A 19-year-old male complaining of shortness of breath was transferred from our facility’s urgent care unit to our emergency department. He had a 2-week history of hemoptysis and vomiting, and over the previous week, he had developed mild hematemesis. His other symptoms included left thigh, flank, and upper quadrant pain; left chest pain exacerbated by exertion, light-headedness, and palpitations. He said that over the past 8 months, he’d been tired and lost some weight.

His blood pressure was 138/77 mm Hg, pulse was 142 beats per min, respiratory rate was 22 breaths per min, and oxygen saturation was 93% on room air. The physical exam revealed normal breath sounds and a diffusely tender abdomen. We ordered a chest X-ray (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Metastatic testicular cancer

The chest x-ray showed multiple bilateral discrete nodules throughout all of the lung fields. These findings, along with the age of the patient, prompted the radiologist to suspect metastatic testicular cancer. An examination of the patient’s scrotum revealed an 11-cm mass encompassing the patient’s left testicle. When asked about the mass, the patient acknowledged that it had been there for about 8 months.

A rare cancer seen in younger men

Although relatively uncommon, testicular cancer accounts for 1% to 2% of all tumors in men.¹ If caught it is highly treatable.

An examination of the patient's scrotum revealed an 11-cm mass encompassing the patient's left testicle. Testicular cancer is classified into germ cell tumors (which our patient had) and sex cord-stromal tumors. Germ cell tumors are the most common malignancy in men ages 15 to 44 years, and have a 95% cure rate when identified early and promptly treated.^2,3 Sex cordstromal tumors are more common in pediatric patients and are more often benign.²

Diagnosis usually is made clinically and pathologically at resection. Left untreated, testicular cancer spreads via the lymphatic system to the retroperitoneal lymph nodes and through the bloodstream to the lungs (predominantly),⁴ as well as to bone, the liver, and the brain. Metastatic testicular cancer to the lungs, liver, and retroperitoneum occurs in advanced disease and has a poor prognosis.^4,5

Differential diagnosis includes pneumonia, septic emboli

The differential diagnosis includes atypical pneumonia, septic emboli (ie, endocarditis or Lemierre’s syndrome), or sarcoidosis. Patients with atypical pneumonia often present with a cough, fever, and malaise. Patients with septic emboli will have an x-ray that looks similar to that of our patient. Their signs and symptoms will include malaise, shortness of breath, hypoxia, tachycardia, and tachypnea. Risk factors and physical exam findings might include a history of intravenous drug abuse (endocarditis) or deep tissue neck infection (Lemierre’s syndrome). Sarcoidosis can be a challenging diagnosis without further study.

Successful treatment hinges on early detection

Treatment for testicular cancer often is successful if the condition is localized.

The choice of treatment depends on tumor type and stage. Options include orchiectomy, retroperitoneal lymph node dissection, chemotherapy, and radiation.^2-5 After being diagnosed with testicular cancer 95% of patients live for 5 or more years.6 For localized testicular cancer, the 5-year survival rate is 99%.⁶

An eye toward prevention. The US Preventive Services Task Force recommends against screening with clinical examination or testicular self examination⁷; however, some clinicians support regular screening and self examinations.

When silence is deadly

Although physicians expect that patients will disclose obvious physical manifestations of disease, we know that this is not always the case. Patients often have barriers to care, including their own reluctance to share certain types of information with a provider.

Our patient. After we diagnosed metastatic testicular cancer in our patient, he was transferred to the medical intensive care unit. His overall clinical status declined and he died 14 days later.

A 19-year-old male complaining of shortness of breath was transferred from our facility’s urgent care unit to our emergency department. He had a 2-week history of hemoptysis and vomiting, and over the previous week, he had developed mild hematemesis. His other symptoms included left thigh, flank, and upper quadrant pain; left chest pain exacerbated by exertion, light-headedness, and palpitations. He said that over the past 8 months, he’d been tired and lost some weight.

His blood pressure was 138/77 mm Hg, pulse was 142 beats per min, respiratory rate was 22 breaths per min, and oxygen saturation was 93% on room air. The physical exam revealed normal breath sounds and a diffusely tender abdomen. We ordered a chest X-ray (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Metastatic testicular cancer

The chest x-ray showed multiple bilateral discrete nodules throughout all of the lung fields. These findings, along with the age of the patient, prompted the radiologist to suspect metastatic testicular cancer. An examination of the patient’s scrotum revealed an 11-cm mass encompassing the patient’s left testicle. When asked about the mass, the patient acknowledged that it had been there for about 8 months.

A rare cancer seen in younger men

Although relatively uncommon, testicular cancer accounts for 1% to 2% of all tumors in men.¹ If caught it is highly treatable.

An examination of the patient's scrotum revealed an 11-cm mass encompassing the patient's left testicle. Testicular cancer is classified into germ cell tumors (which our patient had) and sex cord-stromal tumors. Germ cell tumors are the most common malignancy in men ages 15 to 44 years, and have a 95% cure rate when identified early and promptly treated.^2,3 Sex cordstromal tumors are more common in pediatric patients and are more often benign.²

Diagnosis usually is made clinically and pathologically at resection. Left untreated, testicular cancer spreads via the lymphatic system to the retroperitoneal lymph nodes and through the bloodstream to the lungs (predominantly),⁴ as well as to bone, the liver, and the brain. Metastatic testicular cancer to the lungs, liver, and retroperitoneum occurs in advanced disease and has a poor prognosis.^4,5

Differential diagnosis includes pneumonia, septic emboli

The differential diagnosis includes atypical pneumonia, septic emboli (ie, endocarditis or Lemierre’s syndrome), or sarcoidosis. Patients with atypical pneumonia often present with a cough, fever, and malaise. Patients with septic emboli will have an x-ray that looks similar to that of our patient. Their signs and symptoms will include malaise, shortness of breath, hypoxia, tachycardia, and tachypnea. Risk factors and physical exam findings might include a history of intravenous drug abuse (endocarditis) or deep tissue neck infection (Lemierre’s syndrome). Sarcoidosis can be a challenging diagnosis without further study.

Successful treatment hinges on early detection

Treatment for testicular cancer often is successful if the condition is localized.

The choice of treatment depends on tumor type and stage. Options include orchiectomy, retroperitoneal lymph node dissection, chemotherapy, and radiation.^2-5 After being diagnosed with testicular cancer 95% of patients live for 5 or more years.6 For localized testicular cancer, the 5-year survival rate is 99%.⁶

An eye toward prevention. The US Preventive Services Task Force recommends against screening with clinical examination or testicular self examination⁷; however, some clinicians support regular screening and self examinations.

When silence is deadly

Although physicians expect that patients will disclose obvious physical manifestations of disease, we know that this is not always the case. Patients often have barriers to care, including their own reluctance to share certain types of information with a provider.

Our patient. After we diagnosed metastatic testicular cancer in our patient, he was transferred to the medical intensive care unit. His overall clinical status declined and he died 14 days later.

A 19-year-old male complaining of shortness of breath was transferred from our facility’s urgent care unit to our emergency department. He had a 2-week history of hemoptysis and vomiting, and over the previous week, he had developed mild hematemesis. His other symptoms included left thigh, flank, and upper quadrant pain; left chest pain exacerbated by exertion, light-headedness, and palpitations. He said that over the past 8 months, he’d been tired and lost some weight.

His blood pressure was 138/77 mm Hg, pulse was 142 beats per min, respiratory rate was 22 breaths per min, and oxygen saturation was 93% on room air. The physical exam revealed normal breath sounds and a diffusely tender abdomen. We ordered a chest X-ray (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Metastatic testicular cancer

The chest x-ray showed multiple bilateral discrete nodules throughout all of the lung fields. These findings, along with the age of the patient, prompted the radiologist to suspect metastatic testicular cancer. An examination of the patient’s scrotum revealed an 11-cm mass encompassing the patient’s left testicle. When asked about the mass, the patient acknowledged that it had been there for about 8 months.

A rare cancer seen in younger men

Although relatively uncommon, testicular cancer accounts for 1% to 2% of all tumors in men.¹ If caught it is highly treatable.

