No. Using N-acetylcysteine (NAC) routinely to prevent contrast-induced acute kidney injury is not supported by the evidence at this time.^1,2 However, there is evidence to suggest using it for patients at high risk, ie, those with significant baseline renal dysfunction.^3,4

INCIDENCE AND IMPACT OF ACUTE KIDNEY INJURY

Intraarterial use of contrast is associated with a higher risk of acute kidney injury than intravenous use. Most studies of NAC for the prevention of contrast-induced acute kidney injury have focused on patients receiving contrast intraarterially. The reported rates of contrast-induced acute kidney injury also vary depending on how acute kidney injury was defined.

Although the incidence is low (1% to 2%) in patients with normal renal function, it can be as high as 25% in patients with renal impairment or a chronic condition such as diabetes or congestive heart failure, or in elderly patients.⁵

The development of acute kidney injury after percutaneous coronary intervention is associated with a longer hospital stay, a higher cost of care, and higher rates of morbidity and death.⁶

RATIONALE FOR USING N-ACETYLCYSTEINE

Contrast-induced acute kidney injury is thought to involve vasoconstriction and medullary ischemia mediated by reactive oxygen species.⁵ As an antioxidant and a scavenger of free radicals, NAC showed early promise in reducing the risk of this complication, but subsequent trials raised doubts about its efficacy. ^1,2 In clinical practice, the drug is often used to prevent acute kidney injury because it is easy to give, cheap, and has few side effects. Recently, however, there have been suggestions that giving it intravenously may be associated with adverse effects that include anaphylactoid reactions.⁷

THE POSITIVE TRIALS

Tepel et al³ performed one of the earliest trials that found that NAC prevented contrast-induced acute kidney injury. The trial included 83 patients with stable chronic kidney disease (mean serum creatinine 2.4 mg/dL) who underwent computed tomography with about 75 mL of a nonionic, low-osmolality contrast agent. Participants were randomized to receive either NAC (600 mg orally twice daily) and 0.45% saline intravenously or placebo and saline. Acute kidney injury was defined as an increase of at least 0.5 mg/dL in the serum creatinine level 48 hours after the contrast dye was given.

The rate of acute kidney injury was significantly lower in the treatment group (2% vs 21%, P = .01). None of the patients who developed acute kidney injury needed hemodialysis.

Shyu et al⁴ studied 121 patients with chronic kidney disease (mean serum creatinine 2.8 mg/dL) who underwent a coronary procedure. Patients were randomized to receive NAC 400 mg orally twice daily or placebo in addition to 0.45% saline in both groups. Two (3.3%) of the 60 patients in the treated group and 15 (24.6%) of the 61 patients in the control group had an increase in creatinine concentration greater than 0.5 mg/dL at 48 hours (P < .001).

Both of these single-center studies were limited by small sample sizes and very short follow-up. Further, the impact of the drug on important clinical outcomes such as death and progression of chronic kidney disease was not reported.

Marenzi et al⁸ randomized 354 patients undergoing coronary angioplasty as the primary treatment for acute myocardial infarction to one of three treatment groups:

• NAC in a standard dosage (a 600-mg intravenous bolus before the procedure and then 600 mg orally twice daily for 48 hours afterward)
• NAC in a high dosage (a 1,200-mg intravenous bolus and then 1,200 mg orally twice daily for 48 hours)
• Placebo.

The two treatment groups had significantly lower rates of acute kidney injury than the placebo group. In addition, the hospital mortality rate and the rate of a composite end point of death, need for renal replacement therapy, or need for mechanical ventilation were significantly lower in the treated groups. However, the number of events was small, and a beneficial effect on the death rate has not been confirmed by other studies.⁵

THE NEGATIVE TRIALS

Several studies found that NAC did not prevent contrast-induced acute kidney injury.^1,2,9

The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,¹ was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.

The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).

Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.

Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).¹

The ACT differed from the “positive” study by Marenzi et al⁸ in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.

Webb et al² found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.

Gurm et al⁹ found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.

MIXED RESULTS IN META-ANALYSES

Results from meta-analyses have been mixed,^10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.

CURRENT GUIDELINES

After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.¹²

However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).⁵

WHAT WE RECOMMEND

The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m².

In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:

• Clarify whether contrast is truly needed
• When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
• Discontinue nephrotoxic agents
• Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
• Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m²), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
• Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.^7,13

We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.

No. Using N-acetylcysteine (NAC) routinely to prevent contrast-induced acute kidney injury is not supported by the evidence at this time.^1,2 However, there is evidence to suggest using it for patients at high risk, ie, those with significant baseline renal dysfunction.^3,4

INCIDENCE AND IMPACT OF ACUTE KIDNEY INJURY

Intraarterial use of contrast is associated with a higher risk of acute kidney injury than intravenous use. Most studies of NAC for the prevention of contrast-induced acute kidney injury have focused on patients receiving contrast intraarterially. The reported rates of contrast-induced acute kidney injury also vary depending on how acute kidney injury was defined.

Although the incidence is low (1% to 2%) in patients with normal renal function, it can be as high as 25% in patients with renal impairment or a chronic condition such as diabetes or congestive heart failure, or in elderly patients.⁵

The development of acute kidney injury after percutaneous coronary intervention is associated with a longer hospital stay, a higher cost of care, and higher rates of morbidity and death.⁶

RATIONALE FOR USING N-ACETYLCYSTEINE

Contrast-induced acute kidney injury is thought to involve vasoconstriction and medullary ischemia mediated by reactive oxygen species.⁵ As an antioxidant and a scavenger of free radicals, NAC showed early promise in reducing the risk of this complication, but subsequent trials raised doubts about its efficacy. ^1,2 In clinical practice, the drug is often used to prevent acute kidney injury because it is easy to give, cheap, and has few side effects. Recently, however, there have been suggestions that giving it intravenously may be associated with adverse effects that include anaphylactoid reactions.⁷

THE POSITIVE TRIALS

Tepel et al³ performed one of the earliest trials that found that NAC prevented contrast-induced acute kidney injury. The trial included 83 patients with stable chronic kidney disease (mean serum creatinine 2.4 mg/dL) who underwent computed tomography with about 75 mL of a nonionic, low-osmolality contrast agent. Participants were randomized to receive either NAC (600 mg orally twice daily) and 0.45% saline intravenously or placebo and saline. Acute kidney injury was defined as an increase of at least 0.5 mg/dL in the serum creatinine level 48 hours after the contrast dye was given.

