in patients with normal liver tests (39%).
An added benefit was the reduction in ALT/AST levels during treatment for patients with NAFLD who were taking a statin, an average decrease of 47% in AST levels and 35% in ALT levels. In addition, 89% of the patients in the statin group had normal ALT, AST, and gamma-glutamyl transferase levels by the end of the 3-year follow-up. Patients with NAFLD who did not receive statins had a 12% increase in AST and ALT by the end of the 3-year study.
Only 10 of 880 patients taking statins developed liver enzymes more than 3× ULN. In 3 of these patients, dose adjustments brought the liver enzymes back to normal. Only 7 (<1%) patients who received a statin had to discontinue therapy because of liver-related adverse effects.
WHAT’S NEW: Liver enzymes improve, with few adverse effects
Preliminary studies have shown an improvement in liver enzymes in patients with NAFLD treated with a statin.9,10 This is the first study to show survival benefits and significant reduction in major cardiovascular morbidity for such patients, as well.
This is also the first large-scale study that shows that treating NAFLD patients with a statin decreases liver enzyme levels, with minimal adverse effects.
CAVEATS: Differences in groups, few women could skew results
This study cannot be considered the final word on this topic. Patients in the “structured care” group were followed at a university clinic, while those in the “usual care” group were followed by either a family physician or a cardiologist outside the hospital, based on their choice. There may have been other differences in the care received by the 2 groups that could account for the difference in mortality and morbidity reduction.
In addition, study participants had coronary artery disease, and atorvastatin was not used for primary prevention. Moreover, nearly 80% of the study participants were male, which raises the question of generalizability. And this study was a post hoc analysis of the larger GREACE study, which also raises concerns about the validity of findings.
In the absence of a larger prospective RCT, however, this is the best available evidence to support the use of statins in this population, and suggests that treating patients with NAFLD with statins is safe and effective.
CHALLENGES TO IMPLEMENTATION: Extensive Dx tests are costly
Study participants were evaluated to rule out other causes of their abnormal liver tests, with extensive laboratory tests and an ultrasound evaluation of the liver. Such extensive testing may be cost prohibitive in some situations.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analysis. Lancet. 2010;376:1916-1922.
2. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med. 2008;75:721-728.
3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231.
4. Adams LA, LympJ F, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113-121.
5. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595-602.
6. Targher G, Day CP, Bonora E. Risk of cardiovascular diseases in patients with nonalcoholic fatty liver. N Engl J Med. 2010;363:1341-1350.
7. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121-129.
8. Angelico F, Burattin M, Alessandri C, et al. Drugs improving insulin resistance for nonalcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007;(1):CD005166.-
9. Hyogo H, Tazuma S, Arihiro K, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism. 2008;57:1711-1718.
10. Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis. 2007;16:39-46.
11. Rzouq FS, Volk ML, Hatoum HH, et al. Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians. Am J Med Sci. 2010;340:89-93.
Treat patients with hyperlipidemia and presumed nonalcoholic fatty liver disease with atorvastatin to reduce the risk of cardiovascular events.1
STRENGTH OF RECOMMENDATION
B: Based on a single prospective randomized controlled trial (RCT).
Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analysis. Lancet. 2010; 376:1916-1922.
ILLUSTRATIVE CASE
An obese 58-year-old man with type 2 diabetes comes to your office for follow-up. His low-density lipoprotein cholesterol (LDL-C) is 130 mg/dL; triglycerides, 300 mg/dL; alanine transaminase (ALT), 110 units/L; and aspartate transaminase (AST), 120 units/L. The patient’s work-up for chronic hepatitis B and C, autoimmune hepatitis, hemochromatosis, and Wilson’s disease are negative, and you rule out alcohol misuse based on his medical history. An ultrasound of the patient’s liver reveals hepatic steatosis, and you diagnose nonalcoholic fatty liver disease (NAFLD). Should you start him on a statin?
Patients with central obesity, diabetes, hypertension, hyperlipidemia, and metabolic syndrome are at high risk of developing NAFLD. These conditions have increased in prevalence, and NAFLD is now the most common cause of liver disease in the United States.2 In Western industrialized countries, approximately 30% of the general population and 70% to 90% of patients with diabetes will develop NAFLD.3 Although most patients are asymptomatic, their liver enzymes are elevated. To diagnose NAFLD, it is necessary to rule out alcoholic hepatitis with a medical history, and viral hepatitis, hereditary hemochromatosis, Wilson’s disease, and autoimmune hepatitis with laboratory testing. Ultrasound reveals fat accumulation in the liver.
Treatment for NAFLD has little evidence of benefit
Patients with NAFLD have a much higher mortality rate than that of the general public, primarily because of cardiovascular disease.4-6 Increased physical activity and weight loss is the only therapy that has solid evidence of a benefit,7 although other treatments, such as insulin-sensitizing drugs (metformin or pioglitazone), may be beneficial.8 Surprisingly, atorvastatin has been found to reduce aminotransferase levels in patients with NAFLD,9,10 but clinicians are often concerned about prescribing a statin for patients with elevated liver enzymes. In one study, 50% of primary care physicians said they would not prescribe statins for patients whose liver enzymes are 1.5× the upper limit of normal (ULN).11
STUDY SUMMARY: Statins lower risk of cardiovascular morbidity and mortality
The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study was a randomized, prospective open-label, intention-to-treat trial involving 1600 patients. All had established coronary heart disease (CHD), were younger than 75 years, and had triglycerides <400 mg/dL and LDL-C >100 mg/dL. The study reviewed here—evaluating the risk-to-benefit ratio of using a statin to treat hyperlipidemia in patients with NAFLD—was a post hoc analysis of the GREACE study.1
Participants were randomized to either usual care or structured care with atorvastatin, starting at 10 mg/d and adjusted to 80 mg/d to bring the LDL-C level below 100 mg/dL. In the usual care group, treatment included lifestyle changes plus necessary drug treatments (only 30% of those in the usual care group received hyperlipidemia drugs). Patients were followed after medication dose titration, then every 6 months for 3 years. Serum ALT and AST were measured at baseline, at 6 weeks, and every 6 months.
At baseline, mild-to-moderate increases (<3× ULN) in ALT/AST were noted in 437 of the 1600 patients. For these patients, alcoholic hepatitis, chronic hepatitis B and C, Wilson’s disease, and autoimmune hepatitis were excluded by history, laboratory tests, and ultrasound, and the elevated liver enzymes were attributed to NAFLD.
The primary endpoints were the first occurrence of any cardiovascular event, including nonfatal myocardial infarction, revascularization, unstable angina, heart failure, and stroke; all-cause mortality; and CHD mortality. The relative risk (RR) for such events was calculated for the 437 patients with elevated liver enzymes, compared with that of patients without abnormal liver tests. Elevated liver enzymes and liver-related adverse events were secondary endpoints.
A cardiovascular event occurred in 10% (22/227) of the patients with elevated liver enzymes who received a statin, and 30% (63/210) of patients who had elevated liver enzymes but did not receive a statin.
There were 3.2 events per 100 patient-years in the atorvastatin group, compared with 10 events per 100 patient-years in those not on atorvastatin, a 68% reduction in RR (P<.0001) and an NNT of 15 per year to prevent one cardiovascular event. The risk reduction in cardiovascular events was greater in patients with NAFLD (68%) than in patients with normal liver tests (39%).
An added benefit was the reduction in ALT/AST levels during treatment for patients with NAFLD who were taking a statin, an average decrease of 47% in AST levels and 35% in ALT levels. In addition, 89% of the patients in the statin group had normal ALT, AST, and gamma-glutamyl transferase levels by the end of the 3-year follow-up. Patients with NAFLD who did not receive statins had a 12% increase in AST and ALT by the end of the 3-year study.
Only 10 of 880 patients taking statins developed liver enzymes more than 3× ULN. In 3 of these patients, dose adjustments brought the liver enzymes back to normal. Only 7 (<1%) patients who received a statin had to discontinue therapy because of liver-related adverse effects.
WHAT’S NEW: Liver enzymes improve, with few adverse effects
Preliminary studies have shown an improvement in liver enzymes in patients with NAFLD treated with a statin.9,10 This is the first study to show survival benefits and significant reduction in major cardiovascular morbidity for such patients, as well.
This is also the first large-scale study that shows that treating NAFLD patients with a statin decreases liver enzyme levels, with minimal adverse effects.
CAVEATS: Differences in groups, few women could skew results
This study cannot be considered the final word on this topic. Patients in the “structured care” group were followed at a university clinic, while those in the “usual care” group were followed by either a family physician or a cardiologist outside the hospital, based on their choice. There may have been other differences in the care received by the 2 groups that could account for the difference in mortality and morbidity reduction.
In addition, study participants had coronary artery disease, and atorvastatin was not used for primary prevention. Moreover, nearly 80% of the study participants were male, which raises the question of generalizability. And this study was a post hoc analysis of the larger GREACE study, which also raises concerns about the validity of findings.
In the absence of a larger prospective RCT, however, this is the best available evidence to support the use of statins in this population, and suggests that treating patients with NAFLD with statins is safe and effective.
CHALLENGES TO IMPLEMENTATION: Extensive Dx tests are costly
Study participants were evaluated to rule out other causes of their abnormal liver tests, with extensive laboratory tests and an ultrasound evaluation of the liver. Such extensive testing may be cost prohibitive in some situations.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
Treat patients with hyperlipidemia and presumed nonalcoholic fatty liver disease with atorvastatin to reduce the risk of cardiovascular events.1
STRENGTH OF RECOMMENDATION
B: Based on a single prospective randomized controlled trial (RCT).
Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analysis. Lancet. 2010; 376:1916-1922.
ILLUSTRATIVE CASE
An obese 58-year-old man with type 2 diabetes comes to your office for follow-up. His low-density lipoprotein cholesterol (LDL-C) is 130 mg/dL; triglycerides, 300 mg/dL; alanine transaminase (ALT), 110 units/L; and aspartate transaminase (AST), 120 units/L. The patient’s work-up for chronic hepatitis B and C, autoimmune hepatitis, hemochromatosis, and Wilson’s disease are negative, and you rule out alcohol misuse based on his medical history. An ultrasound of the patient’s liver reveals hepatic steatosis, and you diagnose nonalcoholic fatty liver disease (NAFLD). Should you start him on a statin?
Patients with central obesity, diabetes, hypertension, hyperlipidemia, and metabolic syndrome are at high risk of developing NAFLD. These conditions have increased in prevalence, and NAFLD is now the most common cause of liver disease in the United States.2 In Western industrialized countries, approximately 30% of the general population and 70% to 90% of patients with diabetes will develop NAFLD.3 Although most patients are asymptomatic, their liver enzymes are elevated. To diagnose NAFLD, it is necessary to rule out alcoholic hepatitis with a medical history, and viral hepatitis, hereditary hemochromatosis, Wilson’s disease, and autoimmune hepatitis with laboratory testing. Ultrasound reveals fat accumulation in the liver.
Treatment for NAFLD has little evidence of benefit
Patients with NAFLD have a much higher mortality rate than that of the general public, primarily because of cardiovascular disease.4-6 Increased physical activity and weight loss is the only therapy that has solid evidence of a benefit,7 although other treatments, such as insulin-sensitizing drugs (metformin or pioglitazone), may be beneficial.8 Surprisingly, atorvastatin has been found to reduce aminotransferase levels in patients with NAFLD,9,10 but clinicians are often concerned about prescribing a statin for patients with elevated liver enzymes. In one study, 50% of primary care physicians said they would not prescribe statins for patients whose liver enzymes are 1.5× the upper limit of normal (ULN).11
STUDY SUMMARY: Statins lower risk of cardiovascular morbidity and mortality
The Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study was a randomized, prospective open-label, intention-to-treat trial involving 1600 patients. All had established coronary heart disease (CHD), were younger than 75 years, and had triglycerides <400 mg/dL and LDL-C >100 mg/dL. The study reviewed here—evaluating the risk-to-benefit ratio of using a statin to treat hyperlipidemia in patients with NAFLD—was a post hoc analysis of the GREACE study.1
Participants were randomized to either usual care or structured care with atorvastatin, starting at 10 mg/d and adjusted to 80 mg/d to bring the LDL-C level below 100 mg/dL. In the usual care group, treatment included lifestyle changes plus necessary drug treatments (only 30% of those in the usual care group received hyperlipidemia drugs). Patients were followed after medication dose titration, then every 6 months for 3 years. Serum ALT and AST were measured at baseline, at 6 weeks, and every 6 months.