An examination of the patient's scrotum revealed an 11-cm mass encompassing the patient's left testicle. Testicular cancer is classified into germ cell tumors (which our patient had) and sex cord-stromal tumors. Germ cell tumors are the most common malignancy in men ages 15 to 44 years, and have a 95% cure rate when identified early and promptly treated.^2,3 Sex cordstromal tumors are more common in pediatric patients and are more often benign.²

Diagnosis usually is made clinically and pathologically at resection. Left untreated, testicular cancer spreads via the lymphatic system to the retroperitoneal lymph nodes and through the bloodstream to the lungs (predominantly),⁴ as well as to bone, the liver, and the brain. Metastatic testicular cancer to the lungs, liver, and retroperitoneum occurs in advanced disease and has a poor prognosis.^4,5

Differential diagnosis includes pneumonia, septic emboli

The differential diagnosis includes atypical pneumonia, septic emboli (ie, endocarditis or Lemierre’s syndrome), or sarcoidosis. Patients with atypical pneumonia often present with a cough, fever, and malaise. Patients with septic emboli will have an x-ray that looks similar to that of our patient. Their signs and symptoms will include malaise, shortness of breath, hypoxia, tachycardia, and tachypnea. Risk factors and physical exam findings might include a history of intravenous drug abuse (endocarditis) or deep tissue neck infection (Lemierre’s syndrome). Sarcoidosis can be a challenging diagnosis without further study.

Successful treatment hinges on early detection

Treatment for testicular cancer often is successful if the condition is localized.

The choice of treatment depends on tumor type and stage. Options include orchiectomy, retroperitoneal lymph node dissection, chemotherapy, and radiation.^2-5 After being diagnosed with testicular cancer 95% of patients live for 5 or more years.6 For localized testicular cancer, the 5-year survival rate is 99%.⁶

An eye toward prevention. The US Preventive Services Task Force recommends against screening with clinical examination or testicular self examination⁷; however, some clinicians support regular screening and self examinations.

When silence is deadly

Although physicians expect that patients will disclose obvious physical manifestations of disease, we know that this is not always the case. Patients often have barriers to care, including their own reluctance to share certain types of information with a provider.

Our patient. After we diagnosed metastatic testicular cancer in our patient, he was transferred to the medical intensive care unit. His overall clinical status declined and he died 14 days later.

To the Editor: We appreciated the thoughtful 1-Minute Consult by Drs. Dobri and Lansang, “How should we manage insulin therapy before surgery?”¹ We agree with them in regard to the benefits of perioperative control of blood glucose levels. However, we disagree in general with their assertion that the full dose of the patient’s home dose of basal insulin be administered while the patient is nil per os (NPO) before surgery, with a reduction to 75% of the home dose only if the patient has a history of hypoglycemia, a recommendation that did not differentiate between patients with type 1 and type 2 diabetes mellitus.

The RABBIT 2 Surgery trial,² which showed superiority of basal-bolus insulin over sliding scale insulin in surgical patients with type 2 diabetes mellitus, also showed a surprisingly high rate of hypoglycemia—24 (23.1%) of 104 patients had blood glucose levels lower than 70 mg/dL, compared with a similar trial in nonsurgical patients in which 2 (3.1%) of 65 patients had a blood glucose level less than 60 mg/dL.³ The authors of the two studies explained² that “differences in hypoglycemic events between the two trials could be in part explained by reduced nutritional intake in surgical patients…”

Although patients with well-controlled type 1 diabetes mellitus may tolerate their full dose of basal insulin while NPO, we contend that patients with type 2 diabetes mellitus should be prescribed a reduced dose of basal insulin while NPO, regardless of the dose distribution or the patient’s overall glycemic control. It is routine practice on our consult service to reduce the basal insulin dose in such patients by roughly half.

To the Editor: We appreciated the thoughtful 1-Minute Consult by Drs. Dobri and Lansang, “How should we manage insulin therapy before surgery?”¹ We agree with them in regard to the benefits of perioperative control of blood glucose levels. However, we disagree in general with their assertion that the full dose of the patient’s home dose of basal insulin be administered while the patient is nil per os (NPO) before surgery, with a reduction to 75% of the home dose only if the patient has a history of hypoglycemia, a recommendation that did not differentiate between patients with type 1 and type 2 diabetes mellitus.

The RABBIT 2 Surgery trial,² which showed superiority of basal-bolus insulin over sliding scale insulin in surgical patients with type 2 diabetes mellitus, also showed a surprisingly high rate of hypoglycemia—24 (23.1%) of 104 patients had blood glucose levels lower than 70 mg/dL, compared with a similar trial in nonsurgical patients in which 2 (3.1%) of 65 patients had a blood glucose level less than 60 mg/dL.³ The authors of the two studies explained² that “differences in hypoglycemic events between the two trials could be in part explained by reduced nutritional intake in surgical patients…”

Although patients with well-controlled type 1 diabetes mellitus may tolerate their full dose of basal insulin while NPO, we contend that patients with type 2 diabetes mellitus should be prescribed a reduced dose of basal insulin while NPO, regardless of the dose distribution or the patient’s overall glycemic control. It is routine practice on our consult service to reduce the basal insulin dose in such patients by roughly half.

To the Editor: We appreciated the thoughtful 1-Minute Consult by Drs. Dobri and Lansang, “How should we manage insulin therapy before surgery?”¹ We agree with them in regard to the benefits of perioperative control of blood glucose levels. However, we disagree in general with their assertion that the full dose of the patient’s home dose of basal insulin be administered while the patient is nil per os (NPO) before surgery, with a reduction to 75% of the home dose only if the patient has a history of hypoglycemia, a recommendation that did not differentiate between patients with type 1 and type 2 diabetes mellitus.

The RABBIT 2 Surgery trial,² which showed superiority of basal-bolus insulin over sliding scale insulin in surgical patients with type 2 diabetes mellitus, also showed a surprisingly high rate of hypoglycemia—24 (23.1%) of 104 patients had blood glucose levels lower than 70 mg/dL, compared with a similar trial in nonsurgical patients in which 2 (3.1%) of 65 patients had a blood glucose level less than 60 mg/dL.³ The authors of the two studies explained² that “differences in hypoglycemic events between the two trials could be in part explained by reduced nutritional intake in surgical patients…”

Although patients with well-controlled type 1 diabetes mellitus may tolerate their full dose of basal insulin while NPO, we contend that patients with type 2 diabetes mellitus should be prescribed a reduced dose of basal insulin while NPO, regardless of the dose distribution or the patient’s overall glycemic control. It is routine practice on our consult service to reduce the basal insulin dose in such patients by roughly half.

In Reply: We appreciate the kind words of Drs. Ditch and Moore, as well as their opinion.

Our article was intentionally brief—a 1-Minute Consult—and so could not cover all specific situations we encounter in clinical practice. We meant only to provide a general approach in this matter.

Quite often before surgery, patients receive less basal insulin than needed, or none at all, rather than too much. It has to be borne in mind that perioperative hyperglycemia—not just hypoglycemia—is linked with poor outcomes in cardiac¹ and noncardiac surgery.^2,3

Through our scenarios and suggestions, we have taken steps to err on the side of preventing hypoglycemia while averting hyperglycemia, at the same time making it easy to calculate the dose. In a scenario in which the basal insulin dose is about the same as the total of the prandial boluses, we have not yet seen evidence that raises concern for hypoglycemia, maybe because many of the patients with type 2 diabetes seen in our institution for surgery take, in addition to insulin, oral agents or noninsulin injections (which are appropriately withheld before surgery), and have suboptimal glycemic control on their home regimen. But if a physician has concerns for hypoglycemia, a dose reduction should be made.