The rate of acute kidney injury was significantly lower in the treatment group (2% vs 21%, P = .01). None of the patients who developed acute kidney injury needed hemodialysis.

Shyu et al⁴ studied 121 patients with chronic kidney disease (mean serum creatinine 2.8 mg/dL) who underwent a coronary procedure. Patients were randomized to receive NAC 400 mg orally twice daily or placebo in addition to 0.45% saline in both groups. Two (3.3%) of the 60 patients in the treated group and 15 (24.6%) of the 61 patients in the control group had an increase in creatinine concentration greater than 0.5 mg/dL at 48 hours (P < .001).

Both of these single-center studies were limited by small sample sizes and very short follow-up. Further, the impact of the drug on important clinical outcomes such as death and progression of chronic kidney disease was not reported.

Marenzi et al⁸ randomized 354 patients undergoing coronary angioplasty as the primary treatment for acute myocardial infarction to one of three treatment groups:

• NAC in a standard dosage (a 600-mg intravenous bolus before the procedure and then 600 mg orally twice daily for 48 hours afterward)
• NAC in a high dosage (a 1,200-mg intravenous bolus and then 1,200 mg orally twice daily for 48 hours)
• Placebo.

The two treatment groups had significantly lower rates of acute kidney injury than the placebo group. In addition, the hospital mortality rate and the rate of a composite end point of death, need for renal replacement therapy, or need for mechanical ventilation were significantly lower in the treated groups. However, the number of events was small, and a beneficial effect on the death rate has not been confirmed by other studies.⁵

THE NEGATIVE TRIALS

Several studies found that NAC did not prevent contrast-induced acute kidney injury.^1,2,9

The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,¹ was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.

The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).

Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.

Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).¹

The ACT differed from the “positive” study by Marenzi et al⁸ in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.

Webb et al² found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.

Gurm et al⁹ found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.

MIXED RESULTS IN META-ANALYSES

Results from meta-analyses have been mixed,^10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.

CURRENT GUIDELINES

After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.¹²

However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).⁵

WHAT WE RECOMMEND

The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m².

In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:

• Clarify whether contrast is truly needed
• When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
• Discontinue nephrotoxic agents
• Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
• Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m²), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
• Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.^7,13

We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.

No. Using N-acetylcysteine (NAC) routinely to prevent contrast-induced acute kidney injury is not supported by the evidence at this time.^1,2 However, there is evidence to suggest using it for patients at high risk, ie, those with significant baseline renal dysfunction.^3,4

INCIDENCE AND IMPACT OF ACUTE KIDNEY INJURY

Intraarterial use of contrast is associated with a higher risk of acute kidney injury than intravenous use. Most studies of NAC for the prevention of contrast-induced acute kidney injury have focused on patients receiving contrast intraarterially. The reported rates of contrast-induced acute kidney injury also vary depending on how acute kidney injury was defined.

Although the incidence is low (1% to 2%) in patients with normal renal function, it can be as high as 25% in patients with renal impairment or a chronic condition such as diabetes or congestive heart failure, or in elderly patients.⁵

The development of acute kidney injury after percutaneous coronary intervention is associated with a longer hospital stay, a higher cost of care, and higher rates of morbidity and death.⁶

RATIONALE FOR USING N-ACETYLCYSTEINE

Contrast-induced acute kidney injury is thought to involve vasoconstriction and medullary ischemia mediated by reactive oxygen species.⁵ As an antioxidant and a scavenger of free radicals, NAC showed early promise in reducing the risk of this complication, but subsequent trials raised doubts about its efficacy. ^1,2 In clinical practice, the drug is often used to prevent acute kidney injury because it is easy to give, cheap, and has few side effects. Recently, however, there have been suggestions that giving it intravenously may be associated with adverse effects that include anaphylactoid reactions.⁷

THE POSITIVE TRIALS

Tepel et al³ performed one of the earliest trials that found that NAC prevented contrast-induced acute kidney injury. The trial included 83 patients with stable chronic kidney disease (mean serum creatinine 2.4 mg/dL) who underwent computed tomography with about 75 mL of a nonionic, low-osmolality contrast agent. Participants were randomized to receive either NAC (600 mg orally twice daily) and 0.45% saline intravenously or placebo and saline. Acute kidney injury was defined as an increase of at least 0.5 mg/dL in the serum creatinine level 48 hours after the contrast dye was given.

The rate of acute kidney injury was significantly lower in the treatment group (2% vs 21%, P = .01). None of the patients who developed acute kidney injury needed hemodialysis.

Shyu et al⁴ studied 121 patients with chronic kidney disease (mean serum creatinine 2.8 mg/dL) who underwent a coronary procedure. Patients were randomized to receive NAC 400 mg orally twice daily or placebo in addition to 0.45% saline in both groups. Two (3.3%) of the 60 patients in the treated group and 15 (24.6%) of the 61 patients in the control group had an increase in creatinine concentration greater than 0.5 mg/dL at 48 hours (P < .001).

Both of these single-center studies were limited by small sample sizes and very short follow-up. Further, the impact of the drug on important clinical outcomes such as death and progression of chronic kidney disease was not reported.

Marenzi et al⁸ randomized 354 patients undergoing coronary angioplasty as the primary treatment for acute myocardial infarction to one of three treatment groups:

• NAC in a standard dosage (a 600-mg intravenous bolus before the procedure and then 600 mg orally twice daily for 48 hours afterward)
• NAC in a high dosage (a 1,200-mg intravenous bolus and then 1,200 mg orally twice daily for 48 hours)
• Placebo.