At baseline, mild-to-moderate increases (<3× ULN) in ALT/AST were noted in 437 of the 1600 patients. For these patients, alcoholic hepatitis, chronic hepatitis B and C, Wilson’s disease, and autoimmune hepatitis were excluded by history, laboratory tests, and ultrasound, and the elevated liver enzymes were attributed to NAFLD.
The primary endpoints were the first occurrence of any cardiovascular event, including nonfatal myocardial infarction, revascularization, unstable angina, heart failure, and stroke; all-cause mortality; and CHD mortality. The relative risk (RR) for such events was calculated for the 437 patients with elevated liver enzymes, compared with that of patients without abnormal liver tests. Elevated liver enzymes and liver-related adverse events were secondary endpoints.
A cardiovascular event occurred in 10% (22/227) of the patients with elevated liver enzymes who received a statin, and 30% (63/210) of patients who had elevated liver enzymes but did not receive a statin.
There were 3.2 events per 100 patient-years in the atorvastatin group, compared with 10 events per 100 patient-years in those not on atorvastatin, a 68% reduction in RR (P<.0001) and an NNT of 15 per year to prevent one cardiovascular event. The risk reduction in cardiovascular events was greater in patients with NAFLD (68%) than in patients with normal liver tests (39%).
An added benefit was the reduction in ALT/AST levels during treatment for patients with NAFLD who were taking a statin, an average decrease of 47% in AST levels and 35% in ALT levels. In addition, 89% of the patients in the statin group had normal ALT, AST, and gamma-glutamyl transferase levels by the end of the 3-year follow-up. Patients with NAFLD who did not receive statins had a 12% increase in AST and ALT by the end of the 3-year study.
Only 10 of 880 patients taking statins developed liver enzymes more than 3× ULN. In 3 of these patients, dose adjustments brought the liver enzymes back to normal. Only 7 (<1%) patients who received a statin had to discontinue therapy because of liver-related adverse effects.
WHAT’S NEW: Liver enzymes improve, with few adverse effects
Preliminary studies have shown an improvement in liver enzymes in patients with NAFLD treated with a statin.9,10 This is the first study to show survival benefits and significant reduction in major cardiovascular morbidity for such patients, as well.
This is also the first large-scale study that shows that treating NAFLD patients with a statin decreases liver enzyme levels, with minimal adverse effects.
CAVEATS: Differences in groups, few women could skew results
This study cannot be considered the final word on this topic. Patients in the “structured care” group were followed at a university clinic, while those in the “usual care” group were followed by either a family physician or a cardiologist outside the hospital, based on their choice. There may have been other differences in the care received by the 2 groups that could account for the difference in mortality and morbidity reduction.
In addition, study participants had coronary artery disease, and atorvastatin was not used for primary prevention. Moreover, nearly 80% of the study participants were male, which raises the question of generalizability. And this study was a post hoc analysis of the larger GREACE study, which also raises concerns about the validity of findings.
In the absence of a larger prospective RCT, however, this is the best available evidence to support the use of statins in this population, and suggests that treating patients with NAFLD with statins is safe and effective.
CHALLENGES TO IMPLEMENTATION: Extensive Dx tests are costly
Study participants were evaluated to rule out other causes of their abnormal liver tests, with extensive laboratory tests and an ultrasound evaluation of the liver. Such extensive testing may be cost prohibitive in some situations.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analysis. Lancet. 2010;376:1916-1922.
2. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med. 2008;75:721-728.
3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231.
4. Adams LA, LympJ F, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113-121.
5. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595-602.
6. Targher G, Day CP, Bonora E. Risk of cardiovascular diseases in patients with nonalcoholic fatty liver. N Engl J Med. 2010;363:1341-1350.
7. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121-129.
8. Angelico F, Burattin M, Alessandri C, et al. Drugs improving insulin resistance for nonalcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007;(1):CD005166.-
9. Hyogo H, Tazuma S, Arihiro K, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism. 2008;57:1711-1718.
10. Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis. 2007;16:39-46.
11. Rzouq FS, Volk ML, Hatoum HH, et al. Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians. Am J Med Sci. 2010;340:89-93.
1. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post hoc analysis. Lancet. 2010;376:1916-1922.
2. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med. 2008;75:721-728.
3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231.
4. Adams LA, LympJ F, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113-121.
5. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595-602.
6. Targher G, Day CP, Bonora E. Risk of cardiovascular diseases in patients with nonalcoholic fatty liver. N Engl J Med. 2010;363:1341-1350.
7. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121-129.
8. Angelico F, Burattin M, Alessandri C, et al. Drugs improving insulin resistance for nonalcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007;(1):CD005166.-
9. Hyogo H, Tazuma S, Arihiro K, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism. 2008;57:1711-1718.
10. Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis. 2007;16:39-46.
11. Rzouq FS, Volk ML, Hatoum HH, et al. Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians. Am J Med Sci. 2010;340:89-93.
Copyright © 2011 The Family Physicians Inquiries Network.
All rights reserved.
Screen teens for depression—it’s quicker than you think
Use this 2-question tool to screen adolescent patients for major depression during routine visits.1
STRENGTH OF RECOMMENDATION
B: Based on a single cohort study against gold standard; consistent with studies in other populations.
Richardson LP, Rockhill C, Russo JE, et al. Evaluation of the PHQ-2 as a brief screen for detecting major depression among adolescents. Pediatrics. 2010;125:e1097-e1103.
ILLUSTRATIVE CASE
A mother brings in her 14-year-old daughter for a routine check-up. The girl has no chronic medical problems and an unremarkable physical exam. When you’re alone with your patient, you inquire about substance abuse and sexual activity. She denies both. What questions would you ask to screen for depression?
Estimates of the prevalence of adolescent depression range from 3% to 9%,2-4 and nearly 20% of teens will experience a depressive disorder before the age of 20.2 But less than half of depressed adolescents are diagnosed or treated.2
Depressed teens face multiple risks
Teens with depressive disorders are at elevated risk, not only for poor family and social relationships and difficulties at school, but also for early pregnancy, substance abuse, hospitalization, recurrent episodes of depression, and suicide.2,4 Thirteen percent of adolescents have seriously contemplated suicide, and 6.3% have made a suicide attempt in the previous 12 months.5
The US Preventive Services Task Force (USPSTF) recommends screening all adolescents for depression—provided that effective treatments and counseling are available for those who need it.6 Nearly all primary care clinicians agree that it is important to screen for adolescent depression, yet many feel hindered by both a lack of training and time constraints.2 The study by Richardson et al1 shows that targeted screening can be effective, even when time is tight.
STUDY SUMMARY: 2-question screen is fairly accurate
The Patient Health Questionnaire (PHQ)-9 is a simple and reasonably accurate test for depression in adults.7 A much shorter version, using only the first 2 of the PHQ-9’s questions, is an effective screening tool for adults.8 Richardson et al evaluated this brief screen—the PHQ-2—for adolescent depression.1
The researchers invited 4000 teens (ages 13-17) who had seen a clinician within the previous 12 months to participate in a mailed survey, with parental or guardian approval. The survey included questions about age, gender, height, weight, sedentary and functional behaviors, and overall health, as well as depressive symptoms identified with the PHQ-2. This simple screen asks patients to rate how often in the past 2 weeks they have had:
1) a depressed mood, and/or
2) a lack of pleasure in usual activities.
Each question is scored from 0 to 3, with 0=not at all, and 3=nearly every day.
Next, the authors randomly selected 271 respondents with scores of ≥3 and 228 respondents with scores <3, matched for age and gender. Of those, 89% (n=444) participated in a longer telephone interview, which included the PHQ-9 and the Diagnostic Interview Schedule for Children (DISC-IV). Participants were predominantly female (60%), Caucasian (71%), and from urban areas (83%), with a mean household income of $57,442.
Compared with the DISC-IV—which the researchers considered the gold standard—the PHQ-2 had a sensitivity of 74% and a specificity of 75% at a cut point score ≥3; the sensitivity and specificity were 96% and 82%, respectively, for detecting young people who met the criteria for major depression on the PHQ-9. The area under the receiver operating curve was 0.84 (95% confidence interval, 0.75-0.92), meaning that the PHQ-2 correctly classified 84% of the participants as depressed or not depressed.
PHQ-2 helps identify related symptoms
Most of those with false-positive screens had other mental health problems. These included depressive symptoms that did not meet the criteria for major depression, an episode of major depression within the past year (but not in the last month), significant psychosocial impairment, and clinically significant anxiety symptoms.
WHAT’S NEW: Screening can be quick
Prior to this study, most validated tools for depression screening of adolescents were relatively time-consuming, and not likely to be performed during routine visits. The PHQ-2 is a reasonably accurate screen that requires minimal time (and minimal training).
CAVEATS: Study assessed a homogenous group
This study included mostly white girls from urban areas, relatively few of whom had public insurance. Whether the results are applicable to teens from different backgrounds is unclear. While the accuracy of the PHQ-2 was not perfect, almost 95% of those with a positive screen had some psychological problems.
CHALLENGES TO IMPLEMENTATION: Physicians may lack psych resources
Routinely using a 2-question screen for adolescent depression is unlikely to interfere with workflow in most practices. However, the USPSTF recommends screening teens only when there are systems in place to ensure accurate diagnosis, psychotherapy, and follow-up. Unfortunately, not all clinicians are adequately trained to diagnose or treat depressed teens, and some may lack access to appropriate psychotherapy referrals or consultation.
Despite the benefit of medications such as selective serotonin reuptake inhibitors (SSRIs) for teens with major depression, the antidepressants carry some risk. The black box warning for suicidality among adolescents treated with SSRIs9 necessitates accurate diagnosis, informed consent, and appropriate follow-up with clinicians who are comfortable treating adolescents.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Richardson LP, Rockhill C, Russo JE, et al. Evaluation of the PHQ-2 as a brief screen for detecting major depression among adolescents. Pediatrics. 2010;125:e1097-e1103.
2. Zuckerbrot RA, Maxon L, Pagar D, et al. Adolescent depression screening in primary care: feasibility and acceptability. Pediatrics. 2007;119:101-108.
3. Williams SB, O’Connor EA, Eder M, et al. Screening for child and adolescent depression in primary care settings: a systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2009;123:e716-e735.
4. Bhatia SK, Bhatia SC. Childhood and adolescent depression. Am Fam Physician. 2007;75:73-80.
5. Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance-United States, 2009. MMWR Surveill Summ. 2010;59:1-142.
6. U.S. Preventive Services Task Force. Screening and treatment for major depressive disorder in children and adolescents: US Preventive Services Task Force Recommendation Statement. Pediatrics 2009;123:1223-1228.
7. Williams JW, Jr, Noel PH, Cordes JA, et al. Is this patient clinically depressed? JAMA. 2002;287:1160-1170.
8. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41:1284-1292.
9. US Food and Drug Administration. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096273.htm. Accessed October 19, 2010.
Use this 2-question tool to screen adolescent patients for major depression during routine visits.1
STRENGTH OF RECOMMENDATION
B: Based on a single cohort study against gold standard; consistent with studies in other populations.
Richardson LP, Rockhill C, Russo JE, et al. Evaluation of the PHQ-2 as a brief screen for detecting major depression among adolescents. Pediatrics. 2010;125:e1097-e1103.
ILLUSTRATIVE CASE
A mother brings in her 14-year-old daughter for a routine check-up. The girl has no chronic medical problems and an unremarkable physical exam. When you’re alone with your patient, you inquire about substance abuse and sexual activity. She denies both. What questions would you ask to screen for depression?