There were some differences between the RABBIT 2 trial in medical patients⁴ and the RABBIT 2 Surgery trial⁵ that would make the results not completely comparable. In RABBIT 2, the medical patients included were on diet alone or any combination of oral antidiabetic agents (not on insulin), and they were started on a total daily dose of insulin of either 0.4 or 0.5 U/kg/day, depending on the glucose level. In RABBIT 2 Surgery, patients who were on insulin at home with a total daily dose of 0.4 U/kg or less were also included, and the starting daily dose of insulin was 0.5 U/kg (unless they were older or had a high serum creatinine).

In view of all the above, we agree with Drs. Ditch and Moore that if there is concern for hypoglycemia, the clinician should reduce the insulin dose in the manner that evidence from the local practice suggests, without causing undue hyperglycemia and postsurgical complications.

In Reply: We appreciate the kind words of Drs. Ditch and Moore, as well as their opinion.

Our article was intentionally brief—a 1-Minute Consult—and so could not cover all specific situations we encounter in clinical practice. We meant only to provide a general approach in this matter.

Quite often before surgery, patients receive less basal insulin than needed, or none at all, rather than too much. It has to be borne in mind that perioperative hyperglycemia—not just hypoglycemia—is linked with poor outcomes in cardiac¹ and noncardiac surgery.^2,3

Through our scenarios and suggestions, we have taken steps to err on the side of preventing hypoglycemia while averting hyperglycemia, at the same time making it easy to calculate the dose. In a scenario in which the basal insulin dose is about the same as the total of the prandial boluses, we have not yet seen evidence that raises concern for hypoglycemia, maybe because many of the patients with type 2 diabetes seen in our institution for surgery take, in addition to insulin, oral agents or noninsulin injections (which are appropriately withheld before surgery), and have suboptimal glycemic control on their home regimen. But if a physician has concerns for hypoglycemia, a dose reduction should be made.

There were some differences between the RABBIT 2 trial in medical patients⁴ and the RABBIT 2 Surgery trial⁵ that would make the results not completely comparable. In RABBIT 2, the medical patients included were on diet alone or any combination of oral antidiabetic agents (not on insulin), and they were started on a total daily dose of insulin of either 0.4 or 0.5 U/kg/day, depending on the glucose level. In RABBIT 2 Surgery, patients who were on insulin at home with a total daily dose of 0.4 U/kg or less were also included, and the starting daily dose of insulin was 0.5 U/kg (unless they were older or had a high serum creatinine).

In view of all the above, we agree with Drs. Ditch and Moore that if there is concern for hypoglycemia, the clinician should reduce the insulin dose in the manner that evidence from the local practice suggests, without causing undue hyperglycemia and postsurgical complications.

In Reply: We appreciate the kind words of Drs. Ditch and Moore, as well as their opinion.

Our article was intentionally brief—a 1-Minute Consult—and so could not cover all specific situations we encounter in clinical practice. We meant only to provide a general approach in this matter.

Quite often before surgery, patients receive less basal insulin than needed, or none at all, rather than too much. It has to be borne in mind that perioperative hyperglycemia—not just hypoglycemia—is linked with poor outcomes in cardiac¹ and noncardiac surgery.^2,3

Through our scenarios and suggestions, we have taken steps to err on the side of preventing hypoglycemia while averting hyperglycemia, at the same time making it easy to calculate the dose. In a scenario in which the basal insulin dose is about the same as the total of the prandial boluses, we have not yet seen evidence that raises concern for hypoglycemia, maybe because many of the patients with type 2 diabetes seen in our institution for surgery take, in addition to insulin, oral agents or noninsulin injections (which are appropriately withheld before surgery), and have suboptimal glycemic control on their home regimen. But if a physician has concerns for hypoglycemia, a dose reduction should be made.

There were some differences between the RABBIT 2 trial in medical patients⁴ and the RABBIT 2 Surgery trial⁵ that would make the results not completely comparable. In RABBIT 2, the medical patients included were on diet alone or any combination of oral antidiabetic agents (not on insulin), and they were started on a total daily dose of insulin of either 0.4 or 0.5 U/kg/day, depending on the glucose level. In RABBIT 2 Surgery, patients who were on insulin at home with a total daily dose of 0.4 U/kg or less were also included, and the starting daily dose of insulin was 0.5 U/kg (unless they were older or had a high serum creatinine).

In view of all the above, we agree with Drs. Ditch and Moore that if there is concern for hypoglycemia, the clinician should reduce the insulin dose in the manner that evidence from the local practice suggests, without causing undue hyperglycemia and postsurgical complications.

To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”

While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.

I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.

To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”

While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.

I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.

To the Editor: Question 1 of the December 2013 CME test “Can an ARB be given to patients who have had angioedema on an ACE inhibitor?” presents the case of a 73-year-old woman with angioedema thought to be due to her taking enalapril; in addition, she takes hydrochlorothiazide. Her blood pressure is 118/72 mm Hg, and her heart rate is not specified. The question is what the next best step would be to manage her blood pressure medications. The “correct” answer is given as “substitute metoprolol for enalapril in her regimen.”

While this answer is the best choice given, I would take issue with it for two reasons. First, many elderly hypertension patients are overmedicated. With a blood pressure of 118/72 on two medications, it is entirely possible that she may not need to replace the enalapril with any other medication to maintain her pressure below the new JNC 8 threshold of 150/90 for the elderly, or even the 140/90 level specified in other guidelines.

I would recheck her pressure daily on her diuretic alone before adding back a second medication. If she does require a second blood pressure medication, JNC 8 (in agreement with other recent guidelines) recommends adding a calcium channel blocker. Beta-blockers are not recommended by any recent guidelines for first-line or second-line treatment of hypertension for elderly patients without special indications, such as tachyarrhythmias or history of myocardial infarction. No special indications for a beta-blocker were mentioned in this case. Indeed, elderly hypertensive patients often have slow-normal heart rates, or even mild resting bradycardia, which would make the addition of metoprolol contraindicated and potentially dangerous.

To the Editor: In the January 2014 issue, Eisa et al¹ suggested that patients who require prolonged mechanical ventilatory support, ie, for more than 48 hours, should receive stress ulcer prophylaxis. This recommendation came from a study by Cook et al² in 1994, which found a significant increase in the risk of gastrointestinal blood loss in this group of patients. Other studies have shown a different result. Zandstra et al³ found an extremely low rate of stress ulcer-related bleeding in this group in the absence of stress ulcer prophylaxis. Another study⁴ in critically ill patients also found no relationship between stress ulcer incidence and prolonged mechanical ventilatory support. Interestingly, that study found that prolonged use of a nasogastric tube is the major risk factor for developing a stress ulcer.⁴ The explanation for why newer studies did not demonstrate the relationship between mechanical ventilation and stress ulcer development may lie in the result of a meta-analysis by Marik et al,⁵ which showed that stress ulcer prophylaxis may not be required in a patient who receives early enteral nutrition. That practice was not common in the past, including at the time the original study was conducted.

According to current evidence, mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer. The medical community should start questioning the routine practice of stress ulcer prophylaxis in this group of patients. In addition, more studies have identified the adverse effects of acid-suppression therapy in this group of patients, and these effects likely make the harms outweigh the benefits. This notion was confirmed in the most recent meta-analysis by Krag et al.⁶ In summary, the practice of routine stress ulcer prophylaxis in all mechanically ventilated patients will likely change in the future, with more focus on patients who are at higher risk.

To the Editor: In the January 2014 issue, Eisa et al¹ suggested that patients who require prolonged mechanical ventilatory support, ie, for more than 48 hours, should receive stress ulcer prophylaxis. This recommendation came from a study by Cook et al² in 1994, which found a significant increase in the risk of gastrointestinal blood loss in this group of patients. Other studies have shown a different result. Zandstra et al³ found an extremely low rate of stress ulcer-related bleeding in this group in the absence of stress ulcer prophylaxis. Another study⁴ in critically ill patients also found no relationship between stress ulcer incidence and prolonged mechanical ventilatory support. Interestingly, that study found that prolonged use of a nasogastric tube is the major risk factor for developing a stress ulcer.⁴ The explanation for why newer studies did not demonstrate the relationship between mechanical ventilation and stress ulcer development may lie in the result of a meta-analysis by Marik et al,⁵ which showed that stress ulcer prophylaxis may not be required in a patient who receives early enteral nutrition. That practice was not common in the past, including at the time the original study was conducted.