The two treatment groups had significantly lower rates of acute kidney injury than the placebo group. In addition, the hospital mortality rate and the rate of a composite end point of death, need for renal replacement therapy, or need for mechanical ventilation were significantly lower in the treated groups. However, the number of events was small, and a beneficial effect on the death rate has not been confirmed by other studies.⁵

THE NEGATIVE TRIALS

Several studies found that NAC did not prevent contrast-induced acute kidney injury.^1,2,9

The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,¹ was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.

The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).

Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.

Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).¹

The ACT differed from the “positive” study by Marenzi et al⁸ in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.

Webb et al² found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.

Gurm et al⁹ found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.

MIXED RESULTS IN META-ANALYSES

Results from meta-analyses have been mixed,^10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.

CURRENT GUIDELINES

After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.¹²

However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).⁵

WHAT WE RECOMMEND

The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m².

In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:

• Clarify whether contrast is truly needed
• When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
• Discontinue nephrotoxic agents
• Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
• Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m²), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
• Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.^7,13

We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.

As autumn arrives and thoughts turn to pumpkins, football, and Thanks-giving dinner, it is time for health systems and physicians to prepare for the upcoming influenza season. In this issue of the Journal, Drs. Jin and Mossad review some practical virology and remind us why we must continue to encourage our patients and staff to be immunized against the flu.

Last year the flu season was surprisingly mild. The infection incidence seemed to peak late in the season, a reasonable number of people got vaccinated, and the level of viral antigenic drift was low. New hybrid viral strains did appear, but apparently with low prevalence, and the avian strains did not mutate to permit efficient human-to-human infection. But the relatively benign 2011–2012 flu season should not lull us into a lackadaisical approach to offering vaccination to all of our patients.

Ever since my own encounter with the flu a number of years ago, I have been pushing the vaccine with the zeal of a telemarketer. I was pleased that the vaccine arrived early this time, but continue to be surprised by the reasons patients offer for not receiving it—some strike me as akin to “the dog ate my homework.” For example: “I got the vaccine once and I got walking pneumonia.” And the always-popular “I got the vaccine and I got the flu.” Many patients don’t think they need the vaccine because they have never gotten the flu. (To them, I relate my tale of spending a weekend lying curled up on the floor of my bedroom having chills despite a sweatsuit and blanket). Some voice the scientifically irrational but common concern that since their immune system has been weakened by medications, they don’t want to get sick from the shot. And creatively, this year several patients have told me that they heard it is too early to get the vaccine—the effect won’t last all season.

Whatever our patients’ reason for recalcitrance, we should persevere and follow the national recommendation to vaccinate all persons over the age of 6 months. The vaccine may not be perfect, but with an estimated success rate of about 60%, it is better than any alternative approach. Plus, as Drs. Jin and Mossad note in their article, there is concern about emerging strains that are resistant to available antiviral therapies—0.5 mL of prevention trumps a pound of ineffective treatment.

As autumn arrives and thoughts turn to pumpkins, football, and Thanks-giving dinner, it is time for health systems and physicians to prepare for the upcoming influenza season. In this issue of the Journal, Drs. Jin and Mossad review some practical virology and remind us why we must continue to encourage our patients and staff to be immunized against the flu.

Last year the flu season was surprisingly mild. The infection incidence seemed to peak late in the season, a reasonable number of people got vaccinated, and the level of viral antigenic drift was low. New hybrid viral strains did appear, but apparently with low prevalence, and the avian strains did not mutate to permit efficient human-to-human infection. But the relatively benign 2011–2012 flu season should not lull us into a lackadaisical approach to offering vaccination to all of our patients.

Ever since my own encounter with the flu a number of years ago, I have been pushing the vaccine with the zeal of a telemarketer. I was pleased that the vaccine arrived early this time, but continue to be surprised by the reasons patients offer for not receiving it—some strike me as akin to “the dog ate my homework.” For example: “I got the vaccine once and I got walking pneumonia.” And the always-popular “I got the vaccine and I got the flu.” Many patients don’t think they need the vaccine because they have never gotten the flu. (To them, I relate my tale of spending a weekend lying curled up on the floor of my bedroom having chills despite a sweatsuit and blanket). Some voice the scientifically irrational but common concern that since their immune system has been weakened by medications, they don’t want to get sick from the shot. And creatively, this year several patients have told me that they heard it is too early to get the vaccine—the effect won’t last all season.

Whatever our patients’ reason for recalcitrance, we should persevere and follow the national recommendation to vaccinate all persons over the age of 6 months. The vaccine may not be perfect, but with an estimated success rate of about 60%, it is better than any alternative approach. Plus, as Drs. Jin and Mossad note in their article, there is concern about emerging strains that are resistant to available antiviral therapies—0.5 mL of prevention trumps a pound of ineffective treatment.

As autumn arrives and thoughts turn to pumpkins, football, and Thanks-giving dinner, it is time for health systems and physicians to prepare for the upcoming influenza season. In this issue of the Journal, Drs. Jin and Mossad review some practical virology and remind us why we must continue to encourage our patients and staff to be immunized against the flu.

Last year the flu season was surprisingly mild. The infection incidence seemed to peak late in the season, a reasonable number of people got vaccinated, and the level of viral antigenic drift was low. New hybrid viral strains did appear, but apparently with low prevalence, and the avian strains did not mutate to permit efficient human-to-human infection. But the relatively benign 2011–2012 flu season should not lull us into a lackadaisical approach to offering vaccination to all of our patients.

Ever since my own encounter with the flu a number of years ago, I have been pushing the vaccine with the zeal of a telemarketer. I was pleased that the vaccine arrived early this time, but continue to be surprised by the reasons patients offer for not receiving it—some strike me as akin to “the dog ate my homework.” For example: “I got the vaccine once and I got walking pneumonia.” And the always-popular “I got the vaccine and I got the flu.” Many patients don’t think they need the vaccine because they have never gotten the flu. (To them, I relate my tale of spending a weekend lying curled up on the floor of my bedroom having chills despite a sweatsuit and blanket). Some voice the scientifically irrational but common concern that since their immune system has been weakened by medications, they don’t want to get sick from the shot. And creatively, this year several patients have told me that they heard it is too early to get the vaccine—the effect won’t last all season.