Estimates of the prevalence of adolescent depression range from 3% to 9%,2-4 and nearly 20% of teens will experience a depressive disorder before the age of 20.2 But less than half of depressed adolescents are diagnosed or treated.2
Depressed teens face multiple risks
Teens with depressive disorders are at elevated risk, not only for poor family and social relationships and difficulties at school, but also for early pregnancy, substance abuse, hospitalization, recurrent episodes of depression, and suicide.2,4 Thirteen percent of adolescents have seriously contemplated suicide, and 6.3% have made a suicide attempt in the previous 12 months.5
The US Preventive Services Task Force (USPSTF) recommends screening all adolescents for depression—provided that effective treatments and counseling are available for those who need it.6 Nearly all primary care clinicians agree that it is important to screen for adolescent depression, yet many feel hindered by both a lack of training and time constraints.2 The study by Richardson et al1 shows that targeted screening can be effective, even when time is tight.
STUDY SUMMARY: 2-question screen is fairly accurate
The Patient Health Questionnaire (PHQ)-9 is a simple and reasonably accurate test for depression in adults.7 A much shorter version, using only the first 2 of the PHQ-9’s questions, is an effective screening tool for adults.8 Richardson et al evaluated this brief screen—the PHQ-2—for adolescent depression.1
The researchers invited 4000 teens (ages 13-17) who had seen a clinician within the previous 12 months to participate in a mailed survey, with parental or guardian approval. The survey included questions about age, gender, height, weight, sedentary and functional behaviors, and overall health, as well as depressive symptoms identified with the PHQ-2. This simple screen asks patients to rate how often in the past 2 weeks they have had:
1) a depressed mood, and/or
2) a lack of pleasure in usual activities.
Each question is scored from 0 to 3, with 0=not at all, and 3=nearly every day.
Next, the authors randomly selected 271 respondents with scores of ≥3 and 228 respondents with scores <3, matched for age and gender. Of those, 89% (n=444) participated in a longer telephone interview, which included the PHQ-9 and the Diagnostic Interview Schedule for Children (DISC-IV). Participants were predominantly female (60%), Caucasian (71%), and from urban areas (83%), with a mean household income of $57,442.
Compared with the DISC-IV—which the researchers considered the gold standard—the PHQ-2 had a sensitivity of 74% and a specificity of 75% at a cut point score ≥3; the sensitivity and specificity were 96% and 82%, respectively, for detecting young people who met the criteria for major depression on the PHQ-9. The area under the receiver operating curve was 0.84 (95% confidence interval, 0.75-0.92), meaning that the PHQ-2 correctly classified 84% of the participants as depressed or not depressed.
PHQ-2 helps identify related symptoms
Most of those with false-positive screens had other mental health problems. These included depressive symptoms that did not meet the criteria for major depression, an episode of major depression within the past year (but not in the last month), significant psychosocial impairment, and clinically significant anxiety symptoms.
WHAT’S NEW: Screening can be quick
Prior to this study, most validated tools for depression screening of adolescents were relatively time-consuming, and not likely to be performed during routine visits. The PHQ-2 is a reasonably accurate screen that requires minimal time (and minimal training).
CAVEATS: Study assessed a homogenous group
This study included mostly white girls from urban areas, relatively few of whom had public insurance. Whether the results are applicable to teens from different backgrounds is unclear. While the accuracy of the PHQ-2 was not perfect, almost 95% of those with a positive screen had some psychological problems.
CHALLENGES TO IMPLEMENTATION: Physicians may lack psych resources
Routinely using a 2-question screen for adolescent depression is unlikely to interfere with workflow in most practices. However, the USPSTF recommends screening teens only when there are systems in place to ensure accurate diagnosis, psychotherapy, and follow-up. Unfortunately, not all clinicians are adequately trained to diagnose or treat depressed teens, and some may lack access to appropriate psychotherapy referrals or consultation.
Despite the benefit of medications such as selective serotonin reuptake inhibitors (SSRIs) for teens with major depression, the antidepressants carry some risk. The black box warning for suicidality among adolescents treated with SSRIs9 necessitates accurate diagnosis, informed consent, and appropriate follow-up with clinicians who are comfortable treating adolescents.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
Use this 2-question tool to screen adolescent patients for major depression during routine visits.1
STRENGTH OF RECOMMENDATION
B: Based on a single cohort study against gold standard; consistent with studies in other populations.
Richardson LP, Rockhill C, Russo JE, et al. Evaluation of the PHQ-2 as a brief screen for detecting major depression among adolescents. Pediatrics. 2010;125:e1097-e1103.
ILLUSTRATIVE CASE
A mother brings in her 14-year-old daughter for a routine check-up. The girl has no chronic medical problems and an unremarkable physical exam. When you’re alone with your patient, you inquire about substance abuse and sexual activity. She denies both. What questions would you ask to screen for depression?
Estimates of the prevalence of adolescent depression range from 3% to 9%,2-4 and nearly 20% of teens will experience a depressive disorder before the age of 20.2 But less than half of depressed adolescents are diagnosed or treated.2
Depressed teens face multiple risks
Teens with depressive disorders are at elevated risk, not only for poor family and social relationships and difficulties at school, but also for early pregnancy, substance abuse, hospitalization, recurrent episodes of depression, and suicide.2,4 Thirteen percent of adolescents have seriously contemplated suicide, and 6.3% have made a suicide attempt in the previous 12 months.5
The US Preventive Services Task Force (USPSTF) recommends screening all adolescents for depression—provided that effective treatments and counseling are available for those who need it.6 Nearly all primary care clinicians agree that it is important to screen for adolescent depression, yet many feel hindered by both a lack of training and time constraints.2 The study by Richardson et al1 shows that targeted screening can be effective, even when time is tight.
STUDY SUMMARY: 2-question screen is fairly accurate
The Patient Health Questionnaire (PHQ)-9 is a simple and reasonably accurate test for depression in adults.7 A much shorter version, using only the first 2 of the PHQ-9’s questions, is an effective screening tool for adults.8 Richardson et al evaluated this brief screen—the PHQ-2—for adolescent depression.1
The researchers invited 4000 teens (ages 13-17) who had seen a clinician within the previous 12 months to participate in a mailed survey, with parental or guardian approval. The survey included questions about age, gender, height, weight, sedentary and functional behaviors, and overall health, as well as depressive symptoms identified with the PHQ-2. This simple screen asks patients to rate how often in the past 2 weeks they have had:
1) a depressed mood, and/or
2) a lack of pleasure in usual activities.
Each question is scored from 0 to 3, with 0=not at all, and 3=nearly every day.
Next, the authors randomly selected 271 respondents with scores of ≥3 and 228 respondents with scores <3, matched for age and gender. Of those, 89% (n=444) participated in a longer telephone interview, which included the PHQ-9 and the Diagnostic Interview Schedule for Children (DISC-IV). Participants were predominantly female (60%), Caucasian (71%), and from urban areas (83%), with a mean household income of $57,442.
Compared with the DISC-IV—which the researchers considered the gold standard—the PHQ-2 had a sensitivity of 74% and a specificity of 75% at a cut point score ≥3; the sensitivity and specificity were 96% and 82%, respectively, for detecting young people who met the criteria for major depression on the PHQ-9. The area under the receiver operating curve was 0.84 (95% confidence interval, 0.75-0.92), meaning that the PHQ-2 correctly classified 84% of the participants as depressed or not depressed.
PHQ-2 helps identify related symptoms
Most of those with false-positive screens had other mental health problems. These included depressive symptoms that did not meet the criteria for major depression, an episode of major depression within the past year (but not in the last month), significant psychosocial impairment, and clinically significant anxiety symptoms.
WHAT’S NEW: Screening can be quick
Prior to this study, most validated tools for depression screening of adolescents were relatively time-consuming, and not likely to be performed during routine visits. The PHQ-2 is a reasonably accurate screen that requires minimal time (and minimal training).
CAVEATS: Study assessed a homogenous group
This study included mostly white girls from urban areas, relatively few of whom had public insurance. Whether the results are applicable to teens from different backgrounds is unclear. While the accuracy of the PHQ-2 was not perfect, almost 95% of those with a positive screen had some psychological problems.
CHALLENGES TO IMPLEMENTATION: Physicians may lack psych resources
Routinely using a 2-question screen for adolescent depression is unlikely to interfere with workflow in most practices. However, the USPSTF recommends screening teens only when there are systems in place to ensure accurate diagnosis, psychotherapy, and follow-up. Unfortunately, not all clinicians are adequately trained to diagnose or treat depressed teens, and some may lack access to appropriate psychotherapy referrals or consultation.
Despite the benefit of medications such as selective serotonin reuptake inhibitors (SSRIs) for teens with major depression, the antidepressants carry some risk. The black box warning for suicidality among adolescents treated with SSRIs9 necessitates accurate diagnosis, informed consent, and appropriate follow-up with clinicians who are comfortable treating adolescents.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Richardson LP, Rockhill C, Russo JE, et al. Evaluation of the PHQ-2 as a brief screen for detecting major depression among adolescents. Pediatrics. 2010;125:e1097-e1103.
2. Zuckerbrot RA, Maxon L, Pagar D, et al. Adolescent depression screening in primary care: feasibility and acceptability. Pediatrics. 2007;119:101-108.
3. Williams SB, O’Connor EA, Eder M, et al. Screening for child and adolescent depression in primary care settings: a systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2009;123:e716-e735.
4. Bhatia SK, Bhatia SC. Childhood and adolescent depression. Am Fam Physician. 2007;75:73-80.
5. Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance-United States, 2009. MMWR Surveill Summ. 2010;59:1-142.
6. U.S. Preventive Services Task Force. Screening and treatment for major depressive disorder in children and adolescents: US Preventive Services Task Force Recommendation Statement. Pediatrics 2009;123:1223-1228.
7. Williams JW, Jr, Noel PH, Cordes JA, et al. Is this patient clinically depressed? JAMA. 2002;287:1160-1170.
8. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41:1284-1292.
9. US Food and Drug Administration. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096273.htm. Accessed October 19, 2010.
1. Richardson LP, Rockhill C, Russo JE, et al. Evaluation of the PHQ-2 as a brief screen for detecting major depression among adolescents. Pediatrics. 2010;125:e1097-e1103.
2. Zuckerbrot RA, Maxon L, Pagar D, et al. Adolescent depression screening in primary care: feasibility and acceptability. Pediatrics. 2007;119:101-108.
3. Williams SB, O’Connor EA, Eder M, et al. Screening for child and adolescent depression in primary care settings: a systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2009;123:e716-e735.
4. Bhatia SK, Bhatia SC. Childhood and adolescent depression. Am Fam Physician. 2007;75:73-80.
5. Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance-United States, 2009. MMWR Surveill Summ. 2010;59:1-142.
6. U.S. Preventive Services Task Force. Screening and treatment for major depressive disorder in children and adolescents: US Preventive Services Task Force Recommendation Statement. Pediatrics 2009;123:1223-1228.
7. Williams JW, Jr, Noel PH, Cordes JA, et al. Is this patient clinically depressed? JAMA. 2002;287:1160-1170.
8. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003;41:1284-1292.
9. US Food and Drug Administration. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096273.htm. Accessed October 19, 2010.
Copyright © 2010 The Family Physicians Inquiries Network.
All rights reserved.
Treating UTIs in reproductive-age women—Proceed with caution
Nitrofurantoin and sulfonamides may cause major birth defects and should be used with caution—if at all—in women of reproductive age.1
Strength of Recommendation
B: Population-based case-control study
1. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163:978-985.
Illustrative case
A 24-year-old woman comes to your clinic because of frequent urination for the past 2 to 3 days. She is not taking any medication, but does take a daily prenatal vitamin because she and her husband are trying to conceive. After your examination, you order a urinalysis and perform a urine pregnancy test. The urinalysis shows bacteriuria ≥100,000 cfu/ml, and the pregnancy test is positive.
