Although most clinicians tend to manage acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by giving more rather than less fluid,^1,2 patients may actually fare better under a strategy of limited fluid intake and increased fluid excretion.

According to the results of the Fluids and Catheters Treatment Trial (FACTT),³ patients managed with fluid restriction (the “dry” or conservative strategy) spent significantly less time in the intensive care unit (ICU) and on mechanical ventilation than did patients who received a high fluid intake (the “wet” or liberal strategy). These benefits of the conservative strategy were attained without any increase in the mortality rate at 60 days or in nonpulmonary organ failure at 28 days.

In this article, I discuss the basis for the FACTT researchers’ conclusion that a conservative fluid strategy is preferable to a liberal fluid strategy in ALI/ARDS.

STUDY RATIONALE

One of the more enduring questions in critical care medicine is which fluid-management strategy is best for patients with ALI/ARDS.

The conservative strategy results in a lower vascular filling pressure, which in turn reduces pulmonary edema and improves gas exchange. The drawback to this strategy is that it may have a negative effect on cardiac output and nonpulmonary organ function.

The liberal strategy results in a higher vascular filling pressure, which may be beneficial in terms of cardiac output and nonpulmonary organ perfusion. However, this strategy does not reduce lung edema.

The evidence accumulated before FACTT did not favor one strategy over the other. However, most deaths among patients with ALI/ARDS are attributable to the failure of organs other than the lungs.^4,5 As a result, aggressive fluid restriction has not been a common approach in hospitals throughout the United States.^1,2

In an effort to resolve the controversy surrounding the management of ALI/ARDS and to broaden the scope of what we know about fluid balance, we undertook this multicenter, randomized, prospective clinical comparison of the two strategies. This study was conducted under the auspices of the National Heart, Lung, and Blood Institute’s Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSnet).

STUDY DESIGN

Between June 8, 2000, and October 3, 2005, we screened more than 11,000 patients with ALI/ARDS at 20 centers in North America.

Eligibility

Eligible patients had experienced ALI/ARDS within the previous 48 hours, had been intubated for positive-pressure ventilation, had a ratio of partial pressure of arterial oxygen (PaO₂) to the fraction of inspired oxygen (FIO₂) of less than 300, and exhibited bilateral infiltrates on chest radiography that were consistent with the presence of pulmonary edema without evidence of left atrial hypertension.⁶

Major exclusion criteria included the placement of a pulmonary artery catheter prior to randomization and the presence of certain illnesses that might have compromised the study results.

Patient population

The target enrollment of 1,000 patients was reached. These patients were randomized into one of four roughly equal groups based on the type of fluid-management strategy—conservative or liberal—and the type of catheter that was placed—pulmonary artery or central venous. (The ARDSnet researchers published the results of the catheter comparison in a separate article.⁷ Those results are not discussed here except to note that there were no statistically significant differences in outcomes between the two catheter groups.)

There were no statistically significant differences between the two groups with respect to baseline demographic characteristics. The conservative-strategy group consisted of 503 patients, of whom 52% were male and 65% were white; the mean age was 50.1 years. The liberal-strategy group consisted of 497 patients, of whom 55% were male and 63% were white; mean age was 49.5 years.

Ventilation according to a low tidal volume strategy (6 mg/kg) was initiated within 1 hour after randomization. The pulmonary artery catheter or central venous catheter was inserted within 4 hours of randomization, and fluid management was started within 2 hours after catheter insertion. Fluid management was continued for 7 days or until 12 hours after extubation in patients who became able to breathe without assistance, whichever occurred first.

Target filling pressures. In the conservative-strategy group, the target filling pressures were low—a pulmonary artery occlusion pressure less than 8 mm Hg for those randomized to receive a pulmonary artery catheter, and a central venous pressure less than 4 mm Hg for those randomized to receive a central venous catheter. Barring adverse effects, patients were to undergo diuresis with furosemide (Lasix) until their goal was achieved, and then they would be maintained on that dosage through day 7. If we experienced difficulty in safely reaching these goals—say, if a patient developed hypoxemia, oliguria, or hypotension—we backed off the diuresis until the patient stabilized, and then we tried again. An inability to reach these filling pressure targets was not considered to be a treatment failure; our actual aim was to get as close to the target as possible as long as the patient tolerated the treatment.

In the liberal-strategy group, the target pressures were in the high-to-normal range—14 to 18 mm Hg for those with a pulmonary artery catheter and 10 to 14 mm Hg for those with a central venous catheter.

Patients with a pulmonary artery catheter who were hemodynamically stable after 3 days could be switched to a central venous catheter at the discretion of the clinician.

Monitoring. Patients were monitored once every 4 hours—more often if the clinician felt it necessary—for four variables:

• Pulmonary artery occlusion pressure or central venous pressure, depending on the type of catheter
• Shock, indicated by a mean arterial pressure of less than 60 mm Hg or the need for a vasopressor
• Oliguria, indicated by a urine output of less than 0.5 mL/kg/hour
• Ineffective circulation, represented by a cardiac index of less than 2.5 L/minute/cm² in the pulmonary artery catheter group and by the presence of cold, mottled skin and a capillary-refilling time of more than 2 seconds in the central venous catheter group.

Depending on what the clinician found during monitoring, patients could receive a fluid bolus (if the filling pressure was too low), furosemide (if the filling pressure was too high), dobutamine (in certain rare circumstances), or nothing.

We monitored compliance with the protocol instructions twice each day—at a set time each morning and later in the day at a randomly selected time. An important aspect of this study is that we had no protocol instructions for managing shock. Individual clinicians were free to treat shock however they deemed best. In essence, then, our study was a comparison of liberal and conservative strategies during the nonshock phase of ALI/ARDS.

End points

The primary end point was the mortality rate at 60 days. Patients who were discharged earlier were assumed to be alive at 60 days.

The secondary end points were the number of ICU-free and ventilator-free days and the number of organ-failure-free days at day 28. Other end points included various indicators of lung physiology.

Statistical analysis

This intention-to-treat analysis was powered so that we had a 90% chance of detecting a 10% difference in mortality rate at day 60 (statistical significance: P < .05).

Protocol safeguards

Prior to treatment, we knew that some patients in the liberal-strategy group would not reach their filling-pressure targets despite the infusion of large amounts of fluid. To avoid “overdosing” these patients, we limited all patients to a maximum of three fluid boluses per 24 hours. Also, we withheld fluid boluses if a patient’s FIO₂ level reached or exceeded 0.7 or if the cardiac index rose to 4.5 L/minute/cm² or higher.

Diuretics were withheld when a patient had received a vasopressor or had emerged from shock within the preceding 12 hours. Also, diuretics were not given to any patient who had received a fluid bolus within the preceding 12 hours or when renal failure was present (these patients were given renal support therapy).

Finally, physicians and coordinators were instructed to assess each protocol instruction for safety and clinical validity before implementing the particular instruction. If, in their medical judgment, a particular protocol instruction should not be implemented, they were authorized to override the instruction and record the reason for doing so in the case report form.

RESULTS

Protocol compliance

Clinicians adhered to the protocol instructions during approximately 90% of the time.

Diuretic administration. In response to high filling pressures, patients in the conservative-strategy and liberal-strategy groups received furosemide during 41% and 10% of assessment periods, respectively (P < .0001). By day 7, the average patient in the conservative-strategy group had received a cumulative dose of approximately 1,000 mg of furosemide, while the average patient in the liberal-strategy group had received 500 mg.

Fluid administration. Low filling pressure prompted the administration of a fluid bolus to the liberal-strategy group during 15% of the assessment periods, compared with 6% in the conservative-strategy group (P < .0001).

The conservative-strategy patients who were in shock at study entry had a net gain of approximately 3 L of fluid by day 7, while the liberal-strategy group had a gain of approximately 10 L. Among the patients who were shock-free at baseline, the conservative-strategy group had a net loss of almost 2 L at day 7 while the liberal-strategy group had a net gain of about 5 L.

The pulmonary artery occlusion pressure fell from 15.6 mm Hg to just below 13 mm Hg in the conservative-strategy group by day 7, although there was a wide variation among individual patients. The pressure in the liberal-strategy group (15.7 mm Hg at baseline) was unchanged at day 7 (Figure 2).

Primary end point

Secondary end points

Through day 7, the average patient in the conservative-strategy group experienced significantly more ICU-free days (0.9 vs 0.6; P <.001) and more days free of central nervous system (CNS) failure (3.4 vs 2.9; P = .02). No significant differences were observed in the number of days free from coagulation abnormalities and renal or hepatic failure at day 28.

Through day 28, the average patient in the conservative-strategy group experienced significantly more ventilator-free days (14.6 vs 12.1; P < .001). The other 7-day results held up after 28 days, as the average conservative-strategy patient continued to experience more ICU-free days (13.4 vs 11.2; P < .001) and more days free of CNS failure (18.8 vs 17.2; P = .03). Again, no significant differences were observed in the number of days free of coagulation abnormalities and cardiovascular, renal, or hepatic failure.

It is not clear if the conservative strategy’s advantage in terms of more CNS-failure-free days was actually the result of the strategy itself or due to the fact that these patients were weaned off ventilation earlier and therefore received less sedation.

Other outcomes

Shock. One concern we had with the conservative strategy was that it might induce shock more frequently, but this did not occur. The percentage of patients who developed shock at least once during the 7-day treatment protocol was quite similar in the two groups. Also, it is interesting that patients who presented with no baseline shock had only about a 30% chance of developing shock during therapy. There was no significant difference in vasopressor use between the two groups.

Lung function. The conservative-strategy group had a significantly better Murray lung injury score at day 7: 2.03 vs 2.27 (P < .001).

Tidal-volume scores (7.4 mL/kg in both groups at baseline) dropped at an equal rate and were virtually identical at day 7 (6.36 mL/kg in the conservative-strategy group and 6.34 in the liberal-strategy group), as expected.The plateau pressure, positive end-expiraory pressure, PaO₂–FIO₂ ratio, and oxygenation index were slightly but not significantly better in the conservative-strategy group at day 7.

Overall, lung function was considerably better in the conservative-strategy group.

Cardiovascular function. The mean arterial pressure was significantly lower in the conservative-strategy group at day 7 (81.00 vs 84.36 mm Hg; P = .03). It is interesting that both levels were higher than the baseline levels (77.1 and 77.2, respectively; not significant).

The stroke volume index and the cardiac index were slightly lower in the conservative-strategy group at day 7, but not significantly so. No differences were seen in heart rate and venous oxygen saturation levels.

Renal and metabolic function. At day 7, the conservative-strategy group had a significantly higher blood urea nitrogen level (33.62 vs 28.44 mg/dL; P = .009). No significant differences were seen between the groups in creatinine levels at day 7 and day 28.

At day 60, dialysis was needed by 10% of the conservative-strategy group and 14% of the liberal-strategy group (P = .06). The important finding here is that there was no trend toward a more frequent need for dialysis in the conservative-strategy group. Also, the average number of days on dialysis in the two groups was essentially the same (11.0 and 10.9, respectively).

Again, there was no difference in the number of renal-failure-free days at either day 7 or day 28.

Hematologic factors. At day 7, the conservative-strategy group had significantly higher hemoglobin (10.22 vs 9.65 g/dL) and albumin (2.30 vs 2.11 g/dL) levels and capillary osmotic pressure (19.18 vs 17.39 mm Hg), even though significantly more patients in the liberal-strategy group received transfusions through day 7 (39% vs 29%; P = .0007).

Safety. Although the number of adverse events—particularly, metabolic alkalosis and electrolyte imbalance—was significantly higher in the conservative-strategy group (42 vs 19; P = .001), the overall incidence was low. No adverse event was associated with arrhythmia.

CONCLUSION

The two fluid-management protocols used in this study were designed to be prudent yet distinctly different. While designing our protocol, we were concerned on the one hand that despite our best efforts fluid balance would turn out to be very similar in the two groups; this did not happen. On the other hand, we were also worried that the fluid level in one of the two groups might turn out to be so bizarre that it would invalidate our study; this too did not occur. Therefore, we are pleased with the way the study was designed and conducted, and we are satisfied that the two protocols were legitimate.

As we went into our study, the literature contained only one other prospective trial that was in some way similar to ours. Mitchell et al⁹ conducted a randomized, prospective study of 101 critically ill patients, including 89 with pulmonary edema. A group of 52 patients were managed with a conservative strategy intended to reduce the amount of extravascular lung water; the other 49 patients were managed with a strategy similar to the liberal strategy used in our study. At the study’s end, the patients in the conservative-strategy group had a significantly lower amount of extravascular lung water and spent significantly fewer days on ventilation and in the ICU. No clinically significant adverse effects were associated with the conservative strategy. This small study was not highly powered, but it did show that aggressive fluid restriction conferred some benefit.