Whatever our patients’ reason for recalcitrance, we should persevere and follow the national recommendation to vaccinate all persons over the age of 6 months. The vaccine may not be perfect, but with an estimated success rate of about 60%, it is better than any alternative approach. Plus, as Drs. Jin and Mossad note in their article, there is concern about emerging strains that are resistant to available antiviral therapies—0.5 mL of prevention trumps a pound of ineffective treatment.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

When an atypical presentation is missed

A 50-YEAR-OLD MORBIDLY OBESE MAN went to his family physician with complaints of back pain radiating to the chest, episodic shortness of breath, and diaphoresis. He had a history of uncontrolled high cholesterol. An electrocardiogram showed a Q wave in an inferior lead, which the physician attributed to an old infarct. The doctor didn’t order cardiac enzymes because his office couldn’t do the test.

The physician discharged the patient with a diagnosis of chest pain and a prescription for acetaminophen and hydrocodone. He was scheduled to see a cardiologist in 10 days, but no further cardiology workup was done.

The man died an hour later.

PLAINTIFF’S CLAIM The doctor was negligent in failing to recognize acute coronary syndrome resulting from obstructive coronary artery disease.

THE DEFENSE The patient was discharged in stable condition; cardiac arrest so soon after discharge increased the likelihood that the patient would have suffered sudden cardiac death even if he’d received emergency treatment.

VERDICT $825,000 Virginia settlement.

COMMENT Common, serious problems can present in atypical ways. A high index of suspicion for coronary artery disease in high-risk patients with thoracic pain and shortness of breath—as well as a rapid, thorough evaluation—should keep you out of court (and your patients alive).

Treatment delayed while infection spins out of control

VOMITING, DIARRHEA, AND PAIN AND SWELLING IN THE RIGHT HAND led to an ambulance trip to the emergency department (ED) for a 31-year-old woman. The ED physician diagnosed cellulitis and sepsis. Later that day, the patient was admitted to the intensive care unit, where the admitting physician noted lethargy and confusion, tachycardia, and blueness of the middle and ring fingers on the woman’s right hand. Her medical record suggested that she might have been bitten by a spider.

The patient spent the next 3 days in the ICU in deteriorating condition. She was then transferred to another hospital for treatment of necrotizing fasciitis. She underwent a number of surgeries, including amputation of her right middle and ring fingers, which resulted in significant scarring and deformity of her right hand and forearm.

PLAINTIFF’S CLAIM The defendants were negligent in failing to diagnose necrotizing fasciitis promptly.

THE DEFENSE The defendants who didn’t settle denied any negligence.

VERDICT $80,000 Indiana settlement with the defendant hospital and 1 physician; Indiana defense verdict for the other defendants.

COMMENT When serious infections don’t resolve in a timely manner, expert consultation is imperative.

Inattention to history dooms patient to repeat it

HEADACHES, FEVER, CHILLS, AND JOINT AND MUSCLE PAIN prompted a 42-year-old man to visit his medical group. He told the nurse practitioner (NP) who examined him that his mother had died of a ruptured cerebral aneurysm. The NP diagnosed a viral syndrome, ordered blood tests, and sent the patient home with prescriptions for antibiotics and pain medication. The patient didn’t undergo a neurologic examination.

About 2 weeks later, while continuing to suffer from headaches, the man collapsed and was found unresponsive. A computed tomography scan of his brain showed a subarachnoid hemorrhage and intercerebral hematoma. Further tests revealed a ruptured complex aneurysm, the cause of the hemorrhage. Despite aggressive treatment, the patient fell into a coma and died 3 months later.

PLAINTIFF’S CLAIM The NP should have realized that the patient was at high risk of an aneurysm.

THE DEFENSE No information about the defense is available.

VERDICT $1.5 million New Jersey settlement.

COMMENT I provided expert opinion in a similar case a couple of years ago. The lesson: Pay attention to the family history!

Persistent breast lumps, but no biopsy

ABOUT 3 YEARS AFTER GIVING BIRTH, a 38-year-old woman, who was still breastfeeding, went to her primary care physician complaining of pain, a dime-sized lump in her breast, and discharge from the nipple. The patient’s 2-year-old breast implants limited examination by the nurse practitioner (NP) who saw her. Galactorrhea was diagnosed and the woman was told to stop breastfeeding, apply ice packs, and come back in 2 weeks.

When the patient returned, her only remaining complaint was the lump, which the primary care physician attributed to mastitis. At a routine check-up 5 months later, the patient continued to complain of breast lumps. No breast exam was done, but the woman was referred to a gynecologist. An appointment for a breast ultrasound was scheduled for later in the month, but the patient said she didn’t receive notification of the date.

Metastatic breast cancer was subsequently diagnosed, and the woman died about 3 years later.

PLAINTIFF’S CLAIM The NP and primary care physician should have recommended a biopsy sooner.

THE DEFENSE The care given was proper; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $750,000 Massachusetts settlement.

COMMENT Failure to recommend biopsy of breast lumps is a leading cause of malpractice cases against family physicians. All persistent breast lumps require referral for biopsy— regardless of the patient’s age.

A red flag that was ignored for too long

A MAN IN HIS EARLY 30S consulted an orthopedist for mid-back pain. The doctor took radiographs of the man’s lower back and reported that he saw nothing amiss. When the man returned 3 months later complaining of the same kind of pain, the orthopedist examined him, prescribed a muscle relaxant, and sent him for physical therapy. The physician did not take any radiographs.

Four months later, the patient came back with pain in his mid-back and ribs. The orthopedist ordered radiographs of the ribs, which were read as normal.

After 18 months, the patient consulted another orthopedist, who ordered a magnetic resonance imaging scan and diagnosed a spinal plasmacytoma at levels T9 to T11. The tumor had destroyed some vertebrae and was compressing the spinal cord.

The patient underwent surgery to remove the tumor and insert screws from T6 to L2 to stabilize the spine. He wore a brace around his torso for months and had a bone marrow transplant. The patient couldn’t return to work.