What will you prescribe to treat her urinary tract infection?
Antibacterial agents are among the most commonly used medications during pregnancy because treatment of infections is critical to both maternal and fetal well-being.1 Urinary tract infections (UTIs) are the most common medical complication during pregnancy, with Escherichia coli contributing to roughly 90% of the infections.2 Screening for and treating asymptomatic bacteriuria is also recommended during pregnancy to prevent pyelonephritis and increased maternal and fetal morbidity.3 In addition, UTIs are common in reproductive-age women who may not know they are pregnant or who become pregnant during treatment with antibiotics. And nitrofurantoin and sulfonamides are commonly prescribed antibiotics for the treatment of UTIs, both in pregnant women and women of reproductive age.
Prior warnings only address near-term pregnancy
Prior to the study detailed in this PURL, no clinical trials had reported a teratogenic risk associated with either nitrofurantoin (current pregnancy category B) or sulfonamide (current pregnancy category C).4 It is recommended, however, that both of these antibacterials be avoided in pregnant women who are near term because of the risk of hemolytic disease in patients with glucose-6-phosphate dehydrogenase deficiency associated with nitrofurantoin and the risk of kernicterus in neonates exposed to sulfamethoxazole.5
But a rise in E coli resistance to penicillins (resistance to amoxicillin, for example, can be as high as 30-40%6) has led to greater use of nitrofurantoin. The drug has been viewed as a safe and effective alternative treatment for UTIs associated with E coli.7 Indeed, nitrofurantoin has been considered to be the preferred antibiotic for bacteriuria suppression, as both ampicillin and cephalosporins can interfere with the normal gastrointestinal flora. Thus, nitrofurantoin is used extensively in pregnant women. Sulfonamides are also prescribed for pregnant women, although not as frequently.7,8
STUDY SUMMARY: First trimester use linked to many defects
The study by Crider et al1 was based on the National Birth Defects Prevention Study, an ongoing, population-based case control study of an estimated annual birth population of roughly 482,000, including cases identified by birth defects surveillance registries in 10 states.9 The researchers identified pregnancies affected by any of 30 types of birth defects from 1997 to 2003 (n=13,155). The controls (n=4941) were randomly selected from similar geographic locations, and matched for race/ethnicity, age, and prepregnancy body mass index. Exposure to antibacterials from 1 month prepregnancy through the end of the first trimester was recorded.
Crider et al interviewed all the participants up to 24 months after delivery to obtain their exposure history to penicillins, erythromycins, nitrofurantoin, sulfonamides, cephalosporins, quinolones, tetracyclines, other miscellaneous beta-lactams, aminoglycosides, antimycobacterial agents, and other antibiotics. (Exposure to antivirals, antifungals, and antiparasitic agents was not addressed.) Women who didn’t know whether they had been exposed to these agents or could not remember the timing of exposure were excluded.
Overall, antibacterial use ranged from 2% to 5.8%, and peaked in the third month of pregnancy. Penicillins were the most commonly used antibiotics. Odds ratios obtained for birth defects were adjusted for confounders such as maternal age, race, education level, prepregnancy body mass index, time from estimated date of delivery to the interview, use of folic acid or multivitamins from 1 month prior to pregnancy through the first month, and periconceptional smoking and/or alcohol use.
Nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR]=3.7; 95% confidence interval [CI], 1.1-12.2), hypoplastic left heart syndrome (AOR=4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR=1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR=2.1; 95% CI, 1.2-3.9).
Sulfonamides were associated with anencephaly (AOR=3.4; 95% CI, 1.3-8.8), hypoplastic left heart syndrome (AOR=3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR=2.7; 95% CI, 1.3-5.6), choanal atresia (AOR=8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR=2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR=2.4; 95% CI, 1.1-5.4).
Some links between other antibiotics and birth defects were also found. For example, erythromycins were associated with anencephaly and transverse limb deficiency, penicillins with intercalary limb deficiency, and cephalosporins with atrial septal defects. The authors noted, however, that these agents, which are commonly prescribed for pregnant women, were not associated with many birth defects—and that because of limited sample sizes for these drug classes, the associations may be spurious.
WHAT'S NEW: A large-scale study provides evidence of risk
Previous case studies and meta-analysis have shown no link between the use of nitrofurantoin and congenital abnormalities.8 Similarly, sulfonamides have not appeared to pose significant teratogenic risk. This is the first large-scale study evaluating the risk of birth defects associated with antibiotic use during pregnancy, and therefore provides evidence of risk not previously available.
CAVEATS: Study design raises questions of recall bias
The retrospective case-control methodology used in this study leaves open the possibility of recall bias, misclassification bias, and confounding bias. The length of time from actual exposure to data collection could affect the accuracy of participants’ memories. The data gathered were not cross-verified against medical records, and other issues, such as the possible effect of medications for other infections (eg, antivirals and antifungals), could not be measured. However, women who did not know or were unsure of their medication exposure history were excluded from the analysis, which should reduce the risk of this potential bias.
The investigators also controlled for several important sources of potential confounding bias, and the reporting rates were similar among participants in both the case and control groups. These measures provide some assurance that the outcomes are valid.
It would be unethical (and extraordinarily expensive) to conduct a prospective randomized controlled trial to confirm these findings. Case-control methodology is the most practical way to assess for the risk of birth defects, and our literature review suggests that this is the most rigorous study to date. In our view, the potential harm from continuing to use these antibiotics for pregnant women and women who may become pregnant far outweighs the risk that these findings may be erroneous.
That said, a final caveat is the fact that even a several-fold increase in the risk of a rare major birth defect such as those reported in this study is still a rare risk. There may be clinical situations in which the benefits of using nitrofurantoin or sulfonamides in women who are or may become pregnant outweigh the potential risks.
CHALLENGES TO IMPLEMENTATION: Finding an alternative treatment
The main challenge to implementing this new recommendation lies in choosing alternative antibiotics with which to treat UTIs in reproductive-age women and bacteriuria in pregnancy. Obtaining a pregnancy test in sexually active patients of reproductive age who are not using a reliable form of contraception seems like a prudent first step.
If the pregnancy test is positive, cephalexin should be a good initial choice until the results of culture and sensitivities are available. In the event of Enterococcus infection (for which cephalosporins are not active) or other organisms resistant to cephalosporins, the sensitivity results should provide guidance.3
Acknowledgment
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant was a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163:978-985.
2. Gilstrap LC, 3rd, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol. 2001;28:581-591.
3. Macejko AM, Schaeffer AJ. Asymptomatic bacteriuria and symptomatic urinary tract infections during pregnancy. Urol Clin North Am. 2007;34:35-42.
4. Thomson Reuters (Healthcare). Micromedex® Healthcare Series Intranet. 5.1.
5. Czeizel AE, Rockenbauer M, Olsen J. Use of antibiotics during pregnancy. Eur J Obstet Gynecol Reprod Biol. 1998;81:1-8.
6. ABXguide. Urinary tract infections in pregnancy. Available at: http://prod.hopkins-abxguide.org/diagnosis/genitourinary/urinary_tract_infections_in_pregnancy.html?contentInstanceId=255490. Accessed February 15, 2010.
7. Huang ES, Stafford RS. National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Arch Intern Med. 2002;162:41-47.
8. Shrim A, Garcia-Bournissen F, Koren G. Pharmaceutical agents and pregnancy in urology practice. Urol Clin North Am. 2007;34:27-33.
9. Yoon PW, Rasmussen SA, Lynberg MC, et al. The National Birth Defects Prevention Study. Public Health Rep. 2001;116(suppl 1):32-40.
Nitrofurantoin and sulfonamides may cause major birth defects and should be used with caution—if at all—in women of reproductive age.1
Strength of Recommendation
B: Population-based case-control study
1. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163:978-985.
Illustrative case
A 24-year-old woman comes to your clinic because of frequent urination for the past 2 to 3 days. She is not taking any medication, but does take a daily prenatal vitamin because she and her husband are trying to conceive. After your examination, you order a urinalysis and perform a urine pregnancy test. The urinalysis shows bacteriuria ≥100,000 cfu/ml, and the pregnancy test is positive.
What will you prescribe to treat her urinary tract infection?
Antibacterial agents are among the most commonly used medications during pregnancy because treatment of infections is critical to both maternal and fetal well-being.1 Urinary tract infections (UTIs) are the most common medical complication during pregnancy, with Escherichia coli contributing to roughly 90% of the infections.2 Screening for and treating asymptomatic bacteriuria is also recommended during pregnancy to prevent pyelonephritis and increased maternal and fetal morbidity.3 In addition, UTIs are common in reproductive-age women who may not know they are pregnant or who become pregnant during treatment with antibiotics. And nitrofurantoin and sulfonamides are commonly prescribed antibiotics for the treatment of UTIs, both in pregnant women and women of reproductive age.
Prior warnings only address near-term pregnancy
Prior to the study detailed in this PURL, no clinical trials had reported a teratogenic risk associated with either nitrofurantoin (current pregnancy category B) or sulfonamide (current pregnancy category C).4 It is recommended, however, that both of these antibacterials be avoided in pregnant women who are near term because of the risk of hemolytic disease in patients with glucose-6-phosphate dehydrogenase deficiency associated with nitrofurantoin and the risk of kernicterus in neonates exposed to sulfamethoxazole.5
But a rise in E coli resistance to penicillins (resistance to amoxicillin, for example, can be as high as 30-40%6) has led to greater use of nitrofurantoin. The drug has been viewed as a safe and effective alternative treatment for UTIs associated with E coli.7 Indeed, nitrofurantoin has been considered to be the preferred antibiotic for bacteriuria suppression, as both ampicillin and cephalosporins can interfere with the normal gastrointestinal flora. Thus, nitrofurantoin is used extensively in pregnant women. Sulfonamides are also prescribed for pregnant women, although not as frequently.7,8
STUDY SUMMARY: First trimester use linked to many defects
The study by Crider et al1 was based on the National Birth Defects Prevention Study, an ongoing, population-based case control study of an estimated annual birth population of roughly 482,000, including cases identified by birth defects surveillance registries in 10 states.9 The researchers identified pregnancies affected by any of 30 types of birth defects from 1997 to 2003 (n=13,155). The controls (n=4941) were randomly selected from similar geographic locations, and matched for race/ethnicity, age, and prepregnancy body mass index. Exposure to antibacterials from 1 month prepregnancy through the end of the first trimester was recorded.
Crider et al interviewed all the participants up to 24 months after delivery to obtain their exposure history to penicillins, erythromycins, nitrofurantoin, sulfonamides, cephalosporins, quinolones, tetracyclines, other miscellaneous beta-lactams, aminoglycosides, antimycobacterial agents, and other antibiotics. (Exposure to antivirals, antifungals, and antiparasitic agents was not addressed.) Women who didn’t know whether they had been exposed to these agents or could not remember the timing of exposure were excluded.
Overall, antibacterial use ranged from 2% to 5.8%, and peaked in the third month of pregnancy. Penicillins were the most commonly used antibiotics. Odds ratios obtained for birth defects were adjusted for confounders such as maternal age, race, education level, prepregnancy body mass index, time from estimated date of delivery to the interview, use of folic acid or multivitamins from 1 month prior to pregnancy through the first month, and periconceptional smoking and/or alcohol use.
Nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR]=3.7; 95% confidence interval [CI], 1.1-12.2), hypoplastic left heart syndrome (AOR=4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR=1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR=2.1; 95% CI, 1.2-3.9).
Sulfonamides were associated with anencephaly (AOR=3.4; 95% CI, 1.3-8.8), hypoplastic left heart syndrome (AOR=3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR=2.7; 95% CI, 1.3-5.6), choanal atresia (AOR=8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR=2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR=2.4; 95% CI, 1.1-5.4).
Some links between other antibiotics and birth defects were also found. For example, erythromycins were associated with anencephaly and transverse limb deficiency, penicillins with intercalary limb deficiency, and cephalosporins with atrial septal defects. The authors noted, however, that these agents, which are commonly prescribed for pregnant women, were not associated with many birth defects—and that because of limited sample sizes for these drug classes, the associations may be spurious.