In our study, the conservative strategy improved lung function and shortened the duration of mechanical ventilation and ICU stay without increasing nonpulmonary organ failures or increasing the risk of death within 60 days. Therefore, we recommend the conservative strategy for patients with ALI/ARDS.

Although most clinicians tend to manage acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by giving more rather than less fluid,^1,2 patients may actually fare better under a strategy of limited fluid intake and increased fluid excretion.

According to the results of the Fluids and Catheters Treatment Trial (FACTT),³ patients managed with fluid restriction (the “dry” or conservative strategy) spent significantly less time in the intensive care unit (ICU) and on mechanical ventilation than did patients who received a high fluid intake (the “wet” or liberal strategy). These benefits of the conservative strategy were attained without any increase in the mortality rate at 60 days or in nonpulmonary organ failure at 28 days.

In this article, I discuss the basis for the FACTT researchers’ conclusion that a conservative fluid strategy is preferable to a liberal fluid strategy in ALI/ARDS.

STUDY RATIONALE

One of the more enduring questions in critical care medicine is which fluid-management strategy is best for patients with ALI/ARDS.

The conservative strategy results in a lower vascular filling pressure, which in turn reduces pulmonary edema and improves gas exchange. The drawback to this strategy is that it may have a negative effect on cardiac output and nonpulmonary organ function.

The liberal strategy results in a higher vascular filling pressure, which may be beneficial in terms of cardiac output and nonpulmonary organ perfusion. However, this strategy does not reduce lung edema.

The evidence accumulated before FACTT did not favor one strategy over the other. However, most deaths among patients with ALI/ARDS are attributable to the failure of organs other than the lungs.^4,5 As a result, aggressive fluid restriction has not been a common approach in hospitals throughout the United States.^1,2

In an effort to resolve the controversy surrounding the management of ALI/ARDS and to broaden the scope of what we know about fluid balance, we undertook this multicenter, randomized, prospective clinical comparison of the two strategies. This study was conducted under the auspices of the National Heart, Lung, and Blood Institute’s Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSnet).

STUDY DESIGN

Between June 8, 2000, and October 3, 2005, we screened more than 11,000 patients with ALI/ARDS at 20 centers in North America.

Eligibility

Eligible patients had experienced ALI/ARDS within the previous 48 hours, had been intubated for positive-pressure ventilation, had a ratio of partial pressure of arterial oxygen (PaO₂) to the fraction of inspired oxygen (FIO₂) of less than 300, and exhibited bilateral infiltrates on chest radiography that were consistent with the presence of pulmonary edema without evidence of left atrial hypertension.⁶

Major exclusion criteria included the placement of a pulmonary artery catheter prior to randomization and the presence of certain illnesses that might have compromised the study results.

Patient population

The target enrollment of 1,000 patients was reached. These patients were randomized into one of four roughly equal groups based on the type of fluid-management strategy—conservative or liberal—and the type of catheter that was placed—pulmonary artery or central venous. (The ARDSnet researchers published the results of the catheter comparison in a separate article.⁷ Those results are not discussed here except to note that there were no statistically significant differences in outcomes between the two catheter groups.)

There were no statistically significant differences between the two groups with respect to baseline demographic characteristics. The conservative-strategy group consisted of 503 patients, of whom 52% were male and 65% were white; the mean age was 50.1 years. The liberal-strategy group consisted of 497 patients, of whom 55% were male and 63% were white; mean age was 49.5 years.

Ventilation according to a low tidal volume strategy (6 mg/kg) was initiated within 1 hour after randomization. The pulmonary artery catheter or central venous catheter was inserted within 4 hours of randomization, and fluid management was started within 2 hours after catheter insertion. Fluid management was continued for 7 days or until 12 hours after extubation in patients who became able to breathe without assistance, whichever occurred first.

Target filling pressures. In the conservative-strategy group, the target filling pressures were low—a pulmonary artery occlusion pressure less than 8 mm Hg for those randomized to receive a pulmonary artery catheter, and a central venous pressure less than 4 mm Hg for those randomized to receive a central venous catheter. Barring adverse effects, patients were to undergo diuresis with furosemide (Lasix) until their goal was achieved, and then they would be maintained on that dosage through day 7. If we experienced difficulty in safely reaching these goals—say, if a patient developed hypoxemia, oliguria, or hypotension—we backed off the diuresis until the patient stabilized, and then we tried again. An inability to reach these filling pressure targets was not considered to be a treatment failure; our actual aim was to get as close to the target as possible as long as the patient tolerated the treatment.

In the liberal-strategy group, the target pressures were in the high-to-normal range—14 to 18 mm Hg for those with a pulmonary artery catheter and 10 to 14 mm Hg for those with a central venous catheter.

Patients with a pulmonary artery catheter who were hemodynamically stable after 3 days could be switched to a central venous catheter at the discretion of the clinician.

Monitoring. Patients were monitored once every 4 hours—more often if the clinician felt it necessary—for four variables:

• Pulmonary artery occlusion pressure or central venous pressure, depending on the type of catheter
• Shock, indicated by a mean arterial pressure of less than 60 mm Hg or the need for a vasopressor
• Oliguria, indicated by a urine output of less than 0.5 mL/kg/hour
• Ineffective circulation, represented by a cardiac index of less than 2.5 L/minute/cm² in the pulmonary artery catheter group and by the presence of cold, mottled skin and a capillary-refilling time of more than 2 seconds in the central venous catheter group.

Depending on what the clinician found during monitoring, patients could receive a fluid bolus (if the filling pressure was too low), furosemide (if the filling pressure was too high), dobutamine (in certain rare circumstances), or nothing.

We monitored compliance with the protocol instructions twice each day—at a set time each morning and later in the day at a randomly selected time. An important aspect of this study is that we had no protocol instructions for managing shock. Individual clinicians were free to treat shock however they deemed best. In essence, then, our study was a comparison of liberal and conservative strategies during the nonshock phase of ALI/ARDS.

End points

The primary end point was the mortality rate at 60 days. Patients who were discharged earlier were assumed to be alive at 60 days.

The secondary end points were the number of ICU-free and ventilator-free days and the number of organ-failure-free days at day 28. Other end points included various indicators of lung physiology.

Statistical analysis

This intention-to-treat analysis was powered so that we had a 90% chance of detecting a 10% difference in mortality rate at day 60 (statistical significance: P < .05).

Protocol safeguards

Prior to treatment, we knew that some patients in the liberal-strategy group would not reach their filling-pressure targets despite the infusion of large amounts of fluid. To avoid “overdosing” these patients, we limited all patients to a maximum of three fluid boluses per 24 hours. Also, we withheld fluid boluses if a patient’s FIO₂ level reached or exceeded 0.7 or if the cardiac index rose to 4.5 L/minute/cm² or higher.

Diuretics were withheld when a patient had received a vasopressor or had emerged from shock within the preceding 12 hours. Also, diuretics were not given to any patient who had received a fluid bolus within the preceding 12 hours or when renal failure was present (these patients were given renal support therapy).

Finally, physicians and coordinators were instructed to assess each protocol instruction for safety and clinical validity before implementing the particular instruction. If, in their medical judgment, a particular protocol instruction should not be implemented, they were authorized to override the instruction and record the reason for doing so in the case report form.

RESULTS

Protocol compliance

Clinicians adhered to the protocol instructions during approximately 90% of the time.

Diuretic administration. In response to high filling pressures, patients in the conservative-strategy and liberal-strategy groups received furosemide during 41% and 10% of assessment periods, respectively (P < .0001). By day 7, the average patient in the conservative-strategy group had received a cumulative dose of approximately 1,000 mg of furosemide, while the average patient in the liberal-strategy group had received 500 mg.

Fluid administration. Low filling pressure prompted the administration of a fluid bolus to the liberal-strategy group during 15% of the assessment periods, compared with 6% in the conservative-strategy group (P < .0001).

The conservative-strategy patients who were in shock at study entry had a net gain of approximately 3 L of fluid by day 7, while the liberal-strategy group had a gain of approximately 10 L. Among the patients who were shock-free at baseline, the conservative-strategy group had a net loss of almost 2 L at day 7 while the liberal-strategy group had a net gain of about 5 L.

The pulmonary artery occlusion pressure fell from 15.6 mm Hg to just below 13 mm Hg in the conservative-strategy group by day 7, although there was a wide variation among individual patients. The pressure in the liberal-strategy group (15.7 mm Hg at baseline) was unchanged at day 7 (Figure 2).

Primary end point

Secondary end points

Through day 7, the average patient in the conservative-strategy group experienced significantly more ICU-free days (0.9 vs 0.6; P <.001) and more days free of central nervous system (CNS) failure (3.4 vs 2.9; P = .02). No significant differences were observed in the number of days free from coagulation abnormalities and renal or hepatic failure at day 28.

Through day 28, the average patient in the conservative-strategy group experienced significantly more ventilator-free days (14.6 vs 12.1; P < .001). The other 7-day results held up after 28 days, as the average conservative-strategy patient continued to experience more ICU-free days (13.4 vs 11.2; P < .001) and more days free of CNS failure (18.8 vs 17.2; P = .03). Again, no significant differences were observed in the number of days free of coagulation abnormalities and cardiovascular, renal, or hepatic failure.

It is not clear if the conservative strategy’s advantage in terms of more CNS-failure-free days was actually the result of the strategy itself or due to the fact that these patients were weaned off ventilation earlier and therefore received less sedation.

Other outcomes

Shock. One concern we had with the conservative strategy was that it might induce shock more frequently, but this did not occur. The percentage of patients who developed shock at least once during the 7-day treatment protocol was quite similar in the two groups. Also, it is interesting that patients who presented with no baseline shock had only about a 30% chance of developing shock during therapy. There was no significant difference in vasopressor use between the two groups.

Lung function. The conservative-strategy group had a significantly better Murray lung injury score at day 7: 2.03 vs 2.27 (P < .001).

Tidal-volume scores (7.4 mL/kg in both groups at baseline) dropped at an equal rate and were virtually identical at day 7 (6.36 mL/kg in the conservative-strategy group and 6.34 in the liberal-strategy group), as expected.The plateau pressure, positive end-expiraory pressure, PaO₂–FIO₂ ratio, and oxygenation index were slightly but not significantly better in the conservative-strategy group at day 7.

Overall, lung function was considerably better in the conservative-strategy group.

Cardiovascular function. The mean arterial pressure was significantly lower in the conservative-strategy group at day 7 (81.00 vs 84.36 mm Hg; P = .03). It is interesting that both levels were higher than the baseline levels (77.1 and 77.2, respectively; not significant).

The stroke volume index and the cardiac index were slightly lower in the conservative-strategy group at day 7, but not significantly so. No differences were seen in heart rate and venous oxygen saturation levels.

Renal and metabolic function. At day 7, the conservative-strategy group had a significantly higher blood urea nitrogen level (33.62 vs 28.44 mg/dL; P = .009). No significant differences were seen between the groups in creatinine levels at day 7 and day 28.

At day 60, dialysis was needed by 10% of the conservative-strategy group and 14% of the liberal-strategy group (P = .06). The important finding here is that there was no trend toward a more frequent need for dialysis in the conservative-strategy group. Also, the average number of days on dialysis in the two groups was essentially the same (11.0 and 10.9, respectively).

Again, there was no difference in the number of renal-failure-free days at either day 7 or day 28.

Hematologic factors. At day 7, the conservative-strategy group had significantly higher hemoglobin (10.22 vs 9.65 g/dL) and albumin (2.30 vs 2.11 g/dL) levels and capillary osmotic pressure (19.18 vs 17.39 mm Hg), even though significantly more patients in the liberal-strategy group received transfusions through day 7 (39% vs 29%; P = .0007).

Safety. Although the number of adverse events—particularly, metabolic alkalosis and electrolyte imbalance—was significantly higher in the conservative-strategy group (42 vs 19; P = .001), the overall incidence was low. No adverse event was associated with arrhythmia.

CONCLUSION

The two fluid-management protocols used in this study were designed to be prudent yet distinctly different. While designing our protocol, we were concerned on the one hand that despite our best efforts fluid balance would turn out to be very similar in the two groups; this did not happen. On the other hand, we were also worried that the fluid level in one of the two groups might turn out to be so bizarre that it would invalidate our study; this too did not occur. Therefore, we are pleased with the way the study was designed and conducted, and we are satisfied that the two protocols were legitimate.

As we went into our study, the literature contained only one other prospective trial that was in some way similar to ours. Mitchell et al⁹ conducted a randomized, prospective study of 101 critically ill patients, including 89 with pulmonary edema. A group of 52 patients were managed with a conservative strategy intended to reduce the amount of extravascular lung water; the other 49 patients were managed with a strategy similar to the liberal strategy used in our study. At the study’s end, the patients in the conservative-strategy group had a significantly lower amount of extravascular lung water and spent significantly fewer days on ventilation and in the ICU. No clinically significant adverse effects were associated with the conservative strategy. This small study was not highly powered, but it did show that aggressive fluid restriction conferred some benefit.