According to current evidence, mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer. The medical community should start questioning the routine practice of stress ulcer prophylaxis in this group of patients. In addition, more studies have identified the adverse effects of acid-suppression therapy in this group of patients, and these effects likely make the harms outweigh the benefits. This notion was confirmed in the most recent meta-analysis by Krag et al.⁶ In summary, the practice of routine stress ulcer prophylaxis in all mechanically ventilated patients will likely change in the future, with more focus on patients who are at higher risk.

To the Editor: In the January 2014 issue, Eisa et al¹ suggested that patients who require prolonged mechanical ventilatory support, ie, for more than 48 hours, should receive stress ulcer prophylaxis. This recommendation came from a study by Cook et al² in 1994, which found a significant increase in the risk of gastrointestinal blood loss in this group of patients. Other studies have shown a different result. Zandstra et al³ found an extremely low rate of stress ulcer-related bleeding in this group in the absence of stress ulcer prophylaxis. Another study⁴ in critically ill patients also found no relationship between stress ulcer incidence and prolonged mechanical ventilatory support. Interestingly, that study found that prolonged use of a nasogastric tube is the major risk factor for developing a stress ulcer.⁴ The explanation for why newer studies did not demonstrate the relationship between mechanical ventilation and stress ulcer development may lie in the result of a meta-analysis by Marik et al,⁵ which showed that stress ulcer prophylaxis may not be required in a patient who receives early enteral nutrition. That practice was not common in the past, including at the time the original study was conducted.

According to current evidence, mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer. The medical community should start questioning the routine practice of stress ulcer prophylaxis in this group of patients. In addition, more studies have identified the adverse effects of acid-suppression therapy in this group of patients, and these effects likely make the harms outweigh the benefits. This notion was confirmed in the most recent meta-analysis by Krag et al.⁶ In summary, the practice of routine stress ulcer prophylaxis in all mechanically ventilated patients will likely change in the future, with more focus on patients who are at higher risk.

In Reply: We welcome the comments from Dr. Chongnarungsin on our article and the opportunity to further discuss our opinions.

In our paper, we discussed current recommendations for prophylaxis of stress ulcer-related bleeding in hospitalized patients and advocated against the blind administration of drugs without risk stratification.

The landmark trial that provides the most-cited definitions and the risk factors for clinically significant stress ulcer-related bleeding in critically ill patients was published in 1994 by Cook et al.¹ In their multicenter prospective cohort study of 2,252 patients, the authors reported that prolonged mechanical ventilation is an important risk factor for clinically significant stress ulcer-related bleeding.

Another major prospective cohort study observed an incidence rate of clinically significant stress ulcer-related bleeding of 3.5%.²

Dr. Chongnarungsin cites another prospective cohort study of 183 patients from the same era,³ wherein the authors defined stress ulcer-related bleeding as bleeding requiring transfusion of packed red blood cells, found on endoscopy or on postmortem evaluation. This was in contrast to the 1994 study of Cook et al,¹ who had a more rigorous and comprehensive definition for overt and clinically significant stress ulcer-related bleeding, applied by up to three independent adjudicators not involved in the patients’ care. Their definition not only entailed a more accurate transfusion-dependent bleeding criterion, but also included hemodynamic and laboratory criteria. As such, the “very low rate” of stress ulcer-related bleeding reported by Zandstra et al³ should be critically appraised. Of note, the authors in that study did not report the rates of patients who received early enteral feeding, and their patients received cefotaxime for digestive tract decontamination, an important confounder to the interpretation of the study results.

Indeed, the remarkable variation in estimates of the incidence of stress ulcer-related bleeding is probably related to the lack of a uniform definition. Even when rates of endoscopic and occult bleeding are set aside, agreement is lacking as to which category of bleeding is clinically significant.

Dr. Chongnarungsin also cites the study by Ellison et al⁴ of a cohort of 874 patients who had no previous gastrointestinal bleeding or peptic ulcer disease and who were enrolled in a multicenter randomized controlled trial of prophylactic intravenous immune globulin to prevent infections associated with an intensive care unit. In a secondary objective, the authors did not identify coagulopathy or prolonged mechanical ventilation as a principal risk factor for bleeding. The authors ascribed this discrepancy with previously published literature to their unique study population, which consisted predominantly of elderly men and rarely included trauma patients. In light of these unique peculiarities of their population, the lack of an association between prolonged mechanical ventilation and stress ulcer-related bleeding cannot be determined. Moreover, that study showed that prolonged nasogastric tube insertion was one of the risk factors for increased risk of gastrointestinal bleeding, and not the risk factor for development of stress ulcer as stated by Dr. Chongnarungsin.

The decrease in the incidence of stress ulcer-related bleeding in critically ill patients over the years could be attributed to an era effect, from advances in critical care medicine and prophylactic methods.⁵ We agree with Dr. Chongnarungsin that the increased introduction of early enteral feeding may have also contributed to the reduced incidence of stress ulcer-related bleeding.⁶ However, we think the conclusion that “mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer” is overelaborated, and we believe that strong evidence demonstrates this association.^1,2

Alternatively, we recognize the lack of mortality-benefit evidence for stress ulcer prophylaxis. This notwithstanding, according to recent Surviving Sepsis Campaign guidelines, the use of stress ulcer prophylaxis is listed as a 1B recommendation (strong recommendation) for severely septic patients who require prolonged mechanical ventilation. In addition, the updated 2014 guidelines of the American Society of Health-System Pharmacists⁷ continue to recommend stress ulcer prophylaxis in the context of mechanical ventilation, with H2 receptor antagonists being the preferred first-line agents.⁸

It is important to acknowledge that these recommendations were endorsed despite the lack of obvious mortality benefit, and it is our opinion that large randomized controlled studies are needed to evaluate the risks and mortality benefit of these prophylaxis methods.

In Reply: We welcome the comments from Dr. Chongnarungsin on our article and the opportunity to further discuss our opinions.

In our paper, we discussed current recommendations for prophylaxis of stress ulcer-related bleeding in hospitalized patients and advocated against the blind administration of drugs without risk stratification.

The landmark trial that provides the most-cited definitions and the risk factors for clinically significant stress ulcer-related bleeding in critically ill patients was published in 1994 by Cook et al.¹ In their multicenter prospective cohort study of 2,252 patients, the authors reported that prolonged mechanical ventilation is an important risk factor for clinically significant stress ulcer-related bleeding.

Another major prospective cohort study observed an incidence rate of clinically significant stress ulcer-related bleeding of 3.5%.²

Dr. Chongnarungsin cites another prospective cohort study of 183 patients from the same era,³ wherein the authors defined stress ulcer-related bleeding as bleeding requiring transfusion of packed red blood cells, found on endoscopy or on postmortem evaluation. This was in contrast to the 1994 study of Cook et al,¹ who had a more rigorous and comprehensive definition for overt and clinically significant stress ulcer-related bleeding, applied by up to three independent adjudicators not involved in the patients’ care. Their definition not only entailed a more accurate transfusion-dependent bleeding criterion, but also included hemodynamic and laboratory criteria. As such, the “very low rate” of stress ulcer-related bleeding reported by Zandstra et al³ should be critically appraised. Of note, the authors in that study did not report the rates of patients who received early enteral feeding, and their patients received cefotaxime for digestive tract decontamination, an important confounder to the interpretation of the study results.

Indeed, the remarkable variation in estimates of the incidence of stress ulcer-related bleeding is probably related to the lack of a uniform definition. Even when rates of endoscopic and occult bleeding are set aside, agreement is lacking as to which category of bleeding is clinically significant.