WHAT'S NEW: A large-scale study provides evidence of risk
Previous case studies and meta-analysis have shown no link between the use of nitrofurantoin and congenital abnormalities.8 Similarly, sulfonamides have not appeared to pose significant teratogenic risk. This is the first large-scale study evaluating the risk of birth defects associated with antibiotic use during pregnancy, and therefore provides evidence of risk not previously available.
CAVEATS: Study design raises questions of recall bias
The retrospective case-control methodology used in this study leaves open the possibility of recall bias, misclassification bias, and confounding bias. The length of time from actual exposure to data collection could affect the accuracy of participants’ memories. The data gathered were not cross-verified against medical records, and other issues, such as the possible effect of medications for other infections (eg, antivirals and antifungals), could not be measured. However, women who did not know or were unsure of their medication exposure history were excluded from the analysis, which should reduce the risk of this potential bias.
The investigators also controlled for several important sources of potential confounding bias, and the reporting rates were similar among participants in both the case and control groups. These measures provide some assurance that the outcomes are valid.
It would be unethical (and extraordinarily expensive) to conduct a prospective randomized controlled trial to confirm these findings. Case-control methodology is the most practical way to assess for the risk of birth defects, and our literature review suggests that this is the most rigorous study to date. In our view, the potential harm from continuing to use these antibiotics for pregnant women and women who may become pregnant far outweighs the risk that these findings may be erroneous.
That said, a final caveat is the fact that even a several-fold increase in the risk of a rare major birth defect such as those reported in this study is still a rare risk. There may be clinical situations in which the benefits of using nitrofurantoin or sulfonamides in women who are or may become pregnant outweigh the potential risks.
CHALLENGES TO IMPLEMENTATION: Finding an alternative treatment
The main challenge to implementing this new recommendation lies in choosing alternative antibiotics with which to treat UTIs in reproductive-age women and bacteriuria in pregnancy. Obtaining a pregnancy test in sexually active patients of reproductive age who are not using a reliable form of contraception seems like a prudent first step.
If the pregnancy test is positive, cephalexin should be a good initial choice until the results of culture and sensitivities are available. In the event of Enterococcus infection (for which cephalosporins are not active) or other organisms resistant to cephalosporins, the sensitivity results should provide guidance.3
Acknowledgment
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant was a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
Nitrofurantoin and sulfonamides may cause major birth defects and should be used with caution—if at all—in women of reproductive age.1
Strength of Recommendation
B: Population-based case-control study
1. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163:978-985.
Illustrative case
A 24-year-old woman comes to your clinic because of frequent urination for the past 2 to 3 days. She is not taking any medication, but does take a daily prenatal vitamin because she and her husband are trying to conceive. After your examination, you order a urinalysis and perform a urine pregnancy test. The urinalysis shows bacteriuria ≥100,000 cfu/ml, and the pregnancy test is positive.
What will you prescribe to treat her urinary tract infection?
Antibacterial agents are among the most commonly used medications during pregnancy because treatment of infections is critical to both maternal and fetal well-being.1 Urinary tract infections (UTIs) are the most common medical complication during pregnancy, with Escherichia coli contributing to roughly 90% of the infections.2 Screening for and treating asymptomatic bacteriuria is also recommended during pregnancy to prevent pyelonephritis and increased maternal and fetal morbidity.3 In addition, UTIs are common in reproductive-age women who may not know they are pregnant or who become pregnant during treatment with antibiotics. And nitrofurantoin and sulfonamides are commonly prescribed antibiotics for the treatment of UTIs, both in pregnant women and women of reproductive age.
Prior warnings only address near-term pregnancy
Prior to the study detailed in this PURL, no clinical trials had reported a teratogenic risk associated with either nitrofurantoin (current pregnancy category B) or sulfonamide (current pregnancy category C).4 It is recommended, however, that both of these antibacterials be avoided in pregnant women who are near term because of the risk of hemolytic disease in patients with glucose-6-phosphate dehydrogenase deficiency associated with nitrofurantoin and the risk of kernicterus in neonates exposed to sulfamethoxazole.5
But a rise in E coli resistance to penicillins (resistance to amoxicillin, for example, can be as high as 30-40%6) has led to greater use of nitrofurantoin. The drug has been viewed as a safe and effective alternative treatment for UTIs associated with E coli.7 Indeed, nitrofurantoin has been considered to be the preferred antibiotic for bacteriuria suppression, as both ampicillin and cephalosporins can interfere with the normal gastrointestinal flora. Thus, nitrofurantoin is used extensively in pregnant women. Sulfonamides are also prescribed for pregnant women, although not as frequently.7,8
STUDY SUMMARY: First trimester use linked to many defects
The study by Crider et al1 was based on the National Birth Defects Prevention Study, an ongoing, population-based case control study of an estimated annual birth population of roughly 482,000, including cases identified by birth defects surveillance registries in 10 states.9 The researchers identified pregnancies affected by any of 30 types of birth defects from 1997 to 2003 (n=13,155). The controls (n=4941) were randomly selected from similar geographic locations, and matched for race/ethnicity, age, and prepregnancy body mass index. Exposure to antibacterials from 1 month prepregnancy through the end of the first trimester was recorded.
Crider et al interviewed all the participants up to 24 months after delivery to obtain their exposure history to penicillins, erythromycins, nitrofurantoin, sulfonamides, cephalosporins, quinolones, tetracyclines, other miscellaneous beta-lactams, aminoglycosides, antimycobacterial agents, and other antibiotics. (Exposure to antivirals, antifungals, and antiparasitic agents was not addressed.) Women who didn’t know whether they had been exposed to these agents or could not remember the timing of exposure were excluded.
Overall, antibacterial use ranged from 2% to 5.8%, and peaked in the third month of pregnancy. Penicillins were the most commonly used antibiotics. Odds ratios obtained for birth defects were adjusted for confounders such as maternal age, race, education level, prepregnancy body mass index, time from estimated date of delivery to the interview, use of folic acid or multivitamins from 1 month prior to pregnancy through the first month, and periconceptional smoking and/or alcohol use.
Nitrofurantoin was associated with anophthalmia or microphthalmos (adjusted odds ratio [AOR]=3.7; 95% confidence interval [CI], 1.1-12.2), hypoplastic left heart syndrome (AOR=4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR=1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR=2.1; 95% CI, 1.2-3.9).
Sulfonamides were associated with anencephaly (AOR=3.4; 95% CI, 1.3-8.8), hypoplastic left heart syndrome (AOR=3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR=2.7; 95% CI, 1.3-5.6), choanal atresia (AOR=8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR=2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR=2.4; 95% CI, 1.1-5.4).
Some links between other antibiotics and birth defects were also found. For example, erythromycins were associated with anencephaly and transverse limb deficiency, penicillins with intercalary limb deficiency, and cephalosporins with atrial septal defects. The authors noted, however, that these agents, which are commonly prescribed for pregnant women, were not associated with many birth defects—and that because of limited sample sizes for these drug classes, the associations may be spurious.
WHAT'S NEW: A large-scale study provides evidence of risk
Previous case studies and meta-analysis have shown no link between the use of nitrofurantoin and congenital abnormalities.8 Similarly, sulfonamides have not appeared to pose significant teratogenic risk. This is the first large-scale study evaluating the risk of birth defects associated with antibiotic use during pregnancy, and therefore provides evidence of risk not previously available.
CAVEATS: Study design raises questions of recall bias
The retrospective case-control methodology used in this study leaves open the possibility of recall bias, misclassification bias, and confounding bias. The length of time from actual exposure to data collection could affect the accuracy of participants’ memories. The data gathered were not cross-verified against medical records, and other issues, such as the possible effect of medications for other infections (eg, antivirals and antifungals), could not be measured. However, women who did not know or were unsure of their medication exposure history were excluded from the analysis, which should reduce the risk of this potential bias.
The investigators also controlled for several important sources of potential confounding bias, and the reporting rates were similar among participants in both the case and control groups. These measures provide some assurance that the outcomes are valid.
It would be unethical (and extraordinarily expensive) to conduct a prospective randomized controlled trial to confirm these findings. Case-control methodology is the most practical way to assess for the risk of birth defects, and our literature review suggests that this is the most rigorous study to date. In our view, the potential harm from continuing to use these antibiotics for pregnant women and women who may become pregnant far outweighs the risk that these findings may be erroneous.
That said, a final caveat is the fact that even a several-fold increase in the risk of a rare major birth defect such as those reported in this study is still a rare risk. There may be clinical situations in which the benefits of using nitrofurantoin or sulfonamides in women who are or may become pregnant outweigh the potential risks.
CHALLENGES TO IMPLEMENTATION: Finding an alternative treatment
The main challenge to implementing this new recommendation lies in choosing alternative antibiotics with which to treat UTIs in reproductive-age women and bacteriuria in pregnancy. Obtaining a pregnancy test in sexually active patients of reproductive age who are not using a reliable form of contraception seems like a prudent first step.
If the pregnancy test is positive, cephalexin should be a good initial choice until the results of culture and sensitivities are available. In the event of Enterococcus infection (for which cephalosporins are not active) or other organisms resistant to cephalosporins, the sensitivity results should provide guidance.3
Acknowledgment
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant was a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Click here to view PURL METHODOLOGY
1. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163:978-985.
2. Gilstrap LC, 3rd, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol. 2001;28:581-591.
3. Macejko AM, Schaeffer AJ. Asymptomatic bacteriuria and symptomatic urinary tract infections during pregnancy. Urol Clin North Am. 2007;34:35-42.
4. Thomson Reuters (Healthcare). Micromedex® Healthcare Series Intranet. 5.1.
5. Czeizel AE, Rockenbauer M, Olsen J. Use of antibiotics during pregnancy. Eur J Obstet Gynecol Reprod Biol. 1998;81:1-8.
6. ABXguide. Urinary tract infections in pregnancy. Available at: http://prod.hopkins-abxguide.org/diagnosis/genitourinary/urinary_tract_infections_in_pregnancy.html?contentInstanceId=255490. Accessed February 15, 2010.
7. Huang ES, Stafford RS. National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Arch Intern Med. 2002;162:41-47.
8. Shrim A, Garcia-Bournissen F, Koren G. Pharmaceutical agents and pregnancy in urology practice. Urol Clin North Am. 2007;34:27-33.
9. Yoon PW, Rasmussen SA, Lynberg MC, et al. The National Birth Defects Prevention Study. Public Health Rep. 2001;116(suppl 1):32-40.
1. Crider KS, Cleves MA, Reefhuis J, et al. Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study. Arch Pediatr Adolesc Med. 2009;163:978-985.
2. Gilstrap LC, 3rd, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol. 2001;28:581-591.
3. Macejko AM, Schaeffer AJ. Asymptomatic bacteriuria and symptomatic urinary tract infections during pregnancy. Urol Clin North Am. 2007;34:35-42.
4. Thomson Reuters (Healthcare). Micromedex® Healthcare Series Intranet. 5.1.
5. Czeizel AE, Rockenbauer M, Olsen J. Use of antibiotics during pregnancy. Eur J Obstet Gynecol Reprod Biol. 1998;81:1-8.
6. ABXguide. Urinary tract infections in pregnancy. Available at: http://prod.hopkins-abxguide.org/diagnosis/genitourinary/urinary_tract_infections_in_pregnancy.html?contentInstanceId=255490. Accessed February 15, 2010.
7. Huang ES, Stafford RS. National patterns in the treatment of urinary tract infections in women by ambulatory care physicians. Arch Intern Med. 2002;162:41-47.
8. Shrim A, Garcia-Bournissen F, Koren G. Pharmaceutical agents and pregnancy in urology practice. Urol Clin North Am. 2007;34:27-33.
9. Yoon PW, Rasmussen SA, Lynberg MC, et al. The National Birth Defects Prevention Study. Public Health Rep. 2001;116(suppl 1):32-40.