In our study, the conservative strategy improved lung function and shortened the duration of mechanical ventilation and ICU stay without increasing nonpulmonary organ failures or increasing the risk of death within 60 days. Therefore, we recommend the conservative strategy for patients with ALI/ARDS.

Although most clinicians tend to manage acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by giving more rather than less fluid,^1,2 patients may actually fare better under a strategy of limited fluid intake and increased fluid excretion.

According to the results of the Fluids and Catheters Treatment Trial (FACTT),³ patients managed with fluid restriction (the “dry” or conservative strategy) spent significantly less time in the intensive care unit (ICU) and on mechanical ventilation than did patients who received a high fluid intake (the “wet” or liberal strategy). These benefits of the conservative strategy were attained without any increase in the mortality rate at 60 days or in nonpulmonary organ failure at 28 days.

In this article, I discuss the basis for the FACTT researchers’ conclusion that a conservative fluid strategy is preferable to a liberal fluid strategy in ALI/ARDS.

STUDY RATIONALE

One of the more enduring questions in critical care medicine is which fluid-management strategy is best for patients with ALI/ARDS.

The conservative strategy results in a lower vascular filling pressure, which in turn reduces pulmonary edema and improves gas exchange. The drawback to this strategy is that it may have a negative effect on cardiac output and nonpulmonary organ function.

The liberal strategy results in a higher vascular filling pressure, which may be beneficial in terms of cardiac output and nonpulmonary organ perfusion. However, this strategy does not reduce lung edema.

The evidence accumulated before FACTT did not favor one strategy over the other. However, most deaths among patients with ALI/ARDS are attributable to the failure of organs other than the lungs.^4,5 As a result, aggressive fluid restriction has not been a common approach in hospitals throughout the United States.^1,2

In an effort to resolve the controversy surrounding the management of ALI/ARDS and to broaden the scope of what we know about fluid balance, we undertook this multicenter, randomized, prospective clinical comparison of the two strategies. This study was conducted under the auspices of the National Heart, Lung, and Blood Institute’s Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSnet).

STUDY DESIGN

Between June 8, 2000, and October 3, 2005, we screened more than 11,000 patients with ALI/ARDS at 20 centers in North America.

Eligibility

Eligible patients had experienced ALI/ARDS within the previous 48 hours, had been intubated for positive-pressure ventilation, had a ratio of partial pressure of arterial oxygen (PaO₂) to the fraction of inspired oxygen (FIO₂) of less than 300, and exhibited bilateral infiltrates on chest radiography that were consistent with the presence of pulmonary edema without evidence of left atrial hypertension.⁶

Major exclusion criteria included the placement of a pulmonary artery catheter prior to randomization and the presence of certain illnesses that might have compromised the study results.

Patient population

The target enrollment of 1,000 patients was reached. These patients were randomized into one of four roughly equal groups based on the type of fluid-management strategy—conservative or liberal—and the type of catheter that was placed—pulmonary artery or central venous. (The ARDSnet researchers published the results of the catheter comparison in a separate article.⁷ Those results are not discussed here except to note that there were no statistically significant differences in outcomes between the two catheter groups.)

There were no statistically significant differences between the two groups with respect to baseline demographic characteristics. The conservative-strategy group consisted of 503 patients, of whom 52% were male and 65% were white; the mean age was 50.1 years. The liberal-strategy group consisted of 497 patients, of whom 55% were male and 63% were white; mean age was 49.5 years.

Ventilation according to a low tidal volume strategy (6 mg/kg) was initiated within 1 hour after randomization. The pulmonary artery catheter or central venous catheter was inserted within 4 hours of randomization, and fluid management was started within 2 hours after catheter insertion. Fluid management was continued for 7 days or until 12 hours after extubation in patients who became able to breathe without assistance, whichever occurred first.

Target filling pressures. In the conservative-strategy group, the target filling pressures were low—a pulmonary artery occlusion pressure less than 8 mm Hg for those randomized to receive a pulmonary artery catheter, and a central venous pressure less than 4 mm Hg for those randomized to receive a central venous catheter. Barring adverse effects, patients were to undergo diuresis with furosemide (Lasix) until their goal was achieved, and then they would be maintained on that dosage through day 7. If we experienced difficulty in safely reaching these goals—say, if a patient developed hypoxemia, oliguria, or hypotension—we backed off the diuresis until the patient stabilized, and then we tried again. An inability to reach these filling pressure targets was not considered to be a treatment failure; our actual aim was to get as close to the target as possible as long as the patient tolerated the treatment.

In the liberal-strategy group, the target pressures were in the high-to-normal range—14 to 18 mm Hg for those with a pulmonary artery catheter and 10 to 14 mm Hg for those with a central venous catheter.

Patients with a pulmonary artery catheter who were hemodynamically stable after 3 days could be switched to a central venous catheter at the discretion of the clinician.

Monitoring. Patients were monitored once every 4 hours—more often if the clinician felt it necessary—for four variables:

• Pulmonary artery occlusion pressure or central venous pressure, depending on the type of catheter
• Shock, indicated by a mean arterial pressure of less than 60 mm Hg or the need for a vasopressor
• Oliguria, indicated by a urine output of less than 0.5 mL/kg/hour
• Ineffective circulation, represented by a cardiac index of less than 2.5 L/minute/cm² in the pulmonary artery catheter group and by the presence of cold, mottled skin and a capillary-refilling time of more than 2 seconds in the central venous catheter group.

Depending on what the clinician found during monitoring, patients could receive a fluid bolus (if the filling pressure was too low), furosemide (if the filling pressure was too high), dobutamine (in certain rare circumstances), or nothing.

We monitored compliance with the protocol instructions twice each day—at a set time each morning and later in the day at a randomly selected time. An important aspect of this study is that we had no protocol instructions for managing shock. Individual clinicians were free to treat shock however they deemed best. In essence, then, our study was a comparison of liberal and conservative strategies during the nonshock phase of ALI/ARDS.

End points

The primary end point was the mortality rate at 60 days. Patients who were discharged earlier were assumed to be alive at 60 days.

The secondary end points were the number of ICU-free and ventilator-free days and the number of organ-failure-free days at day 28. Other end points included various indicators of lung physiology.

Statistical analysis

This intention-to-treat analysis was powered so that we had a 90% chance of detecting a 10% difference in mortality rate at day 60 (statistical significance: P < .05).

Protocol safeguards

Prior to treatment, we knew that some patients in the liberal-strategy group would not reach their filling-pressure targets despite the infusion of large amounts of fluid. To avoid “overdosing” these patients, we limited all patients to a maximum of three fluid boluses per 24 hours. Also, we withheld fluid boluses if a patient’s FIO₂ level reached or exceeded 0.7 or if the cardiac index rose to 4.5 L/minute/cm² or higher.

Diuretics were withheld when a patient had received a vasopressor or had emerged from shock within the preceding 12 hours. Also, diuretics were not given to any patient who had received a fluid bolus within the preceding 12 hours or when renal failure was present (these patients were given renal support therapy).

Finally, physicians and coordinators were instructed to assess each protocol instruction for safety and clinical validity before implementing the particular instruction. If, in their medical judgment, a particular protocol instruction should not be implemented, they were authorized to override the instruction and record the reason for doing so in the case report form.

RESULTS

Protocol compliance

Clinicians adhered to the protocol instructions during approximately 90% of the time.

Diuretic administration. In response to high filling pressures, patients in the conservative-strategy and liberal-strategy groups received furosemide during 41% and 10% of assessment periods, respectively (P < .0001). By day 7, the average patient in the conservative-strategy group had received a cumulative dose of approximately 1,000 mg of furosemide, while the average patient in the liberal-strategy group had received 500 mg.

Fluid administration. Low filling pressure prompted the administration of a fluid bolus to the liberal-strategy group during 15% of the assessment periods, compared with 6% in the conservative-strategy group (P < .0001).

The conservative-strategy patients who were in shock at study entry had a net gain of approximately 3 L of fluid by day 7, while the liberal-strategy group had a gain of approximately 10 L. Among the patients who were shock-free at baseline, the conservative-strategy group had a net loss of almost 2 L at day 7 while the liberal-strategy group had a net gain of about 5 L.

The pulmonary artery occlusion pressure fell from 15.6 mm Hg to just below 13 mm Hg in the conservative-strategy group by day 7, although there was a wide variation among individual patients. The pressure in the liberal-strategy group (15.7 mm Hg at baseline) was unchanged at day 7 (Figure 2).

Primary end point

Secondary end points

Through day 7, the average patient in the conservative-strategy group experienced significantly more ICU-free days (0.9 vs 0.6; P <.001) and more days free of central nervous system (CNS) failure (3.4 vs 2.9; P = .02). No significant differences were observed in the number of days free from coagulation abnormalities and renal or hepatic failure at day 28.

Through day 28, the average patient in the conservative-strategy group experienced significantly more ventilator-free days (14.6 vs 12.1; P < .001). The other 7-day results held up after 28 days, as the average conservative-strategy patient continued to experience more ICU-free days (13.4 vs 11.2; P < .001) and more days free of CNS failure (18.8 vs 17.2; P = .03). Again, no significant differences were observed in the number of days free of coagulation abnormalities and cardiovascular, renal, or hepatic failure.

It is not clear if the conservative strategy’s advantage in terms of more CNS-failure-free days was actually the result of the strategy itself or due to the fact that these patients were weaned off ventilation earlier and therefore received less sedation.

Other outcomes

Shock. One concern we had with the conservative strategy was that it might induce shock more frequently, but this did not occur. The percentage of patients who developed shock at least once during the 7-day treatment protocol was quite similar in the two groups. Also, it is interesting that patients who presented with no baseline shock had only about a 30% chance of developing shock during therapy. There was no significant difference in vasopressor use between the two groups.

Lung function. The conservative-strategy group had a significantly better Murray lung injury score at day 7: 2.03 vs 2.27 (P < .001).

Tidal-volume scores (7.4 mL/kg in both groups at baseline) dropped at an equal rate and were virtually identical at day 7 (6.36 mL/kg in the conservative-strategy group and 6.34 in the liberal-strategy group), as expected.The plateau pressure, positive end-expiraory pressure, PaO₂–FIO₂ ratio, and oxygenation index were slightly but not significantly better in the conservative-strategy group at day 7.

Overall, lung function was considerably better in the conservative-strategy group.

Cardiovascular function. The mean arterial pressure was significantly lower in the conservative-strategy group at day 7 (81.00 vs 84.36 mm Hg; P = .03). It is interesting that both levels were higher than the baseline levels (77.1 and 77.2, respectively; not significant).

The stroke volume index and the cardiac index were slightly lower in the conservative-strategy group at day 7, but not significantly so. No differences were seen in heart rate and venous oxygen saturation levels.

Renal and metabolic function. At day 7, the conservative-strategy group had a significantly higher blood urea nitrogen level (33.62 vs 28.44 mg/dL; P = .009). No significant differences were seen between the groups in creatinine levels at day 7 and day 28.

At day 60, dialysis was needed by 10% of the conservative-strategy group and 14% of the liberal-strategy group (P = .06). The important finding here is that there was no trend toward a more frequent need for dialysis in the conservative-strategy group. Also, the average number of days on dialysis in the two groups was essentially the same (11.0 and 10.9, respectively).

Again, there was no difference in the number of renal-failure-free days at either day 7 or day 28.

Hematologic factors. At day 7, the conservative-strategy group had significantly higher hemoglobin (10.22 vs 9.65 g/dL) and albumin (2.30 vs 2.11 g/dL) levels and capillary osmotic pressure (19.18 vs 17.39 mm Hg), even though significantly more patients in the liberal-strategy group received transfusions through day 7 (39% vs 29%; P = .0007).

Safety. Although the number of adverse events—particularly, metabolic alkalosis and electrolyte imbalance—was significantly higher in the conservative-strategy group (42 vs 19; P = .001), the overall incidence was low. No adverse event was associated with arrhythmia.

CONCLUSION

The two fluid-management protocols used in this study were designed to be prudent yet distinctly different. While designing our protocol, we were concerned on the one hand that despite our best efforts fluid balance would turn out to be very similar in the two groups; this did not happen. On the other hand, we were also worried that the fluid level in one of the two groups might turn out to be so bizarre that it would invalidate our study; this too did not occur. Therefore, we are pleased with the way the study was designed and conducted, and we are satisfied that the two protocols were legitimate.