Dr. Chongnarungsin also cites the study by Ellison et al⁴ of a cohort of 874 patients who had no previous gastrointestinal bleeding or peptic ulcer disease and who were enrolled in a multicenter randomized controlled trial of prophylactic intravenous immune globulin to prevent infections associated with an intensive care unit. In a secondary objective, the authors did not identify coagulopathy or prolonged mechanical ventilation as a principal risk factor for bleeding. The authors ascribed this discrepancy with previously published literature to their unique study population, which consisted predominantly of elderly men and rarely included trauma patients. In light of these unique peculiarities of their population, the lack of an association between prolonged mechanical ventilation and stress ulcer-related bleeding cannot be determined. Moreover, that study showed that prolonged nasogastric tube insertion was one of the risk factors for increased risk of gastrointestinal bleeding, and not the risk factor for development of stress ulcer as stated by Dr. Chongnarungsin.

The decrease in the incidence of stress ulcer-related bleeding in critically ill patients over the years could be attributed to an era effect, from advances in critical care medicine and prophylactic methods.⁵ We agree with Dr. Chongnarungsin that the increased introduction of early enteral feeding may have also contributed to the reduced incidence of stress ulcer-related bleeding.⁶ However, we think the conclusion that “mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer” is overelaborated, and we believe that strong evidence demonstrates this association.^1,2

Alternatively, we recognize the lack of mortality-benefit evidence for stress ulcer prophylaxis. This notwithstanding, according to recent Surviving Sepsis Campaign guidelines, the use of stress ulcer prophylaxis is listed as a 1B recommendation (strong recommendation) for severely septic patients who require prolonged mechanical ventilation. In addition, the updated 2014 guidelines of the American Society of Health-System Pharmacists⁷ continue to recommend stress ulcer prophylaxis in the context of mechanical ventilation, with H2 receptor antagonists being the preferred first-line agents.⁸

It is important to acknowledge that these recommendations were endorsed despite the lack of obvious mortality benefit, and it is our opinion that large randomized controlled studies are needed to evaluate the risks and mortality benefit of these prophylaxis methods.

In Reply: We welcome the comments from Dr. Chongnarungsin on our article and the opportunity to further discuss our opinions.

In our paper, we discussed current recommendations for prophylaxis of stress ulcer-related bleeding in hospitalized patients and advocated against the blind administration of drugs without risk stratification.

The landmark trial that provides the most-cited definitions and the risk factors for clinically significant stress ulcer-related bleeding in critically ill patients was published in 1994 by Cook et al.¹ In their multicenter prospective cohort study of 2,252 patients, the authors reported that prolonged mechanical ventilation is an important risk factor for clinically significant stress ulcer-related bleeding.

Another major prospective cohort study observed an incidence rate of clinically significant stress ulcer-related bleeding of 3.5%.²

Dr. Chongnarungsin cites another prospective cohort study of 183 patients from the same era,³ wherein the authors defined stress ulcer-related bleeding as bleeding requiring transfusion of packed red blood cells, found on endoscopy or on postmortem evaluation. This was in contrast to the 1994 study of Cook et al,¹ who had a more rigorous and comprehensive definition for overt and clinically significant stress ulcer-related bleeding, applied by up to three independent adjudicators not involved in the patients’ care. Their definition not only entailed a more accurate transfusion-dependent bleeding criterion, but also included hemodynamic and laboratory criteria. As such, the “very low rate” of stress ulcer-related bleeding reported by Zandstra et al³ should be critically appraised. Of note, the authors in that study did not report the rates of patients who received early enteral feeding, and their patients received cefotaxime for digestive tract decontamination, an important confounder to the interpretation of the study results.

Indeed, the remarkable variation in estimates of the incidence of stress ulcer-related bleeding is probably related to the lack of a uniform definition. Even when rates of endoscopic and occult bleeding are set aside, agreement is lacking as to which category of bleeding is clinically significant.

Dr. Chongnarungsin also cites the study by Ellison et al⁴ of a cohort of 874 patients who had no previous gastrointestinal bleeding or peptic ulcer disease and who were enrolled in a multicenter randomized controlled trial of prophylactic intravenous immune globulin to prevent infections associated with an intensive care unit. In a secondary objective, the authors did not identify coagulopathy or prolonged mechanical ventilation as a principal risk factor for bleeding. The authors ascribed this discrepancy with previously published literature to their unique study population, which consisted predominantly of elderly men and rarely included trauma patients. In light of these unique peculiarities of their population, the lack of an association between prolonged mechanical ventilation and stress ulcer-related bleeding cannot be determined. Moreover, that study showed that prolonged nasogastric tube insertion was one of the risk factors for increased risk of gastrointestinal bleeding, and not the risk factor for development of stress ulcer as stated by Dr. Chongnarungsin.

The decrease in the incidence of stress ulcer-related bleeding in critically ill patients over the years could be attributed to an era effect, from advances in critical care medicine and prophylactic methods.⁵ We agree with Dr. Chongnarungsin that the increased introduction of early enteral feeding may have also contributed to the reduced incidence of stress ulcer-related bleeding.⁶ However, we think the conclusion that “mechanical ventilation for more than 48 hours does not seem to increase the risk of stress ulcer” is overelaborated, and we believe that strong evidence demonstrates this association.^1,2

Alternatively, we recognize the lack of mortality-benefit evidence for stress ulcer prophylaxis. This notwithstanding, according to recent Surviving Sepsis Campaign guidelines, the use of stress ulcer prophylaxis is listed as a 1B recommendation (strong recommendation) for severely septic patients who require prolonged mechanical ventilation. In addition, the updated 2014 guidelines of the American Society of Health-System Pharmacists⁷ continue to recommend stress ulcer prophylaxis in the context of mechanical ventilation, with H2 receptor antagonists being the preferred first-line agents.⁸

It is important to acknowledge that these recommendations were endorsed despite the lack of obvious mortality benefit, and it is our opinion that large randomized controlled studies are needed to evaluate the risks and mortality benefit of these prophylaxis methods.

To the Editor: Stephen et al¹ have written a nice review of the implications of albuminuria. However, they are clearly incorrect when they state, “Most of the protein in the urine is albumin filtered from the plasma.”¹ First, as they later point out in the article, the normal upper limit of protein excretion is about 150 mg/day, and only about 20 mg/day is normally albumin. Therefore, most of the protein in normally found in urine is not albumin, but instead is mostly a variety of globulins. Tamm-Horsfall mucoprotein or uromodulin is usually the protein found in highest concentration in normal urine.

To the Editor: Stephen et al¹ have written a nice review of the implications of albuminuria. However, they are clearly incorrect when they state, “Most of the protein in the urine is albumin filtered from the plasma.”¹ First, as they later point out in the article, the normal upper limit of protein excretion is about 150 mg/day, and only about 20 mg/day is normally albumin. Therefore, most of the protein in normally found in urine is not albumin, but instead is mostly a variety of globulins. Tamm-Horsfall mucoprotein or uromodulin is usually the protein found in highest concentration in normal urine.

To the Editor: Stephen et al¹ have written a nice review of the implications of albuminuria. However, they are clearly incorrect when they state, “Most of the protein in the urine is albumin filtered from the plasma.”¹ First, as they later point out in the article, the normal upper limit of protein excretion is about 150 mg/day, and only about 20 mg/day is normally albumin. Therefore, most of the protein in normally found in urine is not albumin, but instead is mostly a variety of globulins. Tamm-Horsfall mucoprotein or uromodulin is usually the protein found in highest concentration in normal urine.

Illustrative case

A 6-year-old girl with a history of reactive airway disease comes to your office complaining of cough and wheezing. On exam, she has mild retractions, a respiratory rate of 35, and an oxygen saturation of 96% on room air. Her lung fields are diffusely wheezy. Her parents would like to keep her out of the hospital. How should you order her albuterol to decrease her wheezing and minimize adverse effects?