PLAINTIFF’S CLAIM The tumor was clearly visible on the radiographs taken at the patient’s third visit to the first orthopedist; thoracic spine radiographs should have been taken at the previous 2 visits.

THE DEFENSE No information about the defense is available.

VERDICT $875,000 New Jersey settlement.

COMMENT Current guidelines recommend a red flags approach to imaging. This patient had a red flag—unremitting pain. When back pain persists unabated, it’s time for a thorough evaluation.

When an atypical presentation is missed

A 50-YEAR-OLD MORBIDLY OBESE MAN went to his family physician with complaints of back pain radiating to the chest, episodic shortness of breath, and diaphoresis. He had a history of uncontrolled high cholesterol. An electrocardiogram showed a Q wave in an inferior lead, which the physician attributed to an old infarct. The doctor didn’t order cardiac enzymes because his office couldn’t do the test.

The physician discharged the patient with a diagnosis of chest pain and a prescription for acetaminophen and hydrocodone. He was scheduled to see a cardiologist in 10 days, but no further cardiology workup was done.

The man died an hour later.

PLAINTIFF’S CLAIM The doctor was negligent in failing to recognize acute coronary syndrome resulting from obstructive coronary artery disease.

THE DEFENSE The patient was discharged in stable condition; cardiac arrest so soon after discharge increased the likelihood that the patient would have suffered sudden cardiac death even if he’d received emergency treatment.

VERDICT $825,000 Virginia settlement.

COMMENT Common, serious problems can present in atypical ways. A high index of suspicion for coronary artery disease in high-risk patients with thoracic pain and shortness of breath—as well as a rapid, thorough evaluation—should keep you out of court (and your patients alive).

Treatment delayed while infection spins out of control

VOMITING, DIARRHEA, AND PAIN AND SWELLING IN THE RIGHT HAND led to an ambulance trip to the emergency department (ED) for a 31-year-old woman. The ED physician diagnosed cellulitis and sepsis. Later that day, the patient was admitted to the intensive care unit, where the admitting physician noted lethargy and confusion, tachycardia, and blueness of the middle and ring fingers on the woman’s right hand. Her medical record suggested that she might have been bitten by a spider.

The patient spent the next 3 days in the ICU in deteriorating condition. She was then transferred to another hospital for treatment of necrotizing fasciitis. She underwent a number of surgeries, including amputation of her right middle and ring fingers, which resulted in significant scarring and deformity of her right hand and forearm.

PLAINTIFF’S CLAIM The defendants were negligent in failing to diagnose necrotizing fasciitis promptly.

THE DEFENSE The defendants who didn’t settle denied any negligence.

VERDICT $80,000 Indiana settlement with the defendant hospital and 1 physician; Indiana defense verdict for the other defendants.

COMMENT When serious infections don’t resolve in a timely manner, expert consultation is imperative.

Inattention to history dooms patient to repeat it

HEADACHES, FEVER, CHILLS, AND JOINT AND MUSCLE PAIN prompted a 42-year-old man to visit his medical group. He told the nurse practitioner (NP) who examined him that his mother had died of a ruptured cerebral aneurysm. The NP diagnosed a viral syndrome, ordered blood tests, and sent the patient home with prescriptions for antibiotics and pain medication. The patient didn’t undergo a neurologic examination.

About 2 weeks later, while continuing to suffer from headaches, the man collapsed and was found unresponsive. A computed tomography scan of his brain showed a subarachnoid hemorrhage and intercerebral hematoma. Further tests revealed a ruptured complex aneurysm, the cause of the hemorrhage. Despite aggressive treatment, the patient fell into a coma and died 3 months later.

PLAINTIFF’S CLAIM The NP should have realized that the patient was at high risk of an aneurysm.

THE DEFENSE No information about the defense is available.

VERDICT $1.5 million New Jersey settlement.

COMMENT I provided expert opinion in a similar case a couple of years ago. The lesson: Pay attention to the family history!

Persistent breast lumps, but no biopsy

ABOUT 3 YEARS AFTER GIVING BIRTH, a 38-year-old woman, who was still breastfeeding, went to her primary care physician complaining of pain, a dime-sized lump in her breast, and discharge from the nipple. The patient’s 2-year-old breast implants limited examination by the nurse practitioner (NP) who saw her. Galactorrhea was diagnosed and the woman was told to stop breastfeeding, apply ice packs, and come back in 2 weeks.

When the patient returned, her only remaining complaint was the lump, which the primary care physician attributed to mastitis. At a routine check-up 5 months later, the patient continued to complain of breast lumps. No breast exam was done, but the woman was referred to a gynecologist. An appointment for a breast ultrasound was scheduled for later in the month, but the patient said she didn’t receive notification of the date.

Metastatic breast cancer was subsequently diagnosed, and the woman died about 3 years later.

PLAINTIFF’S CLAIM The NP and primary care physician should have recommended a biopsy sooner.

THE DEFENSE The care given was proper; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $750,000 Massachusetts settlement.

COMMENT Failure to recommend biopsy of breast lumps is a leading cause of malpractice cases against family physicians. All persistent breast lumps require referral for biopsy— regardless of the patient’s age.

A red flag that was ignored for too long

A MAN IN HIS EARLY 30S consulted an orthopedist for mid-back pain. The doctor took radiographs of the man’s lower back and reported that he saw nothing amiss. When the man returned 3 months later complaining of the same kind of pain, the orthopedist examined him, prescribed a muscle relaxant, and sent him for physical therapy. The physician did not take any radiographs.

Four months later, the patient came back with pain in his mid-back and ribs. The orthopedist ordered radiographs of the ribs, which were read as normal.

After 18 months, the patient consulted another orthopedist, who ordered a magnetic resonance imaging scan and diagnosed a spinal plasmacytoma at levels T9 to T11. The tumor had destroyed some vertebrae and was compressing the spinal cord.

The patient underwent surgery to remove the tumor and insert screws from T6 to L2 to stabilize the spine. He wore a brace around his torso for months and had a bone marrow transplant. The patient couldn’t return to work.