Copyright © 2010 The Family Physicians Inquiries Network.
All rights reserved.
Saline irrigation spells relief for sinusitis sufferers
ILLUSTRATIVE CASE
A 45-year-old woman presents to your office with an 8-month history of nasal congestion and thick nasal discharge. Her symptoms have waxed and waned, the patient reports. She’s tried decongestants, antibiotics, and nasal steroids, with limited success. The patient has not had a recent respiratory infection, has never had sinus surgery, and does not want to be on long-term medication. You wonder if there’s an alternative treatment you can offer.
Rhinosinusitis is one of the most common conditions seen by primary care physicians in the United States, and its incidence and prevalence are increasing.2,3 While acute rhinosinusitis is usually self-limiting and resolves within a month, some patients develop chronic—and hard to treat—sinonasal symptoms.
No single cause, no definitive treatment
We’ve moved away from the notion that chronic rhinosinusitis is always a manifestation of persistent bacterial infection, and now recognize that there’s an inflammatory, nonbacterial component.4 In any given patient, several mechanisms—acting either simultaneously or independently—may contribute to sinonasal symptoms.3
Chronic sinusitis is treated in a variety of ways, including medications, immunotherapy, and surgery. Despite their limited efficacy, antibiotics and nasal steroids have been the mainstays of treatment.5 Treating underlying allergies, when they exist, may be helpful. But regardless of which treatment patients receive for chronic rhinosinusitis, many remain symptomatic.6
Benefits of saline irrigation extend beyond postop care
Otolaryngologists recommend saline irrigation after sinus surgery to clear secretions, debris, and crusts; reduce the risk of postoperative mucosal adhesions; and expedite mucosal healing.7,8 Saline irrigation is also gaining popularity as an alternative approach to chronic sinusitis symptom relief, and several randomized controlled trials (RCTs) have demonstrated both objective and subjective efficacy of this treatment for sinonasal disease.8-11
In 2007, the Cochrane Collaboration reviewed evidence for the effectiveness of nasal saline irrigation for symptoms of chronic rhinosinusitis. The reviewers concluded that it is well tolerated and beneficial, whether used alone or as an adjunctive treatment.12
Nasal saline sprays are often recommended because they’re thought to be better tolerated than other delivery modes.13 There have, however, been no comparisons of the relative efficacy of different means of saline delivery, until now.
STUDY SUMMARY: Nasal irrigation and spray go head-to-head
This study was a high-quality, prospective RCT comparing nasal spray and nasal irrigation.1 Subjects were recruited from the general population. To be eligible, participants had to be 18 years of age or older and have reported at least one of the following chronic rhinosinusitis symptoms on 4 or more days each week in the preceding 2 weeks:
- nasal stuffiness
- nasal dryness or crusting
- nasal congestion
- thick or discolored nasal discharge.
In addition, the symptoms must have been present on at least 15 of the preceding 30 days. Exclusion criteria included recent sinus surgery, a respiratory infection within the past 2 weeks, and the use of nasal saline within the past month.
Researchers enrolled 127 patients in the study; 63 were randomized to the nasal spray group and 64 to the large-volume, low-pressure irrigation group. Demographic and baseline characteristics of the groups were similar. The average ages of those in the irrigation and spray groups were 45 and 48 years, respectively. Most patients were nonsmokers and had been symptomatic for 7 to 12 months.
Twice-daily treatment. Researchers asked the patients to perform the assigned treatment twice daily for 8 weeks, but the patients were also permitted to continue using their usual medications. Symptom severity and disease-specific quality of life were assessed with the Sino-Nasal Outcome Test (SNOT-20), a 20-item survey that measures physical problems, emotional consequences, and functional limitations of sinusitis.14
The SNOT-20 is a validated, self-administered survey that asks patients to score items such as runny nose, postnasal discharge, need to blow the nose, reduced productivity, and embarrassment, on a 0- to 5-point scale (0=never, 5=always). A SNOT-20 score of 100 indicates the worst possible symptoms.
As a measure of chronicity of symptoms, patients were also asked to estimate how many months they’d had these symptoms during the last year. In addition, they were instructed to keep a diary to document treatment compliance and the use of other medications for sinonasal symptoms.
To measure outcomes, the researchers provided patients with mail-in packets so they could send in their completed SNOT-20 questionnaire and the medication diary completed at 2, 4, and 8 weeks after randomization.
Biggest improvements seen in irrigation group
Severity of symptoms. In each outcome measurement period, the saline irrigation group had lower SNOT-20 scores than the nasal spray group. At 2 weeks, the irrigation group scores were 4.4 points lower than the spray group (P=.02); at 4 weeks, the scores were 8.2 points lower (P<.001), and at 8 weeks the scores were 6.4 points lower (P=.002). Those in the irrigation group also had a significantly greater change from baseline than the patients in the spray group at 4 weeks (16.2 vs 7.4, P=.002) and at 8 weeks (15.0 vs 8.5, P=.04). The difference was marginally significant at 2 weeks (12.2 vs 6.7, P=.05).
Frequency of symptoms. At 8 weeks, 40% of the irrigation group and 61% of the nasal spray group reported nasal or sinus symptoms “often or always.” The absolute risk reduction in symptom frequency with saline irrigations, therefore, was 0.21; 95% confidence interval, 0.02-0.38 (P=.01). The odds of frequent nasal symptoms were 50% lower in the irrigation group compared to the spray group.
WHAT’S NEW: One delivery method is better than another
Prior studies had proven the effectiveness of nasal saline for reduction of rhinosinusitis symptoms. This RCT demonstrated that large-volume, low-pressure nasal irrigation brings greater symptom relief than nasal spray.
The researchers found little difference between the 2 groups in the rate of adverse effects, and reported that nasal irrigation appears to be well accepted once patients become accustomed to it. The fact that the participants were recruited from the general population further suggests that the results will be generalizable to primary care patients.
CAVEATS: High dropout rate in irrigation group
The absence of a control group prevents us from knowing the effect of saline nasal spray or irrigation compared with no treatment. In prior studies, however, nasal saline spray was found to be more effective than placebo in reducing rhinosinusitis symptoms.8,15
It is notable that a significant portion (21%) of the irrigation group abandoned this treatment by 8 weeks; in comparison, just 7% of the nasal spray group discontinued treatment.
This lower rate of adherence makes the beneficial effects of the irrigation group even more impressive. But it also suggests that a significant portion of patients are unlikely to stay with this recommended regimen. For those who try saline irrigation and choose not to continue it or are unwilling even to try it, saline spray is a reasonable alternative.
It should be noted that financial support for this study was provided by NeilMed Pharmaceuticals, a manufacturer of nasal saline solution and irrigation devices. However, the sponsor was not involved in the design or conduct of the study, in data collection or analysis, or in the preparation of the manuscript.
CHALLENGES TO IMPLEMENTATION: Tx may “scare away” some patients
Despite its effectiveness in reducing rhinosinusitis symptoms, performing large-volume, low-pressure nasal saline irrigation is not intuitive—and may sound downright scary to some patients. The need to learn how to perform nasal irrigation effectively, overcome the fear of water in the nasal cavity, and find the time to perform irrigation regularly can be barriers to this treatment.
A little bit of coaching can go a long way
A study by Rabago et al16 found that coached practice and patient education are effective tools in mastery of the technique ( PATIENT HANDOUT ).10,17 The researchers also found that several home strategies—incorporating nasal irrigation into the daily hygiene routine, placing the materials in a convenient location, and using warm water—facilitate regular use.
There is evidence, too, that patients who successfully use large-volume, low-pressure saline irrigation gain more than symptom relief. Rabago et al also found that effective use of this technique was associated with a sense of empowerment, and led to improved self-management skills, as well as a rapid, and long-term, improvement in quality of life.16
Saline nasal irrigation Your step-by-step guide
STEP 1: GATHER THE SUPPLIES
- - Salt (kosher, canning, or pickling salt)
- - Baking soda
- - Nasal irrigation pot (available at most pharmacies)
- - Measuring spoons
- - Container with lid
OR
- - An irrigation kit that includes the device and premixed saline packets
STEP 2: PREPARE THE SOLUTION
- - Put 1 tsp salt and ½ tsp baking soda into the container.
- - Add 1 pint of lukewarm tap water.
- - Mix contents.
- - Fill the nasal pot.
STEP 3: POSITION YOUR HEAD
- - Lean over the sink; rotate your head to one side.
- - Insert the spout of the irrigation device into the uppermost nostril.
- - Breathe through your mouth.
- - Raise the handle of the nasal pot so the solution flows into the upper nostril; in a few moments, the solution will begin to drain from the lower nostril.
- - Continue until the pot is empty, then exhale gently through both nostrils and gently blow your nose.
- - Refill the nasal pot, turn your head to the opposite side, and repeat with the other nostril.
- - Do this twice a day or as directed.
STEP 4: CLEAN AND PUT AWAY THE EQUIPMENT
- - Wash the nasal pot daily with warm water and dish detergent; rinse thoroughly.
- - Store unused saline solution in the sealed container; it can be kept at room temperature and reused for 2 days.
Adapted from: University of Wisconsin Department of Family Medicine.17
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.
Click here to view PURL METHODOLOGY
1. Pynnonen MA, Mukerji SS, Kim HM, et al. Nasal saline for chronic sinonasal symptoms: a randomized controlled trial. Arch Otolaryngol Head Neck Surg. 2007;133:11115-1120.
2. Gliklich RE, Metson R. Economic implications of chronic sinusitis. Otolaryngol Head Neck Surg. 1998;118(3 Pt 1):344-349.
3. International Rhinosinusitis Advisory Board. Infectious rhinosinusitis in adults classification, etiology and management. Ear Nose Throat J. 1997;76(12 suppl):s5-s22.
4. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg. 1997;117(3 Pt 2):s1-s7.
5. Sharp HJ, Denman D, Puumala S, et al. Treatment of acute and chronic rhinosinusitis in the United States, 1999-2002. Arch Otolaryngol Head Neck Surg. 2007;133:260-265.
6. Subramanian HN, Schechtman KB, Hamilos DL. A retrospective analysis of treatment outcomes and time to relapse after intensive medical treatment for chronic sinusitis. Am J Rhinol. 2002;16:303-312.
7. Druce HM. Adjuncts to medical management of sinusitis. Otolaryngol Head Neck Surg. 1990;103(5 Pt 2):880-883.
8. Tomooka LT, Murphy C, Davidson TM. Clinical study and literature review of nasal irrigation. Laryngoscope. 2000;110:1189-1193.
9. Heatley DG, McConnell KE, Kille TL, et al. Nasal irrigation for the alleviation of sinonasal symptoms. Otolaryngol Head Neck Surg. 2001;125:44-48.
10. Rabago D, Zgierska A, Mundt M, et al. Efficacy of daily hypertonic saline nasal irrigation among patients with sinusitis: a randomized controlled trial. J Fam Pract. 2002;51:1049-1055.
11. Taccariello M, Parikh A, Darby Y, et al. Nasal douching as a valuable adjunct in the management of chronic rhinosinusitis. Rhinology. 1999;37:29-32.
12. Harvey R, Hannan SA, Badia L, Scadding G. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst Rev. 2007;(3):CD006394.-
13. Keojampa BK, Nguyen MH, Ryan MW. Effects of buffered saline solution on nasal mucociliary clearance and nasal airway patency. Otolaryngol Head Neck Surg. 2004;131:679-682.
14. Piccirillo JF, Merritt MG, Jr, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126:41-47.
15. Hauptman G, Ryan MW. The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients. Otolaryngol Head Neck Surg. 2007;137:815-821.
16. Rabago D, Barrett B, Marchand L, et al. Qualitative aspects of nasal irrigation use by patients with chronic sinus disease in a multimethod study. Ann Fam Med. 2006;4:295-301.
17. University of Wisconsin Department of Family Medicine. Nasal Irrigation Instructions. Available at: http://www.fammed.wisc.edu/files/webfm-uploads/documents/research/nasalirrigationinstructions.pdf. Accessed December 1, 2008.