Asthma affects nearly 19 million adults and 7 million children in the United States.² Asthma exacerbations are the third most common reason for hospitalization in children.^2,3 Treatment usually requires multiple agents, including inhaled beta-agonists. These are most effective when delivered to the peripheral airways, which is a challenge during an asthma exacerbation because of airway swelling and rapid breathing. Two devices have been developed to effectively deliver medication to the peripheral airways: nebulizers and MDIs with a holding chamber (spacer).¹

Several studies have demonstrated that for mild to moderate asthma exacerbations, administering a beta-agonist via an MDI with a spacer is as effective as using a nebulizer.^4,5 Asthma treatment guidelines also state that spacers are either comparable to or preferred over nebulizers for beta-agonist administration in children and adults.^6,7 However, based on our experience, physicians still frequently order nebulizer treatments for patients with asthma exacerbations, despite several advantages of MDIs with spacers. Notably, they cost less and don’t require maintenance or a power source. Physicians administered nebulizer therapy at more than 3.6 million emergency department (ED) visits in 2006.⁸

In this latest Cochrane review, Cates et al¹ added 4 new studies to those included in their earlier Cochrane meta-analysis, and looked at what, if any, effect these studies had on our understanding of nebulizers vs MDIs with spacers.

STUDY SUMMARY: Outcomes with nebulizers are no better than those with spacers

This systematic review and meta-analysis pooled the results of RCTs comparing spacers to nebulizers for administering beta-agonists during acute, non-life-threatening asthma exacerbations.¹ The authors reviewed studies conducted in EDs, hospitals, and outpatient settings that included children and adults. The primary outcomes were hospital admission rates and duration of hospital stay. Secondary outcomes included time spent in the ED, change in pulse rate, and incidence of tremor.

The time children spent in the ED was cut by half an hour when MDIs with spacers were used.Cates et al¹ analyzed 39 trials that included 1897 children and 729 adults and were conducted primarily in an ED or outpatient setting. The 4 new studies added 295 children and 58 adults to the researchers’ earlier meta-analysis. Studies involving adults and children were pooled separately. Most patients received multiple treatments with beta-agonists titrated to the individual’s response.

No differences in hospitalizations. Rates of hospital admissions did not differ between patients receiving beta-agonists via a spacer compared to a nebulizer in both adults (relative risk [RR]=.94; 95% confidence interval [CI], .61-1.43) and children (RR=.71; 95% CI, .47-1.08). Duration of hospital stay did not differ between the 2 delivery methods in adults (mean difference [MD]=-.60 days; 95% CI, -3.23 to 2.03) and children (MD=.33 days; 95% CI, -.10 to .76).

For kids, spacers meant less time in the ED. Duration in the ED was approximately half an hour shorter for children using spacers (MD=-33.48 minutes; 95% CI, -43.3 to -23.6, P<.001). There was no difference in time spent in the ED observed in adults (MD=1.75 minutes; 95% CI, -23.45 to 26.95). The rate of tremor was lower in children using spacers (RR=.64; 95% CI, .44-.95, P=.027), and was similar in adults (RR=1.12; 95% CI, .66-1.9). The rise in pulse rate was lower in children using spacers (MD=-5.41% change from baseline; 95% CI, -8.34 to -2.48; P<.001), and was similar in adults (MD=-1.23%; 95% CI, -4.06 to 1.60).

WHAT'S NEW: Additional evidence that spacers are as effective as nebulizers

This meta-analysis, which included 4 new studies, should finally dispel the myth that nebulizers deliver beta-agonists more effectively than MDIs with spacers. Additionally, in children, spacers are associated with lower rates of side effects, including tremor and elevated pulse rate.

CAVEATS: Most studies involving children were open label

Although most of the adult trials in this meta-analysis involved a double-dummy design, which allows for effective participant blinding, most of the studies involving children were open label. This open-label design might have been a source of reporting bias for symptom-related outcomes, but should not have affected hospital admission rates or duration of hospital stay.

In the double-dummy studies, adults received both a nebulizer and a spacer, which likely explains the similar time spent in the ED by the treatment and control groups.

CHALLENGES TO IMPLEMENTATION: Old habits are hard to break

Doctors may think that patients view nebulizers as more potent or more effective than spacers and thus be more likely to order them. Some patients may prefer nebulizers because of convenience or other factors.

Acknowledgement
The PURLs Surveillance System was 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.

Illustrative case

A 6-year-old girl with a history of reactive airway disease comes to your office complaining of cough and wheezing. On exam, she has mild retractions, a respiratory rate of 35, and an oxygen saturation of 96% on room air. Her lung fields are diffusely wheezy. Her parents would like to keep her out of the hospital. How should you order her albuterol to decrease her wheezing and minimize adverse effects?

Asthma affects nearly 19 million adults and 7 million children in the United States.² Asthma exacerbations are the third most common reason for hospitalization in children.^2,3 Treatment usually requires multiple agents, including inhaled beta-agonists. These are most effective when delivered to the peripheral airways, which is a challenge during an asthma exacerbation because of airway swelling and rapid breathing. Two devices have been developed to effectively deliver medication to the peripheral airways: nebulizers and MDIs with a holding chamber (spacer).¹

Several studies have demonstrated that for mild to moderate asthma exacerbations, administering a beta-agonist via an MDI with a spacer is as effective as using a nebulizer.^4,5 Asthma treatment guidelines also state that spacers are either comparable to or preferred over nebulizers for beta-agonist administration in children and adults.^6,7 However, based on our experience, physicians still frequently order nebulizer treatments for patients with asthma exacerbations, despite several advantages of MDIs with spacers. Notably, they cost less and don’t require maintenance or a power source. Physicians administered nebulizer therapy at more than 3.6 million emergency department (ED) visits in 2006.⁸

In this latest Cochrane review, Cates et al¹ added 4 new studies to those included in their earlier Cochrane meta-analysis, and looked at what, if any, effect these studies had on our understanding of nebulizers vs MDIs with spacers.

STUDY SUMMARY: Outcomes with nebulizers are no better than those with spacers

This systematic review and meta-analysis pooled the results of RCTs comparing spacers to nebulizers for administering beta-agonists during acute, non-life-threatening asthma exacerbations.¹ The authors reviewed studies conducted in EDs, hospitals, and outpatient settings that included children and adults. The primary outcomes were hospital admission rates and duration of hospital stay. Secondary outcomes included time spent in the ED, change in pulse rate, and incidence of tremor.

The time children spent in the ED was cut by half an hour when MDIs with spacers were used.Cates et al¹ analyzed 39 trials that included 1897 children and 729 adults and were conducted primarily in an ED or outpatient setting. The 4 new studies added 295 children and 58 adults to the researchers’ earlier meta-analysis. Studies involving adults and children were pooled separately. Most patients received multiple treatments with beta-agonists titrated to the individual’s response.

No differences in hospitalizations. Rates of hospital admissions did not differ between patients receiving beta-agonists via a spacer compared to a nebulizer in both adults (relative risk [RR]=.94; 95% confidence interval [CI], .61-1.43) and children (RR=.71; 95% CI, .47-1.08). Duration of hospital stay did not differ between the 2 delivery methods in adults (mean difference [MD]=-.60 days; 95% CI, -3.23 to 2.03) and children (MD=.33 days; 95% CI, -.10 to .76).

For kids, spacers meant less time in the ED. Duration in the ED was approximately half an hour shorter for children using spacers (MD=-33.48 minutes; 95% CI, -43.3 to -23.6, P<.001). There was no difference in time spent in the ED observed in adults (MD=1.75 minutes; 95% CI, -23.45 to 26.95). The rate of tremor was lower in children using spacers (RR=.64; 95% CI, .44-.95, P=.027), and was similar in adults (RR=1.12; 95% CI, .66-1.9). The rise in pulse rate was lower in children using spacers (MD=-5.41% change from baseline; 95% CI, -8.34 to -2.48; P<.001), and was similar in adults (MD=-1.23%; 95% CI, -4.06 to 1.60).

WHAT'S NEW: Additional evidence that spacers are as effective as nebulizers

This meta-analysis, which included 4 new studies, should finally dispel the myth that nebulizers deliver beta-agonists more effectively than MDIs with spacers. Additionally, in children, spacers are associated with lower rates of side effects, including tremor and elevated pulse rate.

CAVEATS: Most studies involving children were open label

Although most of the adult trials in this meta-analysis involved a double-dummy design, which allows for effective participant blinding, most of the studies involving children were open label. This open-label design might have been a source of reporting bias for symptom-related outcomes, but should not have affected hospital admission rates or duration of hospital stay.