As we went into our study, the literature contained only one other prospective trial that was in some way similar to ours. Mitchell et al⁹ conducted a randomized, prospective study of 101 critically ill patients, including 89 with pulmonary edema. A group of 52 patients were managed with a conservative strategy intended to reduce the amount of extravascular lung water; the other 49 patients were managed with a strategy similar to the liberal strategy used in our study. At the study’s end, the patients in the conservative-strategy group had a significantly lower amount of extravascular lung water and spent significantly fewer days on ventilation and in the ICU. No clinically significant adverse effects were associated with the conservative strategy. This small study was not highly powered, but it did show that aggressive fluid restriction conferred some benefit.

In our study, the conservative strategy improved lung function and shortened the duration of mechanical ventilation and ICU stay without increasing nonpulmonary organ failures or increasing the risk of death within 60 days. Therefore, we recommend the conservative strategy for patients with ALI/ARDS.

“The time has come,” the Walrus said,
“To talk of many things:
Of shoes—and ships—and sealing-wax—
Of cabbages—and kings—
And why the sea is boiling hot
And whether pigs have wings.”
—Lewis Carroll, The Walrus and the Carpenter (from Through the Looking-Glass and What Alice Found There, 1872).

Lewis Carroll's poem of 1872 is a useful starting point for identifying issues resulting from confusion over the variously described acute aortic syndromes—and, for oysters, the dangers of listening to walruses.

See related article

TALK OF MANY THINGS

In cases of aortic dissection (splitting or separation of the layers of the aortic wall), it is important to establish the type (ie, the location and extent) and class (ie, the structure) of the dissection, because these distinctions determine the treatment.¹ Similarly, in cases of painful or leaking degenerative aneurysms, we need to know the location of the aneurysm and whether the presenting pain is from compression of surrounding tissue, particularly of the vertebral bodies, or from leakage.

The location and extent of an aortic dissection can be classified in three ways (see Figure 3 in Smith and Schoenhagen’s excellent review of the use of computed tomography [CT] in acute aortic syndromes in this issue of the Cleveland Clinic Journal of Medicine²):

• The DeBakey system (type I, II, or III)
• The Stanford system (type A or B)
• Distal or proximal to the left subclavian artery.

Of note, the DeBakey system does not include tears in the arch that extend distally without ascending involvement. The original Stanford system included arch tears with distal extension in type B; hence, type B excluded all patients without ascending involvement.

The importance of the extent of dissection is that most patients with Stanford type A or DeBakey type I or II dissections should undergo immediate surgery, as most of them would die without it. Surgery is also indicated for arch tears (non-DeBakey, original Stanford type B).

Because these classifications are somewhat confusing, the simplest approach is to note whether the dissection extends proximal or distal to the left subclavian artery, because proximal dissections need surgery and distal ones are first managed medically.

The classes of dissection also have bearing on treatment.¹ These are:

• Class I—classic aortic dissection in the media with two lumens separated by a “flap” or septum
• Class II—intramural hematoma in the aortic wall from dissection in which the intimal tear cannot be imaged (these are nearly always found duringsurgery or autopsy)
• Class III—localized confined intimal tears without extensive undermining of the intima or flap formation. These are often seen with Marfan syndrome and can rupture or cause tamponade, as can any type of proximal dissection. The typical appearance is of a bulging bubble in the aortic wall.
• Class IV—penetrating atherosclerotic ulcers with localized dissections or wall hematomas, often with calcium at the base of a mushroom-shaped area of extraluminal contrast. Of note, the plane of dissection is often between the media and adventitia.
• Class V—iatrogenic or posttraumatic dissection.

All class I to class IV tears of the proximal aorta require surgery, whereas distal class IV and V tears may require either open or endovascular surgical intervention. Surgery is also indicated for patients with distal dissections who have severe narrowing of the true lumen, distal ischemia, uncontrolled pain, severe hypertension, or evidence of leaking, particularly with class IV tears.

In distal dissections that are subacute (2–6 week sold), the Investigation of Stent grafts in Patients With Type B Aortic Dissection (INSTEAD) trial found that inserting a stent prophylactically provided no benefit. Further-more, there is no proof that stenting is beneficial if the aortic dissection is chronic, ie, more than 6 weeks old.^1,3–5

WHICH SHOE FITS?

There is no ideal procedure to detect dissection, although the trend is towards CT angiography, as Smith and Schoenhagen report.² Although some investigators have optimistically estimated CT’s sensitivity and specificity as 100%, cardiovascular surgeons are well aware of both false-positive and false-negative CT studies. Thus, for emergency repairs of proximal dissections, transesophageal echocardiography should be done after intubation and before opening a patient’s chest if time allows. Magnetic resonance imaging, CT, and transesophageal echocardiography may all miss class III tears, but these are frequently evidenced by eccentric “bubbles”or “ballooning.”¹

SHIPS

Patients with either acute aortic dissection or severe pain associated with degenerative aneurysms need to be “shipped” promptly to a tertiary medical center after diagnosis, since larger volumes of procedures appear to be associated with better outcomes.

SEALING WAX

Using current surgical methods, the aortic valve can be preserved during aortic dissection repair unless the valve is bicuspid or the patient has Marfan syndrome.^1,3,4,6–8

Sealing wax in the form of biological glues, rather than for letters, is a new innovation. A caveat remains, however: we have seen patients who have required reoperation for false aneurysms or infection. Hence, glues should be used with caution.

CABBAGES

A dilemma is whether patients should undergo coronary catheterization (or CT angiography—a separate question) and subsequent coronary artery bypass grafting (CABG), if needed, at the time of aortic dissection repair. The problem is that approximately one-third of patients have coronary artery disease that may require CABG, but the delay for catheterization increases the risk of rupture or tamponade before surgery.

Indeed, 40% of patients with proximal dissections die immediately, and 1% to 3% die in the hour before surgery. The short-term (in-hospital and 30-day) mortality rates range from 3.4% (Cleveland Clinic 2006 data) to 25%, and of the survivors only about 50% area live 5 years after surgery.

Though dismal, the prognosis is improving. In 162 patients with aortic dissection and Marfan syndrome or connective tissue disorders who underwent surgery at Cleveland Clinic in the years 1978–2003, the 5-year survival rate in those with aortic dissection was 75% and the 10-year rate was 55%.⁷ In those without dissection, the 10-year survival rate was approximately 90% (P < .001).

KINGS

Noted personalities who have had aortic dissection include King George II of England (who died in 1760), Lucille Ball, Conway Twitty, Jan Larson, and most recently John Ritter. None of these famous people survived their aortic dissections. Indeed, dissection and diseases of the aorta or its branches cause between 43,000 and 47,000 deaths annually,⁹ more than from breast cancer, murders, or motor vehicle accidents. The main reason for these dismal statistics is that the disease is often misdiagnosed at the time of presentation.

BOILING SEA

Careful studies from Olmsted County, Minnesota,¹⁰ have shown a tripling of the incidence of aortic disease, particularly in women, even though the rate of deaths from coronary artery disease has been decreasing. Furthermore, Olsson et al¹¹ report that the incidence of aortic dissection in men in Sweden increased to approximately¹⁶ per 100,000 per year from 1987 to 2002, a 52% increase. The aging of the population must play a large role, but other factors may exist that are not well understood or defined and require further research.

PIGS HAVE WINGS

Will it be possible to overcome this rising problem? The answer is a definite yes. The results of aortic surgery have never been better. Many new innovations are available, such as aortic root preservation and endovascular stenting procedures. It may be possible to slow the growth of or prevent some aneurysms and aortic dissections, particularly with beta-blockers and, potentially, with losartan (Cozaar) for Marfan syndrome patients.

One of the keys to preventing aortic catastrophes and aortic dissection is to repair aortic aneurysms. The threshold for surgery, however, depends on a surgeon’s experience and results, the underlying pathology, and the aortic size.

We observed that 12.5% of dissections in patients with bicuspid valves and 15% of those in patients with Marfan syndrome were in aortas smaller than 5.0 cm in diameter, that aortic dissection occurred at smaller diameters in shorter patients, and that the risk of dissection increased exponentially with the size of the aorta. Subsequently, we found that a better measure of risk is the maximal aortic cross-sectional area in cm² divided by the patient’s height in meters; if this ratio exceeds 10, then surgery is recommended.¹²

Results of surgery are good in experienced hands. In patients who undergo surgical repair of bicuspid aortic valves with or without concurrent repair of the ascending aorta (mostly in patients with an aortic cross-section-to-height ratio > 10), the perioperative mortality rate is about 1.0% for both groups, and at 10 years about 98% of patients are free from re-operation on the aorta and more than 90% are free from re-operation on the aortic valve.⁸ This is important because these are typically young patients who would do better without biological replacement valves (which are not very durable) or mechanical valves (which necessitate lifelong anticoagulation). Results are also good in surgery of the aortic arch and even better in patients with tricuspid aortic valves.^4,6,8

Increasingly, in patients at high risk, we are inserting thoracic, abdominal, and thoracoabdominal stent grafts, with excellent early results. An even newer innovation is to replace the aortic valve in high-risk patients via a transcatheter balloon-expandable valve stent inserted through the groin or left ventricular apex.

These treatment innovations have been big strides, but aortic disease continues to increase. Indeed, our volume of thoracic aortic surgery at Cleveland Clinic increased from 190 procedures in 1999 to 717 in 2006. Early detection—before acute emergency surgery is required, with its concomitant high risk of death—is the key to successful surgical outcome and long-term survival.

“The time has come,” the Walrus said,
“To talk of many things:
Of shoes—and ships—and sealing-wax—
Of cabbages—and kings—
And why the sea is boiling hot
And whether pigs have wings.”
—Lewis Carroll, The Walrus and the Carpenter (from Through the Looking-Glass and What Alice Found There, 1872).

Lewis Carroll's poem of 1872 is a useful starting point for identifying issues resulting from confusion over the variously described acute aortic syndromes—and, for oysters, the dangers of listening to walruses.

See related article

TALK OF MANY THINGS

In cases of aortic dissection (splitting or separation of the layers of the aortic wall), it is important to establish the type (ie, the location and extent) and class (ie, the structure) of the dissection, because these distinctions determine the treatment.¹ Similarly, in cases of painful or leaking degenerative aneurysms, we need to know the location of the aneurysm and whether the presenting pain is from compression of surrounding tissue, particularly of the vertebral bodies, or from leakage.

The location and extent of an aortic dissection can be classified in three ways (see Figure 3 in Smith and Schoenhagen’s excellent review of the use of computed tomography [CT] in acute aortic syndromes in this issue of the Cleveland Clinic Journal of Medicine²):

• The DeBakey system (type I, II, or III)
• The Stanford system (type A or B)
• Distal or proximal to the left subclavian artery.

Of note, the DeBakey system does not include tears in the arch that extend distally without ascending involvement. The original Stanford system included arch tears with distal extension in type B; hence, type B excluded all patients without ascending involvement.

The importance of the extent of dissection is that most patients with Stanford type A or DeBakey type I or II dissections should undergo immediate surgery, as most of them would die without it. Surgery is also indicated for arch tears (non-DeBakey, original Stanford type B).

Because these classifications are somewhat confusing, the simplest approach is to note whether the dissection extends proximal or distal to the left subclavian artery, because proximal dissections need surgery and distal ones are first managed medically.

The classes of dissection also have bearing on treatment.¹ These are:

• Class I—classic aortic dissection in the media with two lumens separated by a “flap” or septum
• Class II—intramural hematoma in the aortic wall from dissection in which the intimal tear cannot be imaged (these are nearly always found duringsurgery or autopsy)
• Class III—localized confined intimal tears without extensive undermining of the intima or flap formation. These are often seen with Marfan syndrome and can rupture or cause tamponade, as can any type of proximal dissection. The typical appearance is of a bulging bubble in the aortic wall.
• Class IV—penetrating atherosclerotic ulcers with localized dissections or wall hematomas, often with calcium at the base of a mushroom-shaped area of extraluminal contrast. Of note, the plane of dissection is often between the media and adventitia.
• Class V—iatrogenic or posttraumatic dissection.

All class I to class IV tears of the proximal aorta require surgery, whereas distal class IV and V tears may require either open or endovascular surgical intervention. Surgery is also indicated for patients with distal dissections who have severe narrowing of the true lumen, distal ischemia, uncontrolled pain, severe hypertension, or evidence of leaking, particularly with class IV tears.

In distal dissections that are subacute (2–6 week sold), the Investigation of Stent grafts in Patients With Type B Aortic Dissection (INSTEAD) trial found that inserting a stent prophylactically provided no benefit. Further-more, there is no proof that stenting is beneficial if the aortic dissection is chronic, ie, more than 6 weeks old.^1,3–5

WHICH SHOE FITS?

There is no ideal procedure to detect dissection, although the trend is towards CT angiography, as Smith and Schoenhagen report.² Although some investigators have optimistically estimated CT’s sensitivity and specificity as 100%, cardiovascular surgeons are well aware of both false-positive and false-negative CT studies. Thus, for emergency repairs of proximal dissections, transesophageal echocardiography should be done after intubation and before opening a patient’s chest if time allows. Magnetic resonance imaging, CT, and transesophageal echocardiography may all miss class III tears, but these are frequently evidenced by eccentric “bubbles”or “ballooning.”¹

SHIPS

Patients with either acute aortic dissection or severe pain associated with degenerative aneurysms need to be “shipped” promptly to a tertiary medical center after diagnosis, since larger volumes of procedures appear to be associated with better outcomes.