ILLUSTRATIVE CASE
A 45-year-old woman presents to your office with an 8-month history of nasal congestion and thick nasal discharge. Her symptoms have waxed and waned, the patient reports. She’s tried decongestants, antibiotics, and nasal steroids, with limited success. The patient has not had a recent respiratory infection, has never had sinus surgery, and does not want to be on long-term medication. You wonder if there’s an alternative treatment you can offer.
Rhinosinusitis is one of the most common conditions seen by primary care physicians in the United States, and its incidence and prevalence are increasing.2,3 While acute rhinosinusitis is usually self-limiting and resolves within a month, some patients develop chronic—and hard to treat—sinonasal symptoms.
No single cause, no definitive treatment
We’ve moved away from the notion that chronic rhinosinusitis is always a manifestation of persistent bacterial infection, and now recognize that there’s an inflammatory, nonbacterial component.4 In any given patient, several mechanisms—acting either simultaneously or independently—may contribute to sinonasal symptoms.3
Chronic sinusitis is treated in a variety of ways, including medications, immunotherapy, and surgery. Despite their limited efficacy, antibiotics and nasal steroids have been the mainstays of treatment.5 Treating underlying allergies, when they exist, may be helpful. But regardless of which treatment patients receive for chronic rhinosinusitis, many remain symptomatic.6
Benefits of saline irrigation extend beyond postop care
Otolaryngologists recommend saline irrigation after sinus surgery to clear secretions, debris, and crusts; reduce the risk of postoperative mucosal adhesions; and expedite mucosal healing.7,8 Saline irrigation is also gaining popularity as an alternative approach to chronic sinusitis symptom relief, and several randomized controlled trials (RCTs) have demonstrated both objective and subjective efficacy of this treatment for sinonasal disease.8-11
In 2007, the Cochrane Collaboration reviewed evidence for the effectiveness of nasal saline irrigation for symptoms of chronic rhinosinusitis. The reviewers concluded that it is well tolerated and beneficial, whether used alone or as an adjunctive treatment.12
Nasal saline sprays are often recommended because they’re thought to be better tolerated than other delivery modes.13 There have, however, been no comparisons of the relative efficacy of different means of saline delivery, until now.
STUDY SUMMARY: Nasal irrigation and spray go head-to-head
This study was a high-quality, prospective RCT comparing nasal spray and nasal irrigation.1 Subjects were recruited from the general population. To be eligible, participants had to be 18 years of age or older and have reported at least one of the following chronic rhinosinusitis symptoms on 4 or more days each week in the preceding 2 weeks:
- nasal stuffiness
- nasal dryness or crusting
- nasal congestion
- thick or discolored nasal discharge.
In addition, the symptoms must have been present on at least 15 of the preceding 30 days. Exclusion criteria included recent sinus surgery, a respiratory infection within the past 2 weeks, and the use of nasal saline within the past month.
Researchers enrolled 127 patients in the study; 63 were randomized to the nasal spray group and 64 to the large-volume, low-pressure irrigation group. Demographic and baseline characteristics of the groups were similar. The average ages of those in the irrigation and spray groups were 45 and 48 years, respectively. Most patients were nonsmokers and had been symptomatic for 7 to 12 months.
Twice-daily treatment. Researchers asked the patients to perform the assigned treatment twice daily for 8 weeks, but the patients were also permitted to continue using their usual medications. Symptom severity and disease-specific quality of life were assessed with the Sino-Nasal Outcome Test (SNOT-20), a 20-item survey that measures physical problems, emotional consequences, and functional limitations of sinusitis.14
The SNOT-20 is a validated, self-administered survey that asks patients to score items such as runny nose, postnasal discharge, need to blow the nose, reduced productivity, and embarrassment, on a 0- to 5-point scale (0=never, 5=always). A SNOT-20 score of 100 indicates the worst possible symptoms.
As a measure of chronicity of symptoms, patients were also asked to estimate how many months they’d had these symptoms during the last year. In addition, they were instructed to keep a diary to document treatment compliance and the use of other medications for sinonasal symptoms.
To measure outcomes, the researchers provided patients with mail-in packets so they could send in their completed SNOT-20 questionnaire and the medication diary completed at 2, 4, and 8 weeks after randomization.
Biggest improvements seen in irrigation group
Severity of symptoms. In each outcome measurement period, the saline irrigation group had lower SNOT-20 scores than the nasal spray group. At 2 weeks, the irrigation group scores were 4.4 points lower than the spray group (P=.02); at 4 weeks, the scores were 8.2 points lower (P<.001), and at 8 weeks the scores were 6.4 points lower (P=.002). Those in the irrigation group also had a significantly greater change from baseline than the patients in the spray group at 4 weeks (16.2 vs 7.4, P=.002) and at 8 weeks (15.0 vs 8.5, P=.04). The difference was marginally significant at 2 weeks (12.2 vs 6.7, P=.05).
Frequency of symptoms. At 8 weeks, 40% of the irrigation group and 61% of the nasal spray group reported nasal or sinus symptoms “often or always.” The absolute risk reduction in symptom frequency with saline irrigations, therefore, was 0.21; 95% confidence interval, 0.02-0.38 (P=.01). The odds of frequent nasal symptoms were 50% lower in the irrigation group compared to the spray group.
WHAT’S NEW: One delivery method is better than another
Prior studies had proven the effectiveness of nasal saline for reduction of rhinosinusitis symptoms. This RCT demonstrated that large-volume, low-pressure nasal irrigation brings greater symptom relief than nasal spray.
The researchers found little difference between the 2 groups in the rate of adverse effects, and reported that nasal irrigation appears to be well accepted once patients become accustomed to it. The fact that the participants were recruited from the general population further suggests that the results will be generalizable to primary care patients.
CAVEATS: High dropout rate in irrigation group
The absence of a control group prevents us from knowing the effect of saline nasal spray or irrigation compared with no treatment. In prior studies, however, nasal saline spray was found to be more effective than placebo in reducing rhinosinusitis symptoms.8,15
It is notable that a significant portion (21%) of the irrigation group abandoned this treatment by 8 weeks; in comparison, just 7% of the nasal spray group discontinued treatment.
This lower rate of adherence makes the beneficial effects of the irrigation group even more impressive. But it also suggests that a significant portion of patients are unlikely to stay with this recommended regimen. For those who try saline irrigation and choose not to continue it or are unwilling even to try it, saline spray is a reasonable alternative.
It should be noted that financial support for this study was provided by NeilMed Pharmaceuticals, a manufacturer of nasal saline solution and irrigation devices. However, the sponsor was not involved in the design or conduct of the study, in data collection or analysis, or in the preparation of the manuscript.
CHALLENGES TO IMPLEMENTATION: Tx may “scare away” some patients
Despite its effectiveness in reducing rhinosinusitis symptoms, performing large-volume, low-pressure nasal saline irrigation is not intuitive—and may sound downright scary to some patients. The need to learn how to perform nasal irrigation effectively, overcome the fear of water in the nasal cavity, and find the time to perform irrigation regularly can be barriers to this treatment.
A little bit of coaching can go a long way
A study by Rabago et al16 found that coached practice and patient education are effective tools in mastery of the technique ( PATIENT HANDOUT ).10,17 The researchers also found that several home strategies—incorporating nasal irrigation into the daily hygiene routine, placing the materials in a convenient location, and using warm water—facilitate regular use.
There is evidence, too, that patients who successfully use large-volume, low-pressure saline irrigation gain more than symptom relief. Rabago et al also found that effective use of this technique was associated with a sense of empowerment, and led to improved self-management skills, as well as a rapid, and long-term, improvement in quality of life.16
Saline nasal irrigation Your step-by-step guide
STEP 1: GATHER THE SUPPLIES
- - Salt (kosher, canning, or pickling salt)
- - Baking soda
- - Nasal irrigation pot (available at most pharmacies)
- - Measuring spoons
- - Container with lid
OR
- - An irrigation kit that includes the device and premixed saline packets
STEP 2: PREPARE THE SOLUTION
- - Put 1 tsp salt and ½ tsp baking soda into the container.
- - Add 1 pint of lukewarm tap water.
- - Mix contents.
- - Fill the nasal pot.
STEP 3: POSITION YOUR HEAD
- - Lean over the sink; rotate your head to one side.
- - Insert the spout of the irrigation device into the uppermost nostril.
- - Breathe through your mouth.
- - Raise the handle of the nasal pot so the solution flows into the upper nostril; in a few moments, the solution will begin to drain from the lower nostril.
- - Continue until the pot is empty, then exhale gently through both nostrils and gently blow your nose.
- - Refill the nasal pot, turn your head to the opposite side, and repeat with the other nostril.
- - Do this twice a day or as directed.
STEP 4: CLEAN AND PUT AWAY THE EQUIPMENT
- - Wash the nasal pot daily with warm water and dish detergent; rinse thoroughly.
- - Store unused saline solution in the sealed container; it can be kept at room temperature and reused for 2 days.
Adapted from: University of Wisconsin Department of Family Medicine.17
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.
Click here to view PURL METHODOLOGY
ILLUSTRATIVE CASE
A 45-year-old woman presents to your office with an 8-month history of nasal congestion and thick nasal discharge. Her symptoms have waxed and waned, the patient reports. She’s tried decongestants, antibiotics, and nasal steroids, with limited success. The patient has not had a recent respiratory infection, has never had sinus surgery, and does not want to be on long-term medication. You wonder if there’s an alternative treatment you can offer.
Rhinosinusitis is one of the most common conditions seen by primary care physicians in the United States, and its incidence and prevalence are increasing.2,3 While acute rhinosinusitis is usually self-limiting and resolves within a month, some patients develop chronic—and hard to treat—sinonasal symptoms.
No single cause, no definitive treatment
We’ve moved away from the notion that chronic rhinosinusitis is always a manifestation of persistent bacterial infection, and now recognize that there’s an inflammatory, nonbacterial component.4 In any given patient, several mechanisms—acting either simultaneously or independently—may contribute to sinonasal symptoms.3
Chronic sinusitis is treated in a variety of ways, including medications, immunotherapy, and surgery. Despite their limited efficacy, antibiotics and nasal steroids have been the mainstays of treatment.5 Treating underlying allergies, when they exist, may be helpful. But regardless of which treatment patients receive for chronic rhinosinusitis, many remain symptomatic.6
Benefits of saline irrigation extend beyond postop care
Otolaryngologists recommend saline irrigation after sinus surgery to clear secretions, debris, and crusts; reduce the risk of postoperative mucosal adhesions; and expedite mucosal healing.7,8 Saline irrigation is also gaining popularity as an alternative approach to chronic sinusitis symptom relief, and several randomized controlled trials (RCTs) have demonstrated both objective and subjective efficacy of this treatment for sinonasal disease.8-11
In 2007, the Cochrane Collaboration reviewed evidence for the effectiveness of nasal saline irrigation for symptoms of chronic rhinosinusitis. The reviewers concluded that it is well tolerated and beneficial, whether used alone or as an adjunctive treatment.12
Nasal saline sprays are often recommended because they’re thought to be better tolerated than other delivery modes.13 There have, however, been no comparisons of the relative efficacy of different means of saline delivery, until now.
STUDY SUMMARY: Nasal irrigation and spray go head-to-head
This study was a high-quality, prospective RCT comparing nasal spray and nasal irrigation.1 Subjects were recruited from the general population. To be eligible, participants had to be 18 years of age or older and have reported at least one of the following chronic rhinosinusitis symptoms on 4 or more days each week in the preceding 2 weeks:
- nasal stuffiness
- nasal dryness or crusting
- nasal congestion
- thick or discolored nasal discharge.
In addition, the symptoms must have been present on at least 15 of the preceding 30 days. Exclusion criteria included recent sinus surgery, a respiratory infection within the past 2 weeks, and the use of nasal saline within the past month.