PLAINTIFF’S CLAIM The tumor was clearly visible on the radiographs taken at the patient’s third visit to the first orthopedist; thoracic spine radiographs should have been taken at the previous 2 visits.

THE DEFENSE No information about the defense is available.

VERDICT $875,000 New Jersey settlement.

COMMENT Current guidelines recommend a red flags approach to imaging. This patient had a red flag—unremitting pain. When back pain persists unabated, it’s time for a thorough evaluation.

When an atypical presentation is missed

A 50-YEAR-OLD MORBIDLY OBESE MAN went to his family physician with complaints of back pain radiating to the chest, episodic shortness of breath, and diaphoresis. He had a history of uncontrolled high cholesterol. An electrocardiogram showed a Q wave in an inferior lead, which the physician attributed to an old infarct. The doctor didn’t order cardiac enzymes because his office couldn’t do the test.

The physician discharged the patient with a diagnosis of chest pain and a prescription for acetaminophen and hydrocodone. He was scheduled to see a cardiologist in 10 days, but no further cardiology workup was done.

The man died an hour later.

PLAINTIFF’S CLAIM The doctor was negligent in failing to recognize acute coronary syndrome resulting from obstructive coronary artery disease.

THE DEFENSE The patient was discharged in stable condition; cardiac arrest so soon after discharge increased the likelihood that the patient would have suffered sudden cardiac death even if he’d received emergency treatment.

VERDICT $825,000 Virginia settlement.

COMMENT Common, serious problems can present in atypical ways. A high index of suspicion for coronary artery disease in high-risk patients with thoracic pain and shortness of breath—as well as a rapid, thorough evaluation—should keep you out of court (and your patients alive).

Treatment delayed while infection spins out of control

VOMITING, DIARRHEA, AND PAIN AND SWELLING IN THE RIGHT HAND led to an ambulance trip to the emergency department (ED) for a 31-year-old woman. The ED physician diagnosed cellulitis and sepsis. Later that day, the patient was admitted to the intensive care unit, where the admitting physician noted lethargy and confusion, tachycardia, and blueness of the middle and ring fingers on the woman’s right hand. Her medical record suggested that she might have been bitten by a spider.

The patient spent the next 3 days in the ICU in deteriorating condition. She was then transferred to another hospital for treatment of necrotizing fasciitis. She underwent a number of surgeries, including amputation of her right middle and ring fingers, which resulted in significant scarring and deformity of her right hand and forearm.

PLAINTIFF’S CLAIM The defendants were negligent in failing to diagnose necrotizing fasciitis promptly.

THE DEFENSE The defendants who didn’t settle denied any negligence.

VERDICT $80,000 Indiana settlement with the defendant hospital and 1 physician; Indiana defense verdict for the other defendants.

COMMENT When serious infections don’t resolve in a timely manner, expert consultation is imperative.

Inattention to history dooms patient to repeat it

HEADACHES, FEVER, CHILLS, AND JOINT AND MUSCLE PAIN prompted a 42-year-old man to visit his medical group. He told the nurse practitioner (NP) who examined him that his mother had died of a ruptured cerebral aneurysm. The NP diagnosed a viral syndrome, ordered blood tests, and sent the patient home with prescriptions for antibiotics and pain medication. The patient didn’t undergo a neurologic examination.

About 2 weeks later, while continuing to suffer from headaches, the man collapsed and was found unresponsive. A computed tomography scan of his brain showed a subarachnoid hemorrhage and intercerebral hematoma. Further tests revealed a ruptured complex aneurysm, the cause of the hemorrhage. Despite aggressive treatment, the patient fell into a coma and died 3 months later.

PLAINTIFF’S CLAIM The NP should have realized that the patient was at high risk of an aneurysm.

THE DEFENSE No information about the defense is available.

VERDICT $1.5 million New Jersey settlement.

COMMENT I provided expert opinion in a similar case a couple of years ago. The lesson: Pay attention to the family history!

Persistent breast lumps, but no biopsy

ABOUT 3 YEARS AFTER GIVING BIRTH, a 38-year-old woman, who was still breastfeeding, went to her primary care physician complaining of pain, a dime-sized lump in her breast, and discharge from the nipple. The patient’s 2-year-old breast implants limited examination by the nurse practitioner (NP) who saw her. Galactorrhea was diagnosed and the woman was told to stop breastfeeding, apply ice packs, and come back in 2 weeks.

When the patient returned, her only remaining complaint was the lump, which the primary care physician attributed to mastitis. At a routine check-up 5 months later, the patient continued to complain of breast lumps. No breast exam was done, but the woman was referred to a gynecologist. An appointment for a breast ultrasound was scheduled for later in the month, but the patient said she didn’t receive notification of the date.

Metastatic breast cancer was subsequently diagnosed, and the woman died about 3 years later.

PLAINTIFF’S CLAIM The NP and primary care physician should have recommended a biopsy sooner.

THE DEFENSE The care given was proper; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $750,000 Massachusetts settlement.

COMMENT Failure to recommend biopsy of breast lumps is a leading cause of malpractice cases against family physicians. All persistent breast lumps require referral for biopsy— regardless of the patient’s age.

A red flag that was ignored for too long

A MAN IN HIS EARLY 30S consulted an orthopedist for mid-back pain. The doctor took radiographs of the man’s lower back and reported that he saw nothing amiss. When the man returned 3 months later complaining of the same kind of pain, the orthopedist examined him, prescribed a muscle relaxant, and sent him for physical therapy. The physician did not take any radiographs.

Four months later, the patient came back with pain in his mid-back and ribs. The orthopedist ordered radiographs of the ribs, which were read as normal.

After 18 months, the patient consulted another orthopedist, who ordered a magnetic resonance imaging scan and diagnosed a spinal plasmacytoma at levels T9 to T11. The tumor had destroyed some vertebrae and was compressing the spinal cord.

The patient underwent surgery to remove the tumor and insert screws from T6 to L2 to stabilize the spine. He wore a brace around his torso for months and had a bone marrow transplant. The patient couldn’t return to work.