SEALING WAX

Using current surgical methods, the aortic valve can be preserved during aortic dissection repair unless the valve is bicuspid or the patient has Marfan syndrome.^1,3,4,6–8

Sealing wax in the form of biological glues, rather than for letters, is a new innovation. A caveat remains, however: we have seen patients who have required reoperation for false aneurysms or infection. Hence, glues should be used with caution.

CABBAGES

A dilemma is whether patients should undergo coronary catheterization (or CT angiography—a separate question) and subsequent coronary artery bypass grafting (CABG), if needed, at the time of aortic dissection repair. The problem is that approximately one-third of patients have coronary artery disease that may require CABG, but the delay for catheterization increases the risk of rupture or tamponade before surgery.

Indeed, 40% of patients with proximal dissections die immediately, and 1% to 3% die in the hour before surgery. The short-term (in-hospital and 30-day) mortality rates range from 3.4% (Cleveland Clinic 2006 data) to 25%, and of the survivors only about 50% area live 5 years after surgery.

Though dismal, the prognosis is improving. In 162 patients with aortic dissection and Marfan syndrome or connective tissue disorders who underwent surgery at Cleveland Clinic in the years 1978–2003, the 5-year survival rate in those with aortic dissection was 75% and the 10-year rate was 55%.⁷ In those without dissection, the 10-year survival rate was approximately 90% (P < .001).

KINGS

Noted personalities who have had aortic dissection include King George II of England (who died in 1760), Lucille Ball, Conway Twitty, Jan Larson, and most recently John Ritter. None of these famous people survived their aortic dissections. Indeed, dissection and diseases of the aorta or its branches cause between 43,000 and 47,000 deaths annually,⁹ more than from breast cancer, murders, or motor vehicle accidents. The main reason for these dismal statistics is that the disease is often misdiagnosed at the time of presentation.

BOILING SEA

Careful studies from Olmsted County, Minnesota,¹⁰ have shown a tripling of the incidence of aortic disease, particularly in women, even though the rate of deaths from coronary artery disease has been decreasing. Furthermore, Olsson et al¹¹ report that the incidence of aortic dissection in men in Sweden increased to approximately¹⁶ per 100,000 per year from 1987 to 2002, a 52% increase. The aging of the population must play a large role, but other factors may exist that are not well understood or defined and require further research.

PIGS HAVE WINGS

Will it be possible to overcome this rising problem? The answer is a definite yes. The results of aortic surgery have never been better. Many new innovations are available, such as aortic root preservation and endovascular stenting procedures. It may be possible to slow the growth of or prevent some aneurysms and aortic dissections, particularly with beta-blockers and, potentially, with losartan (Cozaar) for Marfan syndrome patients.

One of the keys to preventing aortic catastrophes and aortic dissection is to repair aortic aneurysms. The threshold for surgery, however, depends on a surgeon’s experience and results, the underlying pathology, and the aortic size.

We observed that 12.5% of dissections in patients with bicuspid valves and 15% of those in patients with Marfan syndrome were in aortas smaller than 5.0 cm in diameter, that aortic dissection occurred at smaller diameters in shorter patients, and that the risk of dissection increased exponentially with the size of the aorta. Subsequently, we found that a better measure of risk is the maximal aortic cross-sectional area in cm² divided by the patient’s height in meters; if this ratio exceeds 10, then surgery is recommended.¹²

Results of surgery are good in experienced hands. In patients who undergo surgical repair of bicuspid aortic valves with or without concurrent repair of the ascending aorta (mostly in patients with an aortic cross-section-to-height ratio > 10), the perioperative mortality rate is about 1.0% for both groups, and at 10 years about 98% of patients are free from re-operation on the aorta and more than 90% are free from re-operation on the aortic valve.⁸ This is important because these are typically young patients who would do better without biological replacement valves (which are not very durable) or mechanical valves (which necessitate lifelong anticoagulation). Results are also good in surgery of the aortic arch and even better in patients with tricuspid aortic valves.^4,6,8

Increasingly, in patients at high risk, we are inserting thoracic, abdominal, and thoracoabdominal stent grafts, with excellent early results. An even newer innovation is to replace the aortic valve in high-risk patients via a transcatheter balloon-expandable valve stent inserted through the groin or left ventricular apex.

These treatment innovations have been big strides, but aortic disease continues to increase. Indeed, our volume of thoracic aortic surgery at Cleveland Clinic increased from 190 procedures in 1999 to 717 in 2006. Early detection—before acute emergency surgery is required, with its concomitant high risk of death—is the key to successful surgical outcome and long-term survival.

“The time has come,” the Walrus said,
“To talk of many things:
Of shoes—and ships—and sealing-wax—
Of cabbages—and kings—
And why the sea is boiling hot
And whether pigs have wings.”
—Lewis Carroll, The Walrus and the Carpenter (from Through the Looking-Glass and What Alice Found There, 1872).

Lewis Carroll's poem of 1872 is a useful starting point for identifying issues resulting from confusion over the variously described acute aortic syndromes—and, for oysters, the dangers of listening to walruses.

See related article

TALK OF MANY THINGS

In cases of aortic dissection (splitting or separation of the layers of the aortic wall), it is important to establish the type (ie, the location and extent) and class (ie, the structure) of the dissection, because these distinctions determine the treatment.¹ Similarly, in cases of painful or leaking degenerative aneurysms, we need to know the location of the aneurysm and whether the presenting pain is from compression of surrounding tissue, particularly of the vertebral bodies, or from leakage.

The location and extent of an aortic dissection can be classified in three ways (see Figure 3 in Smith and Schoenhagen’s excellent review of the use of computed tomography [CT] in acute aortic syndromes in this issue of the Cleveland Clinic Journal of Medicine²):

• The DeBakey system (type I, II, or III)
• The Stanford system (type A or B)
• Distal or proximal to the left subclavian artery.

Of note, the DeBakey system does not include tears in the arch that extend distally without ascending involvement. The original Stanford system included arch tears with distal extension in type B; hence, type B excluded all patients without ascending involvement.

The importance of the extent of dissection is that most patients with Stanford type A or DeBakey type I or II dissections should undergo immediate surgery, as most of them would die without it. Surgery is also indicated for arch tears (non-DeBakey, original Stanford type B).

Because these classifications are somewhat confusing, the simplest approach is to note whether the dissection extends proximal or distal to the left subclavian artery, because proximal dissections need surgery and distal ones are first managed medically.

The classes of dissection also have bearing on treatment.¹ These are:

• Class I—classic aortic dissection in the media with two lumens separated by a “flap” or septum
• Class II—intramural hematoma in the aortic wall from dissection in which the intimal tear cannot be imaged (these are nearly always found duringsurgery or autopsy)
• Class III—localized confined intimal tears without extensive undermining of the intima or flap formation. These are often seen with Marfan syndrome and can rupture or cause tamponade, as can any type of proximal dissection. The typical appearance is of a bulging bubble in the aortic wall.
• Class IV—penetrating atherosclerotic ulcers with localized dissections or wall hematomas, often with calcium at the base of a mushroom-shaped area of extraluminal contrast. Of note, the plane of dissection is often between the media and adventitia.
• Class V—iatrogenic or posttraumatic dissection.

All class I to class IV tears of the proximal aorta require surgery, whereas distal class IV and V tears may require either open or endovascular surgical intervention. Surgery is also indicated for patients with distal dissections who have severe narrowing of the true lumen, distal ischemia, uncontrolled pain, severe hypertension, or evidence of leaking, particularly with class IV tears.

In distal dissections that are subacute (2–6 week sold), the Investigation of Stent grafts in Patients With Type B Aortic Dissection (INSTEAD) trial found that inserting a stent prophylactically provided no benefit. Further-more, there is no proof that stenting is beneficial if the aortic dissection is chronic, ie, more than 6 weeks old.^1,3–5

WHICH SHOE FITS?

There is no ideal procedure to detect dissection, although the trend is towards CT angiography, as Smith and Schoenhagen report.² Although some investigators have optimistically estimated CT’s sensitivity and specificity as 100%, cardiovascular surgeons are well aware of both false-positive and false-negative CT studies. Thus, for emergency repairs of proximal dissections, transesophageal echocardiography should be done after intubation and before opening a patient’s chest if time allows. Magnetic resonance imaging, CT, and transesophageal echocardiography may all miss class III tears, but these are frequently evidenced by eccentric “bubbles”or “ballooning.”¹

SHIPS

Patients with either acute aortic dissection or severe pain associated with degenerative aneurysms need to be “shipped” promptly to a tertiary medical center after diagnosis, since larger volumes of procedures appear to be associated with better outcomes.

SEALING WAX

Using current surgical methods, the aortic valve can be preserved during aortic dissection repair unless the valve is bicuspid or the patient has Marfan syndrome.^1,3,4,6–8

Sealing wax in the form of biological glues, rather than for letters, is a new innovation. A caveat remains, however: we have seen patients who have required reoperation for false aneurysms or infection. Hence, glues should be used with caution.

CABBAGES

A dilemma is whether patients should undergo coronary catheterization (or CT angiography—a separate question) and subsequent coronary artery bypass grafting (CABG), if needed, at the time of aortic dissection repair. The problem is that approximately one-third of patients have coronary artery disease that may require CABG, but the delay for catheterization increases the risk of rupture or tamponade before surgery.

Indeed, 40% of patients with proximal dissections die immediately, and 1% to 3% die in the hour before surgery. The short-term (in-hospital and 30-day) mortality rates range from 3.4% (Cleveland Clinic 2006 data) to 25%, and of the survivors only about 50% area live 5 years after surgery.

Though dismal, the prognosis is improving. In 162 patients with aortic dissection and Marfan syndrome or connective tissue disorders who underwent surgery at Cleveland Clinic in the years 1978–2003, the 5-year survival rate in those with aortic dissection was 75% and the 10-year rate was 55%.⁷ In those without dissection, the 10-year survival rate was approximately 90% (P < .001).

KINGS

Noted personalities who have had aortic dissection include King George II of England (who died in 1760), Lucille Ball, Conway Twitty, Jan Larson, and most recently John Ritter. None of these famous people survived their aortic dissections. Indeed, dissection and diseases of the aorta or its branches cause between 43,000 and 47,000 deaths annually,⁹ more than from breast cancer, murders, or motor vehicle accidents. The main reason for these dismal statistics is that the disease is often misdiagnosed at the time of presentation.

BOILING SEA

Careful studies from Olmsted County, Minnesota,¹⁰ have shown a tripling of the incidence of aortic disease, particularly in women, even though the rate of deaths from coronary artery disease has been decreasing. Furthermore, Olsson et al¹¹ report that the incidence of aortic dissection in men in Sweden increased to approximately¹⁶ per 100,000 per year from 1987 to 2002, a 52% increase. The aging of the population must play a large role, but other factors may exist that are not well understood or defined and require further research.

PIGS HAVE WINGS

Will it be possible to overcome this rising problem? The answer is a definite yes. The results of aortic surgery have never been better. Many new innovations are available, such as aortic root preservation and endovascular stenting procedures. It may be possible to slow the growth of or prevent some aneurysms and aortic dissections, particularly with beta-blockers and, potentially, with losartan (Cozaar) for Marfan syndrome patients.

One of the keys to preventing aortic catastrophes and aortic dissection is to repair aortic aneurysms. The threshold for surgery, however, depends on a surgeon’s experience and results, the underlying pathology, and the aortic size.

We observed that 12.5% of dissections in patients with bicuspid valves and 15% of those in patients with Marfan syndrome were in aortas smaller than 5.0 cm in diameter, that aortic dissection occurred at smaller diameters in shorter patients, and that the risk of dissection increased exponentially with the size of the aorta. Subsequently, we found that a better measure of risk is the maximal aortic cross-sectional area in cm² divided by the patient’s height in meters; if this ratio exceeds 10, then surgery is recommended.¹²

Results of surgery are good in experienced hands. In patients who undergo surgical repair of bicuspid aortic valves with or without concurrent repair of the ascending aorta (mostly in patients with an aortic cross-section-to-height ratio > 10), the perioperative mortality rate is about 1.0% for both groups, and at 10 years about 98% of patients are free from re-operation on the aorta and more than 90% are free from re-operation on the aortic valve.⁸ This is important because these are typically young patients who would do better without biological replacement valves (which are not very durable) or mechanical valves (which necessitate lifelong anticoagulation). Results are also good in surgery of the aortic arch and even better in patients with tricuspid aortic valves.^4,6,8

Increasingly, in patients at high risk, we are inserting thoracic, abdominal, and thoracoabdominal stent grafts, with excellent early results. An even newer innovation is to replace the aortic valve in high-risk patients via a transcatheter balloon-expandable valve stent inserted through the groin or left ventricular apex.