Researchers enrolled 127 patients in the study; 63 were randomized to the nasal spray group and 64 to the large-volume, low-pressure irrigation group. Demographic and baseline characteristics of the groups were similar. The average ages of those in the irrigation and spray groups were 45 and 48 years, respectively. Most patients were nonsmokers and had been symptomatic for 7 to 12 months.
Twice-daily treatment. Researchers asked the patients to perform the assigned treatment twice daily for 8 weeks, but the patients were also permitted to continue using their usual medications. Symptom severity and disease-specific quality of life were assessed with the Sino-Nasal Outcome Test (SNOT-20), a 20-item survey that measures physical problems, emotional consequences, and functional limitations of sinusitis.14
The SNOT-20 is a validated, self-administered survey that asks patients to score items such as runny nose, postnasal discharge, need to blow the nose, reduced productivity, and embarrassment, on a 0- to 5-point scale (0=never, 5=always). A SNOT-20 score of 100 indicates the worst possible symptoms.
As a measure of chronicity of symptoms, patients were also asked to estimate how many months they’d had these symptoms during the last year. In addition, they were instructed to keep a diary to document treatment compliance and the use of other medications for sinonasal symptoms.
To measure outcomes, the researchers provided patients with mail-in packets so they could send in their completed SNOT-20 questionnaire and the medication diary completed at 2, 4, and 8 weeks after randomization.
Biggest improvements seen in irrigation group
Severity of symptoms. In each outcome measurement period, the saline irrigation group had lower SNOT-20 scores than the nasal spray group. At 2 weeks, the irrigation group scores were 4.4 points lower than the spray group (P=.02); at 4 weeks, the scores were 8.2 points lower (P<.001), and at 8 weeks the scores were 6.4 points lower (P=.002). Those in the irrigation group also had a significantly greater change from baseline than the patients in the spray group at 4 weeks (16.2 vs 7.4, P=.002) and at 8 weeks (15.0 vs 8.5, P=.04). The difference was marginally significant at 2 weeks (12.2 vs 6.7, P=.05).
Frequency of symptoms. At 8 weeks, 40% of the irrigation group and 61% of the nasal spray group reported nasal or sinus symptoms “often or always.” The absolute risk reduction in symptom frequency with saline irrigations, therefore, was 0.21; 95% confidence interval, 0.02-0.38 (P=.01). The odds of frequent nasal symptoms were 50% lower in the irrigation group compared to the spray group.
WHAT’S NEW: One delivery method is better than another
Prior studies had proven the effectiveness of nasal saline for reduction of rhinosinusitis symptoms. This RCT demonstrated that large-volume, low-pressure nasal irrigation brings greater symptom relief than nasal spray.
The researchers found little difference between the 2 groups in the rate of adverse effects, and reported that nasal irrigation appears to be well accepted once patients become accustomed to it. The fact that the participants were recruited from the general population further suggests that the results will be generalizable to primary care patients.
CAVEATS: High dropout rate in irrigation group
The absence of a control group prevents us from knowing the effect of saline nasal spray or irrigation compared with no treatment. In prior studies, however, nasal saline spray was found to be more effective than placebo in reducing rhinosinusitis symptoms.8,15
It is notable that a significant portion (21%) of the irrigation group abandoned this treatment by 8 weeks; in comparison, just 7% of the nasal spray group discontinued treatment.
This lower rate of adherence makes the beneficial effects of the irrigation group even more impressive. But it also suggests that a significant portion of patients are unlikely to stay with this recommended regimen. For those who try saline irrigation and choose not to continue it or are unwilling even to try it, saline spray is a reasonable alternative.
It should be noted that financial support for this study was provided by NeilMed Pharmaceuticals, a manufacturer of nasal saline solution and irrigation devices. However, the sponsor was not involved in the design or conduct of the study, in data collection or analysis, or in the preparation of the manuscript.
CHALLENGES TO IMPLEMENTATION: Tx may “scare away” some patients
Despite its effectiveness in reducing rhinosinusitis symptoms, performing large-volume, low-pressure nasal saline irrigation is not intuitive—and may sound downright scary to some patients. The need to learn how to perform nasal irrigation effectively, overcome the fear of water in the nasal cavity, and find the time to perform irrigation regularly can be barriers to this treatment.
A little bit of coaching can go a long way
A study by Rabago et al16 found that coached practice and patient education are effective tools in mastery of the technique ( PATIENT HANDOUT ).10,17 The researchers also found that several home strategies—incorporating nasal irrigation into the daily hygiene routine, placing the materials in a convenient location, and using warm water—facilitate regular use.
There is evidence, too, that patients who successfully use large-volume, low-pressure saline irrigation gain more than symptom relief. Rabago et al also found that effective use of this technique was associated with a sense of empowerment, and led to improved self-management skills, as well as a rapid, and long-term, improvement in quality of life.16
Saline nasal irrigation Your step-by-step guide
STEP 1: GATHER THE SUPPLIES
- - Salt (kosher, canning, or pickling salt)
- - Baking soda
- - Nasal irrigation pot (available at most pharmacies)
- - Measuring spoons
- - Container with lid
OR
- - An irrigation kit that includes the device and premixed saline packets
STEP 2: PREPARE THE SOLUTION
- - Put 1 tsp salt and ½ tsp baking soda into the container.
- - Add 1 pint of lukewarm tap water.
- - Mix contents.
- - Fill the nasal pot.
STEP 3: POSITION YOUR HEAD
- - Lean over the sink; rotate your head to one side.
- - Insert the spout of the irrigation device into the uppermost nostril.
- - Breathe through your mouth.
- - Raise the handle of the nasal pot so the solution flows into the upper nostril; in a few moments, the solution will begin to drain from the lower nostril.
- - Continue until the pot is empty, then exhale gently through both nostrils and gently blow your nose.
- - Refill the nasal pot, turn your head to the opposite side, and repeat with the other nostril.
- - Do this twice a day or as directed.
STEP 4: CLEAN AND PUT AWAY THE EQUIPMENT
- - Wash the nasal pot daily with warm water and dish detergent; rinse thoroughly.
- - Store unused saline solution in the sealed container; it can be kept at room temperature and reused for 2 days.
Adapted from: University of Wisconsin Department of Family Medicine.17
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.
Click here to view PURL METHODOLOGY
1. Pynnonen MA, Mukerji SS, Kim HM, et al. Nasal saline for chronic sinonasal symptoms: a randomized controlled trial. Arch Otolaryngol Head Neck Surg. 2007;133:11115-1120.
2. Gliklich RE, Metson R. Economic implications of chronic sinusitis. Otolaryngol Head Neck Surg. 1998;118(3 Pt 1):344-349.
3. International Rhinosinusitis Advisory Board. Infectious rhinosinusitis in adults classification, etiology and management. Ear Nose Throat J. 1997;76(12 suppl):s5-s22.
4. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg. 1997;117(3 Pt 2):s1-s7.
5. Sharp HJ, Denman D, Puumala S, et al. Treatment of acute and chronic rhinosinusitis in the United States, 1999-2002. Arch Otolaryngol Head Neck Surg. 2007;133:260-265.
6. Subramanian HN, Schechtman KB, Hamilos DL. A retrospective analysis of treatment outcomes and time to relapse after intensive medical treatment for chronic sinusitis. Am J Rhinol. 2002;16:303-312.
7. Druce HM. Adjuncts to medical management of sinusitis. Otolaryngol Head Neck Surg. 1990;103(5 Pt 2):880-883.
8. Tomooka LT, Murphy C, Davidson TM. Clinical study and literature review of nasal irrigation. Laryngoscope. 2000;110:1189-1193.
9. Heatley DG, McConnell KE, Kille TL, et al. Nasal irrigation for the alleviation of sinonasal symptoms. Otolaryngol Head Neck Surg. 2001;125:44-48.
10. Rabago D, Zgierska A, Mundt M, et al. Efficacy of daily hypertonic saline nasal irrigation among patients with sinusitis: a randomized controlled trial. J Fam Pract. 2002;51:1049-1055.
11. Taccariello M, Parikh A, Darby Y, et al. Nasal douching as a valuable adjunct in the management of chronic rhinosinusitis. Rhinology. 1999;37:29-32.
12. Harvey R, Hannan SA, Badia L, Scadding G. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst Rev. 2007;(3):CD006394.-
13. Keojampa BK, Nguyen MH, Ryan MW. Effects of buffered saline solution on nasal mucociliary clearance and nasal airway patency. Otolaryngol Head Neck Surg. 2004;131:679-682.
14. Piccirillo JF, Merritt MG, Jr, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126:41-47.
15. Hauptman G, Ryan MW. The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients. Otolaryngol Head Neck Surg. 2007;137:815-821.
16. Rabago D, Barrett B, Marchand L, et al. Qualitative aspects of nasal irrigation use by patients with chronic sinus disease in a multimethod study. Ann Fam Med. 2006;4:295-301.
17. University of Wisconsin Department of Family Medicine. Nasal Irrigation Instructions. Available at: http://www.fammed.wisc.edu/files/webfm-uploads/documents/research/nasalirrigationinstructions.pdf. Accessed December 1, 2008.
1. Pynnonen MA, Mukerji SS, Kim HM, et al. Nasal saline for chronic sinonasal symptoms: a randomized controlled trial. Arch Otolaryngol Head Neck Surg. 2007;133:11115-1120.
2. Gliklich RE, Metson R. Economic implications of chronic sinusitis. Otolaryngol Head Neck Surg. 1998;118(3 Pt 1):344-349.
3. International Rhinosinusitis Advisory Board. Infectious rhinosinusitis in adults classification, etiology and management. Ear Nose Throat J. 1997;76(12 suppl):s5-s22.
4. Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg. 1997;117(3 Pt 2):s1-s7.
5. Sharp HJ, Denman D, Puumala S, et al. Treatment of acute and chronic rhinosinusitis in the United States, 1999-2002. Arch Otolaryngol Head Neck Surg. 2007;133:260-265.
6. Subramanian HN, Schechtman KB, Hamilos DL. A retrospective analysis of treatment outcomes and time to relapse after intensive medical treatment for chronic sinusitis. Am J Rhinol. 2002;16:303-312.
7. Druce HM. Adjuncts to medical management of sinusitis. Otolaryngol Head Neck Surg. 1990;103(5 Pt 2):880-883.
8. Tomooka LT, Murphy C, Davidson TM. Clinical study and literature review of nasal irrigation. Laryngoscope. 2000;110:1189-1193.
9. Heatley DG, McConnell KE, Kille TL, et al. Nasal irrigation for the alleviation of sinonasal symptoms. Otolaryngol Head Neck Surg. 2001;125:44-48.
10. Rabago D, Zgierska A, Mundt M, et al. Efficacy of daily hypertonic saline nasal irrigation among patients with sinusitis: a randomized controlled trial. J Fam Pract. 2002;51:1049-1055.
11. Taccariello M, Parikh A, Darby Y, et al. Nasal douching as a valuable adjunct in the management of chronic rhinosinusitis. Rhinology. 1999;37:29-32.
12. Harvey R, Hannan SA, Badia L, Scadding G. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst Rev. 2007;(3):CD006394.-
13. Keojampa BK, Nguyen MH, Ryan MW. Effects of buffered saline solution on nasal mucociliary clearance and nasal airway patency. Otolaryngol Head Neck Surg. 2004;131:679-682.
14. Piccirillo JF, Merritt MG, Jr, Richards ML. Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126:41-47.
15. Hauptman G, Ryan MW. The effect of saline solutions on nasal patency and mucociliary clearance in rhinosinusitis patients. Otolaryngol Head Neck Surg. 2007;137:815-821.
16. Rabago D, Barrett B, Marchand L, et al. Qualitative aspects of nasal irrigation use by patients with chronic sinus disease in a multimethod study. Ann Fam Med. 2006;4:295-301.
17. University of Wisconsin Department of Family Medicine. Nasal Irrigation Instructions. Available at: http://www.fammed.wisc.edu/files/webfm-uploads/documents/research/nasalirrigationinstructions.pdf. Accessed December 1, 2008.
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