In the double-dummy studies, adults received both a nebulizer and a spacer, which likely explains the similar time spent in the ED by the treatment and control groups.

CHALLENGES TO IMPLEMENTATION: Old habits are hard to break

Doctors may think that patients view nebulizers as more potent or more effective than spacers and thus be more likely to order them. Some patients may prefer nebulizers because of convenience or other factors.

Acknowledgement
The PURLs Surveillance System was 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.

Illustrative case

A 6-year-old girl with a history of reactive airway disease comes to your office complaining of cough and wheezing. On exam, she has mild retractions, a respiratory rate of 35, and an oxygen saturation of 96% on room air. Her lung fields are diffusely wheezy. Her parents would like to keep her out of the hospital. How should you order her albuterol to decrease her wheezing and minimize adverse effects?

Asthma affects nearly 19 million adults and 7 million children in the United States.² Asthma exacerbations are the third most common reason for hospitalization in children.^2,3 Treatment usually requires multiple agents, including inhaled beta-agonists. These are most effective when delivered to the peripheral airways, which is a challenge during an asthma exacerbation because of airway swelling and rapid breathing. Two devices have been developed to effectively deliver medication to the peripheral airways: nebulizers and MDIs with a holding chamber (spacer).¹

Several studies have demonstrated that for mild to moderate asthma exacerbations, administering a beta-agonist via an MDI with a spacer is as effective as using a nebulizer.^4,5 Asthma treatment guidelines also state that spacers are either comparable to or preferred over nebulizers for beta-agonist administration in children and adults.^6,7 However, based on our experience, physicians still frequently order nebulizer treatments for patients with asthma exacerbations, despite several advantages of MDIs with spacers. Notably, they cost less and don’t require maintenance or a power source. Physicians administered nebulizer therapy at more than 3.6 million emergency department (ED) visits in 2006.⁸

In this latest Cochrane review, Cates et al¹ added 4 new studies to those included in their earlier Cochrane meta-analysis, and looked at what, if any, effect these studies had on our understanding of nebulizers vs MDIs with spacers.

STUDY SUMMARY: Outcomes with nebulizers are no better than those with spacers

This systematic review and meta-analysis pooled the results of RCTs comparing spacers to nebulizers for administering beta-agonists during acute, non-life-threatening asthma exacerbations.¹ The authors reviewed studies conducted in EDs, hospitals, and outpatient settings that included children and adults. The primary outcomes were hospital admission rates and duration of hospital stay. Secondary outcomes included time spent in the ED, change in pulse rate, and incidence of tremor.

The time children spent in the ED was cut by half an hour when MDIs with spacers were used.Cates et al¹ analyzed 39 trials that included 1897 children and 729 adults and were conducted primarily in an ED or outpatient setting. The 4 new studies added 295 children and 58 adults to the researchers’ earlier meta-analysis. Studies involving adults and children were pooled separately. Most patients received multiple treatments with beta-agonists titrated to the individual’s response.

No differences in hospitalizations. Rates of hospital admissions did not differ between patients receiving beta-agonists via a spacer compared to a nebulizer in both adults (relative risk [RR]=.94; 95% confidence interval [CI], .61-1.43) and children (RR=.71; 95% CI, .47-1.08). Duration of hospital stay did not differ between the 2 delivery methods in adults (mean difference [MD]=-.60 days; 95% CI, -3.23 to 2.03) and children (MD=.33 days; 95% CI, -.10 to .76).

For kids, spacers meant less time in the ED. Duration in the ED was approximately half an hour shorter for children using spacers (MD=-33.48 minutes; 95% CI, -43.3 to -23.6, P<.001). There was no difference in time spent in the ED observed in adults (MD=1.75 minutes; 95% CI, -23.45 to 26.95). The rate of tremor was lower in children using spacers (RR=.64; 95% CI, .44-.95, P=.027), and was similar in adults (RR=1.12; 95% CI, .66-1.9). The rise in pulse rate was lower in children using spacers (MD=-5.41% change from baseline; 95% CI, -8.34 to -2.48; P<.001), and was similar in adults (MD=-1.23%; 95% CI, -4.06 to 1.60).

WHAT'S NEW: Additional evidence that spacers are as effective as nebulizers

This meta-analysis, which included 4 new studies, should finally dispel the myth that nebulizers deliver beta-agonists more effectively than MDIs with spacers. Additionally, in children, spacers are associated with lower rates of side effects, including tremor and elevated pulse rate.

CAVEATS: Most studies involving children were open label

Although most of the adult trials in this meta-analysis involved a double-dummy design, which allows for effective participant blinding, most of the studies involving children were open label. This open-label design might have been a source of reporting bias for symptom-related outcomes, but should not have affected hospital admission rates or duration of hospital stay.

In the double-dummy studies, adults received both a nebulizer and a spacer, which likely explains the similar time spent in the ED by the treatment and control groups.

CHALLENGES TO IMPLEMENTATION: Old habits are hard to break

Doctors may think that patients view nebulizers as more potent or more effective than spacers and thus be more likely to order them. Some patients may prefer nebulizers because of convenience or other factors.

Acknowledgement
The PURLs Surveillance System was 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.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

Lab mouse

Researchers say they’ve found a way to target myeloid-derived suppressor cells (MDSCs) while sparing other immune cells.

In preclinical experiments, the team showed they could deplete MDSCs—and shrink tumors—using peptide antibodies.

These “peptibodies” wiped out MDSCs in the blood, spleen, and tumor cells of mice without binding to other white blood cells or dendritic cells.

The researchers described this work in Nature Medicine.

“We’ve known about [MDSCs] blocking immune response for a decade but haven’t been able to shut them down for lack of an identified target,” said the paper’s senior author, Larry Kwak, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“This is the first demonstration of a molecule on these cells that allows us to make an antibody—in this case, a peptide—to bind to them and get rid of them. It’s a brand new immunotherapy target.”

Dr Kwak and his colleagues began this research by applying a peptide phage library to MDSCs, which allowed for a mass screening of candidate peptides that bind to the surface of MDSCs. This revealed 2 peptides, labeled G3 and H6, that bound only to MDSCs.

The researchers fused the 2 peptides to a portion of mouse immune globulin to generate experimental peptibodies called pep-G3 and pep-H6. Both peptibodies bound to both types of MDSCs—monocytic and granulocytic cells.

Dr Kwak and his colleagues then tested the peptibodies in 2 mouse models of thymic tumors, as well as models of melanoma and lymphoma. The team compared pep-G3 and pep-H6 to a control peptibody and an antibody against Gr-1.

Both pep-G3 and pep-H6 depleted monocytic and granulocytic MDSCs in the blood and spleens of all mice. But the Gr-1 antibody only worked against granulocytic MDSCs.

To see whether MDSC depletion would impede tumor growth, the researchers administered the peptibodies to mice with thymic tumors every other day for 2 weeks.

Mice treated with either pep-G3 or pep-H6 had tumors that were about half the size and weight of those in mice treated with the control peptibody or the Gr-1 antibody.

Lastly, the researchers analyzed surface proteins on the MDSCs and found that S100A9 and S100A8 are the likely binding targets for pep-G3 and pep-H6.

Dr Kwak and his colleagues said they are now working to extend these findings to human MDSCs.

An elemental diet was more than 90% effective in inducing histologic remission in eosinophilic esophagitis patients, reported Dr. Ángel Arias and colleagues in the June issue of Gastroenterology.

The Six Food Elimination Diet was also highly efficacious, reinforcing the idea that dietary modification "should be considered as a first-line therapy in both children and adults affected by this disease," wrote the investigators (doi:10.1053/j.gastro.2014.02.006).

Dr. Arias of the Complejo Hospitalario La Mancha Centro, in Alcázar de San Juan, Spain, searched the MEDLINE, EMBASE, and SCOPUS databases for studies performed prior to June 2013 investigating the efficacy of dietary interventions in eosinophilic esophagitis (EoE).