These treatment innovations have been big strides, but aortic disease continues to increase. Indeed, our volume of thoracic aortic surgery at Cleveland Clinic increased from 190 procedures in 1999 to 717 in 2006. Early detection—before acute emergency surgery is required, with its concomitant high risk of death—is the key to successful surgical outcome and long-term survival.

In our clinical practices, we have repeatedly cared for patients who came into our clinics because of a worrisome irregular breathing pattern characterized by a deep inspiration, and followed by a noisy expiration. We have referred to the set of clinical signs that these patients present with as “sigh syndrome.”

We have long suspected that sigh syndrome is an underdiagnosed and self-limited condition that is often mistaken for a serious respiratory disorder. In our experience, this syndrome runs a benign course. However, we believed that this syndrome had characteristic and consistent features, and should not be considered a diagnosis of exclusion.

Thus, we undertook a study to observe a group of subjects with these features to judge whether this subjectively alarming symptom complex is in fact harmless, and whether it is appropriate to respond to it as we had, by taking a stress-alleviating approach alone.

What is sigh syndrome?

Patients with sigh syndrome exhibit a compulsion to perform single but repeated deep inspirations, accompanied by a sensation of difficulty in inhaling a sufficient quantity of air. Each inspiration is followed by a prolonged, sometimes noisy expiration—namely, a sigh. Observing such abnormal breaths and confirming that the patient feels a concomitant inability to fill his lungs to capacity is sufficient to make the diagnosis.

This breathing compulsion is irregular in nature: It may occur once a minute or several times a minute, and this breathing pattern may continue—on and off throughout the day—for a few days to several weeks. In our experience, it provokes significant anxiety in patients, prompting them to seek medical advice. It does not occur when the patient is asleep, and it is not triggered by physical activity.

Both patient and doctor may, at first, be convinced that the problem reflects a serious illness. The 10 features of sigh syndrome (TABLE 1) constitute a proposed definition. All of our study subjects exhibited these 10 features.

TABLE 1
10 features of sigh syndrome

Sighing as an illness marker

Sighing has been described as one member of a group of signs exhibited by depressed or anxiety-ridden patients.¹ While Perin et al² were the first to point out the importance of distinguishing between sighing and respiratory disease, sighing per se has never been identified as a discrete illness marker.

A number of psychiatric disorders are already well known to incorporate breathing and chest symptoms along with widespread somatization. These include globus hystericus, neurocirculatory asthenia, and Tietze syndrome.^3-6 As such, the acute pain of precordial catch syndrome stands out as an example of a distinguishable, clear-cut clinical state devoid of any apparent organic basis.^7,8

Methods

How we recruited the patients

Data was collected from 3 family practice clinics in Israel from February 2002 to February 2005. We requested that these practices contribute data of consecutive clinical cases presenting with the 10 set symptoms of sigh syndrome (TABLE 1).

Data collected included basic demographics, the circumstances of the onset of symptoms, concurrent medical conditions, and any associated symptoms. We assessed the patients’ education level by asking questions pertaining to their years of schooling and college degrees. Patients rated their own economic status as being below, average, or above-average income.

The main outcome we examined was the clinical course of the sighing episodes during the ensuing months after their visit, in order to determine whether any patients developed a form of significant organic disease or a disorder that led to hospitalization.

Results

40 cases that cut across the socioeconomic spectrum

Forty patients were recruited for this study. Nineteen (47.5%) were male; their ages ranged from 7 to 53 (mean, 31.8; standard deviation, 13.7). Two patients (5%) were Ashkenazi Jews; 34 (85%) were of North African ethnicity (Sephardic Jews); the other 4 were of varied Asian and European ethnicity. The number of patients with North African ethnicity overrepresents that of the population in their communities. Additionally, 3 members of this group were from the same family.

There was no predilection toward any specific education level or socioeconomic status. The occupations of the subjects were diverse.

Their clinical characteristics

The clinical characteristics of the 40 patients are presented in TABLE 2. The subjects’ sighing began at various times of the day, without relationship to eating or any other activity, and disappeared during sleep. All patients reported the same feeling: that of an extra effort demanded to perform full inspiration. In many cases, adult patients were certain their complaints were a sign of cardiac or respiratory disease, and they were very concerned that there was some grave, underlying disorder.

History and examination failed to reveal evidence of any somatic findings related to breathing difficulty. Breathing rate was within normal limits in all cases.

The physicians’ initial encounters with these patients led to further examination in many cases: electrocardiography, blood oxygen saturation, and complete blood counts. However, no abnormalities were found on any of these tests. Medications, if prescribed at all during these consultations, were usually given to alleviate insomnia or anxiety. Further ancillary investigations or referrals were not ordered.

The sole notable finding on physical examination was a typical murmur (which had already been diagnosed) in a young girl with a congenital atrial septal defect. This 7-year-old developed repeated episodes of sigh syndrome just before her annual visit to the pediatric cardiologist; her mother believed that the child was frightened by the thought of possible future surgery.

TABLE 2
Clinical characteristics of the 40 patients studied—One third experienced a traumatic event

Traumatic events, anxiety disorders suggest stress as a cause

Thirteen patient histories disclosed a definite, recent, significant traumatic event that may have triggered the onset of sigh syndrome. Examples of 2 triggering events are the terrorist murder of several members of a neighbor’s family, and a near-miss with a mortar shell. One subject—a teenager—had recently been left alone in the dark with 2 younger siblings during a power blackout; another young woman said that the sighing episodes began when she decided to get married.

Ten patients had previously diagnosed neurotic disorders, mainly generalized anxiety; these included 2 cases of somatization disorder and 1 case of posttraumatic stress disorder. This information from the patients’ histories was documented in their medical files.

Episodes appear to be self-limited

In all patients, the episodes were self-limited. During the follow-up period, lasting an average of 18 months, none of the patients showed additional medical conditions—respiratory or otherwise—that could be linked to episodes of sigh syndrome. Recurrences of sighing episodes were reported by 24 subjects (60%) after the marker episode. One patient was diagnosed with carcinoma of the pancreas 2 years into follow-up, and later died.

Discussion

A benign, transient disorder

Aside from the solitary and unrelated death noted above, examination and follow-up in all 40 cases did not lead to an alternative diagnosis. Sigh syndrome thus seems to be an entirely benign and transient condition with no sequelae aside from possible recurrences.

Although the pathophysiology is unclear, our finding that 32.5% of patients had a recent traumatic incident strongly suggests a stress-related condition. Furthermore, 25% of the patients were already known to suffer from intermittent anxiety or somatoform disorders, although none were taking medications for these conditions. This adds support to the assumption that a mind-body interaction is underpinning the disorder. Large-scale migration, recent war or terrorist acts, or natural disaster are likely to increase the chances that the average physician will see a patient with sigh syndrome.

A tendency towards North African/Sephardic ethnicity, rather than European ethnicity—in addition to the cluster of 3 cases belonging to the same family—suggests the presentation may be a subconscious cultural, learned, or adopted expression of uneasiness.

Making your evaluation: History and physical are enough

The diagnostic evaluation of sigh syndrome—consisting of careful history-taking and a thorough physical examination—should be sufficient to differentiate it from an array of organic diseases. A physical examination is imperative to exclude other causes for this breathing abnormality.

Ancillary testing is rarely, if ever, indicated. It can perhaps be justified only if the condition is accompanied by an additional (if serendipitous) finding such as the cardiac murmur in the 7-year-old girl noted earlier. Physicians sometimes perform unnecessary investigations, being reluctant to base their diagnoses solely on their clinical expertise.⁹ A patient may interpret this testing as uncertainty or begin to doubt the diagnosis, thus augmenting—rather than reducing—any anxiety.¹⁰ The additional burden of the costs and possible side effects compound the futility of testing indiscriminately.¹¹

Identifying these symptoms with the name “sigh syndrome,” and basing this diagnosis on the history and physical examination, stresses certainty and familiarity with the diagnosis.⁹ Not only does this reassure the patient, but it eases communication between professionals and forms a basis for research.

Management: Reassure your patient

Management of sigh syndrome consists largely of providing reassurances to your patient. You should emphasize that the condition is real, albeit benign, and that you understand the concern it causes.

Further treatment is unnecessary, aside perhaps from addressing any associated anxiety. A self-limiting (if sometimes recurrent) course can be confidently predicted, and follow-up visits can safely be left to the patient’s own discretion. Since the major correlation with sigh syndrome seems to be stress and the experience of a recent traumatic event, you should always investigate these 2 possibilities when taking the history of a patient with suspected sigh syndrome.

Acknowledgments

This work was inspired and developed by arthur Furst, MD, who died following the submission of this manuscript. Dr Furst was a distinguished and dedicated family physician, a thorough researcher, and a renowned tutor. We dedicate this article to the fond memory of a true leader in the field of rural medicine, and an exceptionally funny and amicable colleague.

Correspondence
Abby Naimer Sody, MD, Gush Katif Health Center, Neve Dekalim, Goosh Katif, Israel 79779; [email protected]

In our clinical practices, we have repeatedly cared for patients who came into our clinics because of a worrisome irregular breathing pattern characterized by a deep inspiration, and followed by a noisy expiration. We have referred to the set of clinical signs that these patients present with as “sigh syndrome.”

We have long suspected that sigh syndrome is an underdiagnosed and self-limited condition that is often mistaken for a serious respiratory disorder. In our experience, this syndrome runs a benign course. However, we believed that this syndrome had characteristic and consistent features, and should not be considered a diagnosis of exclusion.

Thus, we undertook a study to observe a group of subjects with these features to judge whether this subjectively alarming symptom complex is in fact harmless, and whether it is appropriate to respond to it as we had, by taking a stress-alleviating approach alone.

What is sigh syndrome?

Patients with sigh syndrome exhibit a compulsion to perform single but repeated deep inspirations, accompanied by a sensation of difficulty in inhaling a sufficient quantity of air. Each inspiration is followed by a prolonged, sometimes noisy expiration—namely, a sigh. Observing such abnormal breaths and confirming that the patient feels a concomitant inability to fill his lungs to capacity is sufficient to make the diagnosis.

This breathing compulsion is irregular in nature: It may occur once a minute or several times a minute, and this breathing pattern may continue—on and off throughout the day—for a few days to several weeks. In our experience, it provokes significant anxiety in patients, prompting them to seek medical advice. It does not occur when the patient is asleep, and it is not triggered by physical activity.

Both patient and doctor may, at first, be convinced that the problem reflects a serious illness. The 10 features of sigh syndrome (TABLE 1) constitute a proposed definition. All of our study subjects exhibited these 10 features.

TABLE 1
10 features of sigh syndrome

Sighing as an illness marker

Sighing has been described as one member of a group of signs exhibited by depressed or anxiety-ridden patients.¹ While Perin et al² were the first to point out the importance of distinguishing between sighing and respiratory disease, sighing per se has never been identified as a discrete illness marker.

A number of psychiatric disorders are already well known to incorporate breathing and chest symptoms along with widespread somatization. These include globus hystericus, neurocirculatory asthenia, and Tietze syndrome.^3-6 As such, the acute pain of precordial catch syndrome stands out as an example of a distinguishable, clear-cut clinical state devoid of any apparent organic basis.^7,8

Methods

How we recruited the patients

Data was collected from 3 family practice clinics in Israel from February 2002 to February 2005. We requested that these practices contribute data of consecutive clinical cases presenting with the 10 set symptoms of sigh syndrome (TABLE 1).

Data collected included basic demographics, the circumstances of the onset of symptoms, concurrent medical conditions, and any associated symptoms. We assessed the patients’ education level by asking questions pertaining to their years of schooling and college degrees. Patients rated their own economic status as being below, average, or above-average income.

The main outcome we examined was the clinical course of the sighing episodes during the ensuing months after their visit, in order to determine whether any patients developed a form of significant organic disease or a disorder that led to hospitalization.

Results

40 cases that cut across the socioeconomic spectrum

Forty patients were recruited for this study. Nineteen (47.5%) were male; their ages ranged from 7 to 53 (mean, 31.8; standard deviation, 13.7). Two patients (5%) were Ashkenazi Jews; 34 (85%) were of North African ethnicity (Sephardic Jews); the other 4 were of varied Asian and European ethnicity. The number of patients with North African ethnicity overrepresents that of the population in their communities. Additionally, 3 members of this group were from the same family.

There was no predilection toward any specific education level or socioeconomic status. The occupations of the subjects were diverse.