PLAINTIFF’S CLAIM The tumor was clearly visible on the radiographs taken at the patient’s third visit to the first orthopedist; thoracic spine radiographs should have been taken at the previous 2 visits.

THE DEFENSE No information about the defense is available.

VERDICT $875,000 New Jersey settlement.

COMMENT Current guidelines recommend a red flags approach to imaging. This patient had a red flag—unremitting pain. When back pain persists unabated, it’s time for a thorough evaluation.

ILLUSTRATIVE CASE

A 65-year-old patient has been taking lorazepam for insomnia for more than a year. You are concerned about her ongoing use of the benzodiazepine and want to wean her from the medication. What strategies can you use to decrease, or eliminate, her use of the drug?

Benzodiazepines are commonly used medications, with an estimated 12-month prevalence of use of 8.6% in the United States.² While short-term use of these antianxiety medications can be effective, long-term use (defined as regular use for >3 months) is associated with significant risk.

Abuse linked to chronic use
Prescription drug abuse has recently become the nation’s leading cause of accidental death, overtaking motor vehicle accidents.³ And tranquilizers, including benzodiazepines, are the second most abused prescription medication, after pain relievers.⁴ In addition to dependence and withdrawal, chronic use of benzodiazepines is associated with daytime somnolence, blunted reflexes, memory loss, cognitive impairment, and an increased risk of falls and fractures—particularly in older patients.⁵

Reducing long-term use of benzodiazepines in a primary care setting is important but challenging. Until recently, most of the successful strategies reported were resource intensive and required multiple office visits.⁶

STUDY SUMMARY: Brief interventions are often effective

This study was a meta-analysis of randomized controlled trials in which “minimal interventions” were compared with usual care for their effectiveness in reducing or eliminating benzodiazepine use in primary care patients. A minimal intervention was defined as a letter, self-help information, or short consultation with a primary care provider. In each case, the message to the patient included (a) an expression of concern about the patient’s long-term use of the medication, (b) information about the potential adverse effects of the medication, and (c) advice on how to gradually reduce or stop using it.

Three studies met the inclusion criteria for randomization, blinding, and analysis by intention-to-treat.^7-9 All 3 (n=615) had a 6-month follow-up period, a higher proportion of women (>60%), and participants with a mean age >60 years. Few patients were lost to follow-up; withdrawal rates were low and similar in all 3 studies. Each study compared a letter with usual care; 2 of the 3 had a third arm that included both a letter and a short consultation.

Pooled results from the studies showed twice the reduction in benzodiazepine use in the intervention groups compared with the control groups (risk ratio [RR]=2.04; 95% confidence interval [CI], 1.5-2.8; P< .001). The RR for cessation of benzodiazepine use was 2.3 (95% CI, 1.3-4.2; P= .003). The number needed to treat for a reduction or cessation of use was 12. The studies reported benzodiazepine reduction rates of 20% to 35% in the intervention groups vs 6% to 15% in the usual care groups.^7-9 There appeared to be no additional benefit to adding the brief consultation compared with the letter alone.

WHAT’S NEW?: This strategy is easy to implement

While many methods to reduce benzodiazepine use have been studied, most involved levels of skill and resources that are not feasible for widespread use. This study found that a letter, stating the risks of continued use of the medication and providing a weaning schedule and tips for handling withdrawal, can be effective in reducing chronic use in a small but significant part of the population.

CAVEATS: Effects of withdrawal went unaddressed

The study did not adequately address the adverse effects of withdrawal from benzodiazepines, with one of the studies reporting significantly worse qualitative (but not quantitative) withdrawal symptoms at 6 months.⁷ This is of particular concern, as withdrawal symptoms are associated with the potential for relapse and concomitant abuse of other drugs and alcohol. We recommend that primary care physicians screen for substance abuse prior to the intervention and arrange for adequate follow-up.

All 3 studies in the meta-analysis lasted 6 months; no longer-term outcomes were reported. In addition, the study did not yield enough information to identify patients who would be most likely to respond to this brief intervention.

CHALLENGES TO IMPLEMENTATION: Determining which patients to target

Identifying patients who are appropriate candidates for this brief intervention and providing adequate monitoring for adverse effects of withdrawal are the main challenges of this practice changer. Nonetheless, chronic benzodiazepine use is of considerable concern, and we believe that this is a useful, and manageable intervention.

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.

ILLUSTRATIVE CASE

A 65-year-old patient has been taking lorazepam for insomnia for more than a year. You are concerned about her ongoing use of the benzodiazepine and want to wean her from the medication. What strategies can you use to decrease, or eliminate, her use of the drug?

Benzodiazepines are commonly used medications, with an estimated 12-month prevalence of use of 8.6% in the United States.² While short-term use of these antianxiety medications can be effective, long-term use (defined as regular use for >3 months) is associated with significant risk.

Abuse linked to chronic use
Prescription drug abuse has recently become the nation’s leading cause of accidental death, overtaking motor vehicle accidents.³ And tranquilizers, including benzodiazepines, are the second most abused prescription medication, after pain relievers.⁴ In addition to dependence and withdrawal, chronic use of benzodiazepines is associated with daytime somnolence, blunted reflexes, memory loss, cognitive impairment, and an increased risk of falls and fractures—particularly in older patients.⁵

Reducing long-term use of benzodiazepines in a primary care setting is important but challenging. Until recently, most of the successful strategies reported were resource intensive and required multiple office visits.⁶

STUDY SUMMARY: Brief interventions are often effective

This study was a meta-analysis of randomized controlled trials in which “minimal interventions” were compared with usual care for their effectiveness in reducing or eliminating benzodiazepine use in primary care patients. A minimal intervention was defined as a letter, self-help information, or short consultation with a primary care provider. In each case, the message to the patient included (a) an expression of concern about the patient’s long-term use of the medication, (b) information about the potential adverse effects of the medication, and (c) advice on how to gradually reduce or stop using it.