Abstracts and other relevant material from conferences including Digestive Disease Week, the American College of Gastroenterology meeting, and European Gastroenterology Week were also included.

Overall, 33 studies were included, 23 of which were full articles with the remainder being abstracts; there were a total of 1,128 children and 189 adults included in the analysis.

Of the 13 studies that assessed the efficacy of exclusive feeding with an amino acid–based elemental diet (involving 411 children and 18 adults), 90.8% of patients achieved histologic remission of EoE, defined as fewer than 15 eosinophils per high-power field on esophageal biopsy (95% confidence interval, 84.7%-95.5%).

The next best diet, the Six Food Elimination Diet (SFED), offered a 72.1% efficacy rate (95% CI, 65.8%-78.1%) across 75 children and 122 adults and was "the only one assessed in more adults than children."

On the other hand, the strategy of eliminating foods that gave a positive result in skin allergy tests was assessed in 14 studies (594 children and 32 adults), and demonstrated an overall efficacy of just 45.5% (95% CI, 35.4%-55.7%).

Other less-studied diets included gluten-free and cow’s milk elimination diets, both of which seemed to result in histologic remission (58.7% and 68.2%, respectively).

However, "because studies assessing these dietary treatments are still scarce, making conclusions from them can be risky," wrote the authors.

"For example, although the overall efficacy of a gluten-free diet in achieving histologic remission of EoE was 58.7%, the remission rate ranged from 23.1% to 85.6%," they reported.

"Despite its obvious success, the multiple drawbacks of elemental diets, which include the need to avoid all table food, its unpleasant taste, and high cost, and the psychological effects produced by the social limitations that this diet entails, have probably contributed to the fact that this dietary intervention has been restricted almost exclusively to pediatric patients," commented Dr. Arias.

"In fact, no research on adults was available until 2013, with the reported remission rates being comparable with those documented in children."

On the other hand, the relatively high efficacy of the SFED diet, which avoids many of the disadvantages of the elemental diet, seems to make this the best choice for "children and motivated adult patients," added the researchers.

Future studies and meta-analyses should address whether diet adherence results in changes in esophageal fibrosis as well as quality of life issues brought on by diet adherence.

The authors disclosed no relevant financial conflicts.

ginews@gastro.org

An elemental diet was more than 90% effective in inducing histologic remission in eosinophilic esophagitis patients, reported Dr. Ángel Arias and colleagues in the June issue of Gastroenterology.

The Six Food Elimination Diet was also highly efficacious, reinforcing the idea that dietary modification "should be considered as a first-line therapy in both children and adults affected by this disease," wrote the investigators (doi:10.1053/j.gastro.2014.02.006).

Dr. Arias of the Complejo Hospitalario La Mancha Centro, in Alcázar de San Juan, Spain, searched the MEDLINE, EMBASE, and SCOPUS databases for studies performed prior to June 2013 investigating the efficacy of dietary interventions in eosinophilic esophagitis (EoE).

Abstracts and other relevant material from conferences including Digestive Disease Week, the American College of Gastroenterology meeting, and European Gastroenterology Week were also included.

Overall, 33 studies were included, 23 of which were full articles with the remainder being abstracts; there were a total of 1,128 children and 189 adults included in the analysis.

Of the 13 studies that assessed the efficacy of exclusive feeding with an amino acid–based elemental diet (involving 411 children and 18 adults), 90.8% of patients achieved histologic remission of EoE, defined as fewer than 15 eosinophils per high-power field on esophageal biopsy (95% confidence interval, 84.7%-95.5%).

The next best diet, the Six Food Elimination Diet (SFED), offered a 72.1% efficacy rate (95% CI, 65.8%-78.1%) across 75 children and 122 adults and was "the only one assessed in more adults than children."

On the other hand, the strategy of eliminating foods that gave a positive result in skin allergy tests was assessed in 14 studies (594 children and 32 adults), and demonstrated an overall efficacy of just 45.5% (95% CI, 35.4%-55.7%).

Other less-studied diets included gluten-free and cow’s milk elimination diets, both of which seemed to result in histologic remission (58.7% and 68.2%, respectively).

However, "because studies assessing these dietary treatments are still scarce, making conclusions from them can be risky," wrote the authors.

"For example, although the overall efficacy of a gluten-free diet in achieving histologic remission of EoE was 58.7%, the remission rate ranged from 23.1% to 85.6%," they reported.

"Despite its obvious success, the multiple drawbacks of elemental diets, which include the need to avoid all table food, its unpleasant taste, and high cost, and the psychological effects produced by the social limitations that this diet entails, have probably contributed to the fact that this dietary intervention has been restricted almost exclusively to pediatric patients," commented Dr. Arias.

"In fact, no research on adults was available until 2013, with the reported remission rates being comparable with those documented in children."

On the other hand, the relatively high efficacy of the SFED diet, which avoids many of the disadvantages of the elemental diet, seems to make this the best choice for "children and motivated adult patients," added the researchers.

Future studies and meta-analyses should address whether diet adherence results in changes in esophageal fibrosis as well as quality of life issues brought on by diet adherence.

The authors disclosed no relevant financial conflicts.

ginews@gastro.org

An elemental diet was more than 90% effective in inducing histologic remission in eosinophilic esophagitis patients, reported Dr. Ángel Arias and colleagues in the June issue of Gastroenterology.

The Six Food Elimination Diet was also highly efficacious, reinforcing the idea that dietary modification "should be considered as a first-line therapy in both children and adults affected by this disease," wrote the investigators (doi:10.1053/j.gastro.2014.02.006).

Dr. Arias of the Complejo Hospitalario La Mancha Centro, in Alcázar de San Juan, Spain, searched the MEDLINE, EMBASE, and SCOPUS databases for studies performed prior to June 2013 investigating the efficacy of dietary interventions in eosinophilic esophagitis (EoE).

Abstracts and other relevant material from conferences including Digestive Disease Week, the American College of Gastroenterology meeting, and European Gastroenterology Week were also included.

Overall, 33 studies were included, 23 of which were full articles with the remainder being abstracts; there were a total of 1,128 children and 189 adults included in the analysis.

Of the 13 studies that assessed the efficacy of exclusive feeding with an amino acid–based elemental diet (involving 411 children and 18 adults), 90.8% of patients achieved histologic remission of EoE, defined as fewer than 15 eosinophils per high-power field on esophageal biopsy (95% confidence interval, 84.7%-95.5%).

The next best diet, the Six Food Elimination Diet (SFED), offered a 72.1% efficacy rate (95% CI, 65.8%-78.1%) across 75 children and 122 adults and was "the only one assessed in more adults than children."

On the other hand, the strategy of eliminating foods that gave a positive result in skin allergy tests was assessed in 14 studies (594 children and 32 adults), and demonstrated an overall efficacy of just 45.5% (95% CI, 35.4%-55.7%).

Other less-studied diets included gluten-free and cow’s milk elimination diets, both of which seemed to result in histologic remission (58.7% and 68.2%, respectively).

However, "because studies assessing these dietary treatments are still scarce, making conclusions from them can be risky," wrote the authors.

"For example, although the overall efficacy of a gluten-free diet in achieving histologic remission of EoE was 58.7%, the remission rate ranged from 23.1% to 85.6%," they reported.

"Despite its obvious success, the multiple drawbacks of elemental diets, which include the need to avoid all table food, its unpleasant taste, and high cost, and the psychological effects produced by the social limitations that this diet entails, have probably contributed to the fact that this dietary intervention has been restricted almost exclusively to pediatric patients," commented Dr. Arias.

"In fact, no research on adults was available until 2013, with the reported remission rates being comparable with those documented in children."

On the other hand, the relatively high efficacy of the SFED diet, which avoids many of the disadvantages of the elemental diet, seems to make this the best choice for "children and motivated adult patients," added the researchers.

Future studies and meta-analyses should address whether diet adherence results in changes in esophageal fibrosis as well as quality of life issues brought on by diet adherence.

The authors disclosed no relevant financial conflicts.

ginews@gastro.org