Their clinical characteristics

The clinical characteristics of the 40 patients are presented in TABLE 2. The subjects’ sighing began at various times of the day, without relationship to eating or any other activity, and disappeared during sleep. All patients reported the same feeling: that of an extra effort demanded to perform full inspiration. In many cases, adult patients were certain their complaints were a sign of cardiac or respiratory disease, and they were very concerned that there was some grave, underlying disorder.

History and examination failed to reveal evidence of any somatic findings related to breathing difficulty. Breathing rate was within normal limits in all cases.

The physicians’ initial encounters with these patients led to further examination in many cases: electrocardiography, blood oxygen saturation, and complete blood counts. However, no abnormalities were found on any of these tests. Medications, if prescribed at all during these consultations, were usually given to alleviate insomnia or anxiety. Further ancillary investigations or referrals were not ordered.

The sole notable finding on physical examination was a typical murmur (which had already been diagnosed) in a young girl with a congenital atrial septal defect. This 7-year-old developed repeated episodes of sigh syndrome just before her annual visit to the pediatric cardiologist; her mother believed that the child was frightened by the thought of possible future surgery.

TABLE 2
Clinical characteristics of the 40 patients studied—One third experienced a traumatic event

Traumatic events, anxiety disorders suggest stress as a cause

Thirteen patient histories disclosed a definite, recent, significant traumatic event that may have triggered the onset of sigh syndrome. Examples of 2 triggering events are the terrorist murder of several members of a neighbor’s family, and a near-miss with a mortar shell. One subject—a teenager—had recently been left alone in the dark with 2 younger siblings during a power blackout; another young woman said that the sighing episodes began when she decided to get married.

Ten patients had previously diagnosed neurotic disorders, mainly generalized anxiety; these included 2 cases of somatization disorder and 1 case of posttraumatic stress disorder. This information from the patients’ histories was documented in their medical files.

Episodes appear to be self-limited

In all patients, the episodes were self-limited. During the follow-up period, lasting an average of 18 months, none of the patients showed additional medical conditions—respiratory or otherwise—that could be linked to episodes of sigh syndrome. Recurrences of sighing episodes were reported by 24 subjects (60%) after the marker episode. One patient was diagnosed with carcinoma of the pancreas 2 years into follow-up, and later died.

Discussion

A benign, transient disorder

Aside from the solitary and unrelated death noted above, examination and follow-up in all 40 cases did not lead to an alternative diagnosis. Sigh syndrome thus seems to be an entirely benign and transient condition with no sequelae aside from possible recurrences.

Although the pathophysiology is unclear, our finding that 32.5% of patients had a recent traumatic incident strongly suggests a stress-related condition. Furthermore, 25% of the patients were already known to suffer from intermittent anxiety or somatoform disorders, although none were taking medications for these conditions. This adds support to the assumption that a mind-body interaction is underpinning the disorder. Large-scale migration, recent war or terrorist acts, or natural disaster are likely to increase the chances that the average physician will see a patient with sigh syndrome.

A tendency towards North African/Sephardic ethnicity, rather than European ethnicity—in addition to the cluster of 3 cases belonging to the same family—suggests the presentation may be a subconscious cultural, learned, or adopted expression of uneasiness.

Making your evaluation: History and physical are enough

The diagnostic evaluation of sigh syndrome—consisting of careful history-taking and a thorough physical examination—should be sufficient to differentiate it from an array of organic diseases. A physical examination is imperative to exclude other causes for this breathing abnormality.

Ancillary testing is rarely, if ever, indicated. It can perhaps be justified only if the condition is accompanied by an additional (if serendipitous) finding such as the cardiac murmur in the 7-year-old girl noted earlier. Physicians sometimes perform unnecessary investigations, being reluctant to base their diagnoses solely on their clinical expertise.⁹ A patient may interpret this testing as uncertainty or begin to doubt the diagnosis, thus augmenting—rather than reducing—any anxiety.¹⁰ The additional burden of the costs and possible side effects compound the futility of testing indiscriminately.¹¹

Identifying these symptoms with the name “sigh syndrome,” and basing this diagnosis on the history and physical examination, stresses certainty and familiarity with the diagnosis.⁹ Not only does this reassure the patient, but it eases communication between professionals and forms a basis for research.

Management: Reassure your patient

Management of sigh syndrome consists largely of providing reassurances to your patient. You should emphasize that the condition is real, albeit benign, and that you understand the concern it causes.

Further treatment is unnecessary, aside perhaps from addressing any associated anxiety. A self-limiting (if sometimes recurrent) course can be confidently predicted, and follow-up visits can safely be left to the patient’s own discretion. Since the major correlation with sigh syndrome seems to be stress and the experience of a recent traumatic event, you should always investigate these 2 possibilities when taking the history of a patient with suspected sigh syndrome.

Acknowledgments

This work was inspired and developed by arthur Furst, MD, who died following the submission of this manuscript. Dr Furst was a distinguished and dedicated family physician, a thorough researcher, and a renowned tutor. We dedicate this article to the fond memory of a true leader in the field of rural medicine, and an exceptionally funny and amicable colleague.

Correspondence
Abby Naimer Sody, MD, Gush Katif Health Center, Neve Dekalim, Goosh Katif, Israel 79779; [email protected]

In our clinical practices, we have repeatedly cared for patients who came into our clinics because of a worrisome irregular breathing pattern characterized by a deep inspiration, and followed by a noisy expiration. We have referred to the set of clinical signs that these patients present with as “sigh syndrome.”

We have long suspected that sigh syndrome is an underdiagnosed and self-limited condition that is often mistaken for a serious respiratory disorder. In our experience, this syndrome runs a benign course. However, we believed that this syndrome had characteristic and consistent features, and should not be considered a diagnosis of exclusion.

Thus, we undertook a study to observe a group of subjects with these features to judge whether this subjectively alarming symptom complex is in fact harmless, and whether it is appropriate to respond to it as we had, by taking a stress-alleviating approach alone.

What is sigh syndrome?

Patients with sigh syndrome exhibit a compulsion to perform single but repeated deep inspirations, accompanied by a sensation of difficulty in inhaling a sufficient quantity of air. Each inspiration is followed by a prolonged, sometimes noisy expiration—namely, a sigh. Observing such abnormal breaths and confirming that the patient feels a concomitant inability to fill his lungs to capacity is sufficient to make the diagnosis.

This breathing compulsion is irregular in nature: It may occur once a minute or several times a minute, and this breathing pattern may continue—on and off throughout the day—for a few days to several weeks. In our experience, it provokes significant anxiety in patients, prompting them to seek medical advice. It does not occur when the patient is asleep, and it is not triggered by physical activity.

Both patient and doctor may, at first, be convinced that the problem reflects a serious illness. The 10 features of sigh syndrome (TABLE 1) constitute a proposed definition. All of our study subjects exhibited these 10 features.

TABLE 1
10 features of sigh syndrome

Sighing as an illness marker

Sighing has been described as one member of a group of signs exhibited by depressed or anxiety-ridden patients.¹ While Perin et al² were the first to point out the importance of distinguishing between sighing and respiratory disease, sighing per se has never been identified as a discrete illness marker.

A number of psychiatric disorders are already well known to incorporate breathing and chest symptoms along with widespread somatization. These include globus hystericus, neurocirculatory asthenia, and Tietze syndrome.^3-6 As such, the acute pain of precordial catch syndrome stands out as an example of a distinguishable, clear-cut clinical state devoid of any apparent organic basis.^7,8

Methods

How we recruited the patients

Data was collected from 3 family practice clinics in Israel from February 2002 to February 2005. We requested that these practices contribute data of consecutive clinical cases presenting with the 10 set symptoms of sigh syndrome (TABLE 1).

Data collected included basic demographics, the circumstances of the onset of symptoms, concurrent medical conditions, and any associated symptoms. We assessed the patients’ education level by asking questions pertaining to their years of schooling and college degrees. Patients rated their own economic status as being below, average, or above-average income.

The main outcome we examined was the clinical course of the sighing episodes during the ensuing months after their visit, in order to determine whether any patients developed a form of significant organic disease or a disorder that led to hospitalization.

Results

40 cases that cut across the socioeconomic spectrum

Forty patients were recruited for this study. Nineteen (47.5%) were male; their ages ranged from 7 to 53 (mean, 31.8; standard deviation, 13.7). Two patients (5%) were Ashkenazi Jews; 34 (85%) were of North African ethnicity (Sephardic Jews); the other 4 were of varied Asian and European ethnicity. The number of patients with North African ethnicity overrepresents that of the population in their communities. Additionally, 3 members of this group were from the same family.

There was no predilection toward any specific education level or socioeconomic status. The occupations of the subjects were diverse.

Their clinical characteristics

The clinical characteristics of the 40 patients are presented in TABLE 2. The subjects’ sighing began at various times of the day, without relationship to eating or any other activity, and disappeared during sleep. All patients reported the same feeling: that of an extra effort demanded to perform full inspiration. In many cases, adult patients were certain their complaints were a sign of cardiac or respiratory disease, and they were very concerned that there was some grave, underlying disorder.

History and examination failed to reveal evidence of any somatic findings related to breathing difficulty. Breathing rate was within normal limits in all cases.

The physicians’ initial encounters with these patients led to further examination in many cases: electrocardiography, blood oxygen saturation, and complete blood counts. However, no abnormalities were found on any of these tests. Medications, if prescribed at all during these consultations, were usually given to alleviate insomnia or anxiety. Further ancillary investigations or referrals were not ordered.

The sole notable finding on physical examination was a typical murmur (which had already been diagnosed) in a young girl with a congenital atrial septal defect. This 7-year-old developed repeated episodes of sigh syndrome just before her annual visit to the pediatric cardiologist; her mother believed that the child was frightened by the thought of possible future surgery.

TABLE 2
Clinical characteristics of the 40 patients studied—One third experienced a traumatic event

Traumatic events, anxiety disorders suggest stress as a cause

Thirteen patient histories disclosed a definite, recent, significant traumatic event that may have triggered the onset of sigh syndrome. Examples of 2 triggering events are the terrorist murder of several members of a neighbor’s family, and a near-miss with a mortar shell. One subject—a teenager—had recently been left alone in the dark with 2 younger siblings during a power blackout; another young woman said that the sighing episodes began when she decided to get married.

Ten patients had previously diagnosed neurotic disorders, mainly generalized anxiety; these included 2 cases of somatization disorder and 1 case of posttraumatic stress disorder. This information from the patients’ histories was documented in their medical files.

Episodes appear to be self-limited

In all patients, the episodes were self-limited. During the follow-up period, lasting an average of 18 months, none of the patients showed additional medical conditions—respiratory or otherwise—that could be linked to episodes of sigh syndrome. Recurrences of sighing episodes were reported by 24 subjects (60%) after the marker episode. One patient was diagnosed with carcinoma of the pancreas 2 years into follow-up, and later died.

Discussion

A benign, transient disorder

Aside from the solitary and unrelated death noted above, examination and follow-up in all 40 cases did not lead to an alternative diagnosis. Sigh syndrome thus seems to be an entirely benign and transient condition with no sequelae aside from possible recurrences.

Although the pathophysiology is unclear, our finding that 32.5% of patients had a recent traumatic incident strongly suggests a stress-related condition. Furthermore, 25% of the patients were already known to suffer from intermittent anxiety or somatoform disorders, although none were taking medications for these conditions. This adds support to the assumption that a mind-body interaction is underpinning the disorder. Large-scale migration, recent war or terrorist acts, or natural disaster are likely to increase the chances that the average physician will see a patient with sigh syndrome.

A tendency towards North African/Sephardic ethnicity, rather than European ethnicity—in addition to the cluster of 3 cases belonging to the same family—suggests the presentation may be a subconscious cultural, learned, or adopted expression of uneasiness.

Making your evaluation: History and physical are enough

The diagnostic evaluation of sigh syndrome—consisting of careful history-taking and a thorough physical examination—should be sufficient to differentiate it from an array of organic diseases. A physical examination is imperative to exclude other causes for this breathing abnormality.

Ancillary testing is rarely, if ever, indicated. It can perhaps be justified only if the condition is accompanied by an additional (if serendipitous) finding such as the cardiac murmur in the 7-year-old girl noted earlier. Physicians sometimes perform unnecessary investigations, being reluctant to base their diagnoses solely on their clinical expertise.⁹ A patient may interpret this testing as uncertainty or begin to doubt the diagnosis, thus augmenting—rather than reducing—any anxiety.¹⁰ The additional burden of the costs and possible side effects compound the futility of testing indiscriminately.¹¹

Identifying these symptoms with the name “sigh syndrome,” and basing this diagnosis on the history and physical examination, stresses certainty and familiarity with the diagnosis.⁹ Not only does this reassure the patient, but it eases communication between professionals and forms a basis for research.

Management: Reassure your patient

Management of sigh syndrome consists largely of providing reassurances to your patient. You should emphasize that the condition is real, albeit benign, and that you understand the concern it causes.