Three studies met the inclusion criteria for randomization, blinding, and analysis by intention-to-treat.^7-9 All 3 (n=615) had a 6-month follow-up period, a higher proportion of women (>60%), and participants with a mean age >60 years. Few patients were lost to follow-up; withdrawal rates were low and similar in all 3 studies. Each study compared a letter with usual care; 2 of the 3 had a third arm that included both a letter and a short consultation.

Pooled results from the studies showed twice the reduction in benzodiazepine use in the intervention groups compared with the control groups (risk ratio [RR]=2.04; 95% confidence interval [CI], 1.5-2.8; P< .001). The RR for cessation of benzodiazepine use was 2.3 (95% CI, 1.3-4.2; P= .003). The number needed to treat for a reduction or cessation of use was 12. The studies reported benzodiazepine reduction rates of 20% to 35% in the intervention groups vs 6% to 15% in the usual care groups.^7-9 There appeared to be no additional benefit to adding the brief consultation compared with the letter alone.

WHAT’S NEW?: This strategy is easy to implement

While many methods to reduce benzodiazepine use have been studied, most involved levels of skill and resources that are not feasible for widespread use. This study found that a letter, stating the risks of continued use of the medication and providing a weaning schedule and tips for handling withdrawal, can be effective in reducing chronic use in a small but significant part of the population.

CAVEATS: Effects of withdrawal went unaddressed

The study did not adequately address the adverse effects of withdrawal from benzodiazepines, with one of the studies reporting significantly worse qualitative (but not quantitative) withdrawal symptoms at 6 months.⁷ This is of particular concern, as withdrawal symptoms are associated with the potential for relapse and concomitant abuse of other drugs and alcohol. We recommend that primary care physicians screen for substance abuse prior to the intervention and arrange for adequate follow-up.

All 3 studies in the meta-analysis lasted 6 months; no longer-term outcomes were reported. In addition, the study did not yield enough information to identify patients who would be most likely to respond to this brief intervention.

CHALLENGES TO IMPLEMENTATION: Determining which patients to target

Identifying patients who are appropriate candidates for this brief intervention and providing adequate monitoring for adverse effects of withdrawal are the main challenges of this practice changer. Nonetheless, chronic benzodiazepine use is of considerable concern, and we believe that this is a useful, and manageable intervention.

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.

ILLUSTRATIVE CASE

A 65-year-old patient has been taking lorazepam for insomnia for more than a year. You are concerned about her ongoing use of the benzodiazepine and want to wean her from the medication. What strategies can you use to decrease, or eliminate, her use of the drug?

Benzodiazepines are commonly used medications, with an estimated 12-month prevalence of use of 8.6% in the United States.² While short-term use of these antianxiety medications can be effective, long-term use (defined as regular use for >3 months) is associated with significant risk.

Abuse linked to chronic use
Prescription drug abuse has recently become the nation’s leading cause of accidental death, overtaking motor vehicle accidents.³ And tranquilizers, including benzodiazepines, are the second most abused prescription medication, after pain relievers.⁴ In addition to dependence and withdrawal, chronic use of benzodiazepines is associated with daytime somnolence, blunted reflexes, memory loss, cognitive impairment, and an increased risk of falls and fractures—particularly in older patients.⁵

Reducing long-term use of benzodiazepines in a primary care setting is important but challenging. Until recently, most of the successful strategies reported were resource intensive and required multiple office visits.⁶

STUDY SUMMARY: Brief interventions are often effective

This study was a meta-analysis of randomized controlled trials in which “minimal interventions” were compared with usual care for their effectiveness in reducing or eliminating benzodiazepine use in primary care patients. A minimal intervention was defined as a letter, self-help information, or short consultation with a primary care provider. In each case, the message to the patient included (a) an expression of concern about the patient’s long-term use of the medication, (b) information about the potential adverse effects of the medication, and (c) advice on how to gradually reduce or stop using it.

Three studies met the inclusion criteria for randomization, blinding, and analysis by intention-to-treat.^7-9 All 3 (n=615) had a 6-month follow-up period, a higher proportion of women (>60%), and participants with a mean age >60 years. Few patients were lost to follow-up; withdrawal rates were low and similar in all 3 studies. Each study compared a letter with usual care; 2 of the 3 had a third arm that included both a letter and a short consultation.

Pooled results from the studies showed twice the reduction in benzodiazepine use in the intervention groups compared with the control groups (risk ratio [RR]=2.04; 95% confidence interval [CI], 1.5-2.8; P< .001). The RR for cessation of benzodiazepine use was 2.3 (95% CI, 1.3-4.2; P= .003). The number needed to treat for a reduction or cessation of use was 12. The studies reported benzodiazepine reduction rates of 20% to 35% in the intervention groups vs 6% to 15% in the usual care groups.^7-9 There appeared to be no additional benefit to adding the brief consultation compared with the letter alone.

WHAT’S NEW?: This strategy is easy to implement

While many methods to reduce benzodiazepine use have been studied, most involved levels of skill and resources that are not feasible for widespread use. This study found that a letter, stating the risks of continued use of the medication and providing a weaning schedule and tips for handling withdrawal, can be effective in reducing chronic use in a small but significant part of the population.

CAVEATS: Effects of withdrawal went unaddressed

The study did not adequately address the adverse effects of withdrawal from benzodiazepines, with one of the studies reporting significantly worse qualitative (but not quantitative) withdrawal symptoms at 6 months.⁷ This is of particular concern, as withdrawal symptoms are associated with the potential for relapse and concomitant abuse of other drugs and alcohol. We recommend that primary care physicians screen for substance abuse prior to the intervention and arrange for adequate follow-up.

All 3 studies in the meta-analysis lasted 6 months; no longer-term outcomes were reported. In addition, the study did not yield enough information to identify patients who would be most likely to respond to this brief intervention.

CHALLENGES TO IMPLEMENTATION: Determining which patients to target

Identifying patients who are appropriate candidates for this brief intervention and providing adequate monitoring for adverse effects of withdrawal are the main challenges of this practice changer. Nonetheless, chronic benzodiazepine use is of considerable concern, and we believe that this is a useful, and manageable intervention.

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.