Further treatment is unnecessary, aside perhaps from addressing any associated anxiety. A self-limiting (if sometimes recurrent) course can be confidently predicted, and follow-up visits can safely be left to the patient’s own discretion. Since the major correlation with sigh syndrome seems to be stress and the experience of a recent traumatic event, you should always investigate these 2 possibilities when taking the history of a patient with suspected sigh syndrome.

Acknowledgments

This work was inspired and developed by arthur Furst, MD, who died following the submission of this manuscript. Dr Furst was a distinguished and dedicated family physician, a thorough researcher, and a renowned tutor. We dedicate this article to the fond memory of a true leader in the field of rural medicine, and an exceptionally funny and amicable colleague.

Correspondence
Abby Naimer Sody, MD, Gush Katif Health Center, Neve Dekalim, Goosh Katif, Israel 79779; [email protected]

Old codes 99371–99373 that were used to report a call you made to a patient, or to consult or coordinate medical management with other health-care professionals, are deleted in 2008. In their place? A series of new codes that cover not only physician–patient contact but nonphysician–patient contact on the telephone.

Additional codes have also been added for non–face-to-face physician– provider contact regarding the care of a patient. Although these new codes may not be reimbursed by many payers, they do allow you to bill the patient for such services in many instances. They’ll also help the practice better track the care given by its providers.

Patient-initiated telephone contact

99441  Telephone evaluation and management service provided by a physician to an established patient, parent, or guardian not originating from a related E/M service provided within the previous 7 days nor leading to an E/M service or procedure within the next 24 hours or soonest available appointment; 5–10 minutes of medical discussion

99442  …11–20 minutes of medical discussion

99443  …21–30 minutes of medical discussion

98966   Telephone assessment and management service provided by a qualified nonphysician health care professional to an established patient, parent, or guardian not originating from a related assessment and management service provided within the previous seven days nor leading to an assessment and management service or procedure within the next 24 hours or soonest available appointment; 5–10 minutes of medical discussion

98967  …11–20 minutes of medical discussion

98968  …21–30 minutes of medical discussion

To use these codes, keep in mind a few rules:

• Contact must be initiated by the patient or the established patient’s guardian
  
• Don’t report the new codes if the patient is then seen for the problem within 24 hours after the call or at the next available urgent appointment. When that happens, the call is considered part of the pre-service work and may be counted as part of the billable E/M service
  
• Don’t report the new codes if the call relates to an E/M service that was reported by the provider within the prior 7 days—whether the provider did or did not request that the call be made
  
• Don’t report the new codes for any follow-up regarding a procedure that was performed while the patient is still in the postop period.
  

Conferring with the medical team

99367   Medical team conference with interdisciplinary team of health care professionals, patient and/or family not present, 30 minutes or more; participation by physician

99368  …participation by nonphysician qualified health care professional

The interactions of an interdisciplinary team are more comprehensive and complex than the conversations that might take place during a regular E/M service. So, the rules for these codes are somewhat different:

• The patient must be an established patient who has a chronic health condition or multiple health conditions that require a team approach to manage
  
• The participants in the conference are familiar with the patient and have seen the patient within 60 days prior to the conference call
  
• Only one provider from the same specialty may report these codes for each conference
  
• The conference must be at least 30 minutes long; the clock starts at the beginning of the review of the patient’s case and ends at the conclusion of that review. Time spent writing reports on the conference can’t be counted.
  

Providing your services online

99444  Online evaluation and management service provided by a physician to an established patient, guardian, or health care provider not originating from a related E/M service provided within the previous 7 days, using the Internet or similar electronic communications network

98969  Online assessment and management service provided by a qualified nonphysician health care professional to an established patient, guardian, or health care provider not originating from a related assessment and management service provided within the previous 7 days, using the Internet or similar electronic communications network

Just as telephone calls are becoming a more common method of communicating with providers, online medical services are tracing a similar pattern of use. The Internet has allowed many patients to contact their physician (or nonphysician provider) directly; with assurances of privacy offered by current Internet communications systems, information can be readily shared between patient and physician.

Criteria for using these new codes are:

• The established patient or her guardian must have initiated the online evaluation request
  
• The provider’s response must be timely and must include permanent electronic or hard-copy documentation of the encounter
  
• The online service can only be reported once during a 7-day period for the same problem, but more than one provider can report his (her) separate online communication with the patient
  
• As with the rules for telephone contact with a patient, do not report the new codes if the provider has billed an E/M service related to the online query within the prior 7 days or within the postop period of a procedure.
  

Old codes 99371–99373 that were used to report a call you made to a patient, or to consult or coordinate medical management with other health-care professionals, are deleted in 2008. In their place? A series of new codes that cover not only physician–patient contact but nonphysician–patient contact on the telephone.

Additional codes have also been added for non–face-to-face physician– provider contact regarding the care of a patient. Although these new codes may not be reimbursed by many payers, they do allow you to bill the patient for such services in many instances. They’ll also help the practice better track the care given by its providers.

Patient-initiated telephone contact

99441  Telephone evaluation and management service provided by a physician to an established patient, parent, or guardian not originating from a related E/M service provided within the previous 7 days nor leading to an E/M service or procedure within the next 24 hours or soonest available appointment; 5–10 minutes of medical discussion

99442  …11–20 minutes of medical discussion

99443  …21–30 minutes of medical discussion

98966   Telephone assessment and management service provided by a qualified nonphysician health care professional to an established patient, parent, or guardian not originating from a related assessment and management service provided within the previous seven days nor leading to an assessment and management service or procedure within the next 24 hours or soonest available appointment; 5–10 minutes of medical discussion

98967  …11–20 minutes of medical discussion

98968  …21–30 minutes of medical discussion

To use these codes, keep in mind a few rules:

• Contact must be initiated by the patient or the established patient’s guardian
  
• Don’t report the new codes if the patient is then seen for the problem within 24 hours after the call or at the next available urgent appointment. When that happens, the call is considered part of the pre-service work and may be counted as part of the billable E/M service
  
• Don’t report the new codes if the call relates to an E/M service that was reported by the provider within the prior 7 days—whether the provider did or did not request that the call be made
  
• Don’t report the new codes for any follow-up regarding a procedure that was performed while the patient is still in the postop period.
  

Conferring with the medical team

99367   Medical team conference with interdisciplinary team of health care professionals, patient and/or family not present, 30 minutes or more; participation by physician

99368  …participation by nonphysician qualified health care professional

The interactions of an interdisciplinary team are more comprehensive and complex than the conversations that might take place during a regular E/M service. So, the rules for these codes are somewhat different:

• The patient must be an established patient who has a chronic health condition or multiple health conditions that require a team approach to manage
  
• The participants in the conference are familiar with the patient and have seen the patient within 60 days prior to the conference call
  
• Only one provider from the same specialty may report these codes for each conference
  
• The conference must be at least 30 minutes long; the clock starts at the beginning of the review of the patient’s case and ends at the conclusion of that review. Time spent writing reports on the conference can’t be counted.
  

Providing your services online

99444  Online evaluation and management service provided by a physician to an established patient, guardian, or health care provider not originating from a related E/M service provided within the previous 7 days, using the Internet or similar electronic communications network

98969  Online assessment and management service provided by a qualified nonphysician health care professional to an established patient, guardian, or health care provider not originating from a related assessment and management service provided within the previous 7 days, using the Internet or similar electronic communications network

Just as telephone calls are becoming a more common method of communicating with providers, online medical services are tracing a similar pattern of use. The Internet has allowed many patients to contact their physician (or nonphysician provider) directly; with assurances of privacy offered by current Internet communications systems, information can be readily shared between patient and physician.

Criteria for using these new codes are:

• The established patient or her guardian must have initiated the online evaluation request
  
• The provider’s response must be timely and must include permanent electronic or hard-copy documentation of the encounter
  
• The online service can only be reported once during a 7-day period for the same problem, but more than one provider can report his (her) separate online communication with the patient
  
• As with the rules for telephone contact with a patient, do not report the new codes if the provider has billed an E/M service related to the online query within the prior 7 days or within the postop period of a procedure.
  

Old codes 99371–99373 that were used to report a call you made to a patient, or to consult or coordinate medical management with other health-care professionals, are deleted in 2008. In their place? A series of new codes that cover not only physician–patient contact but nonphysician–patient contact on the telephone.

Additional codes have also been added for non–face-to-face physician– provider contact regarding the care of a patient. Although these new codes may not be reimbursed by many payers, they do allow you to bill the patient for such services in many instances. They’ll also help the practice better track the care given by its providers.

Patient-initiated telephone contact

99441  Telephone evaluation and management service provided by a physician to an established patient, parent, or guardian not originating from a related E/M service provided within the previous 7 days nor leading to an E/M service or procedure within the next 24 hours or soonest available appointment; 5–10 minutes of medical discussion

99442  …11–20 minutes of medical discussion

99443  …21–30 minutes of medical discussion

98966   Telephone assessment and management service provided by a qualified nonphysician health care professional to an established patient, parent, or guardian not originating from a related assessment and management service provided within the previous seven days nor leading to an assessment and management service or procedure within the next 24 hours or soonest available appointment; 5–10 minutes of medical discussion

98967  …11–20 minutes of medical discussion

98968  …21–30 minutes of medical discussion

To use these codes, keep in mind a few rules:

• Contact must be initiated by the patient or the established patient’s guardian
  
• Don’t report the new codes if the patient is then seen for the problem within 24 hours after the call or at the next available urgent appointment. When that happens, the call is considered part of the pre-service work and may be counted as part of the billable E/M service
  
• Don’t report the new codes if the call relates to an E/M service that was reported by the provider within the prior 7 days—whether the provider did or did not request that the call be made
  
• Don’t report the new codes for any follow-up regarding a procedure that was performed while the patient is still in the postop period.
  

Conferring with the medical team

99367   Medical team conference with interdisciplinary team of health care professionals, patient and/or family not present, 30 minutes or more; participation by physician

99368  …participation by nonphysician qualified health care professional

The interactions of an interdisciplinary team are more comprehensive and complex than the conversations that might take place during a regular E/M service. So, the rules for these codes are somewhat different:

• The patient must be an established patient who has a chronic health condition or multiple health conditions that require a team approach to manage
  
• The participants in the conference are familiar with the patient and have seen the patient within 60 days prior to the conference call
  
• Only one provider from the same specialty may report these codes for each conference
  
• The conference must be at least 30 minutes long; the clock starts at the beginning of the review of the patient’s case and ends at the conclusion of that review. Time spent writing reports on the conference can’t be counted.
  

Providing your services online

99444  Online evaluation and management service provided by a physician to an established patient, guardian, or health care provider not originating from a related E/M service provided within the previous 7 days, using the Internet or similar electronic communications network

98969  Online assessment and management service provided by a qualified nonphysician health care professional to an established patient, guardian, or health care provider not originating from a related assessment and management service provided within the previous 7 days, using the Internet or similar electronic communications network

Just as telephone calls are becoming a more common method of communicating with providers, online medical services are tracing a similar pattern of use. The Internet has allowed many patients to contact their physician (or nonphysician provider) directly; with assurances of privacy offered by current Internet communications systems, information can be readily shared between patient and physician.

Criteria for using these new codes are:

• The established patient or her guardian must have initiated the online evaluation request
  
• The provider’s response must be timely and must include permanent electronic or hard-copy documentation of the encounter
  
• The online service can only be reported once during a 7-day period for the same problem, but more than one provider can report his (her) separate online communication with the patient
  
• As with the rules for telephone contact with a patient, do not report the new codes if the provider has billed an E/M service related to the online query within the prior 7 days or within the postop period of a procedure.
  

Illustrative case

A 70-year-old man with newly diagnosed hypertension comes to your office. You don’t want to prescribe a diuretic due to his history of gout. He has no history of coronary artery disease or heart failure.

What is the best antihypertensive agent for him?

Background: Guidelines do not reflect new evidence

Guidelines for the use of beta-blockers in the elderly do not reflect current evidence.

JNC recommendations

The 2003 JNC 7 Report recommended the same antihypertensive medications for adults of all ages.³ (JNC 7 is the most recent report from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.)

JNC 7 recommends thiazide diuretics for first-line treatment of hypertension, and recommends other drugs—including beta-blockers, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs)—for first-line therapy if a thiazide is contraindicated, or in combination with thiazides for higher initial blood pressure.

Compelling indications. Beta-blockers are recommended in the JNC 7 Report as first-line therapy in patients with “compelling indications” such as ischemic heart disease and heart failure.

Clinical context: Seniors taking beta-blockers to their detriment?

Many elderly patients are on beta-blockers, perhaps to their detriment. Treatment choices for hypertension can have an enormous impact on outcomes among older patients:

Two thirds of US adults 60 years of age and older have hypertension, mostly isolated systolic hypertension.^4,5

Multiple studies, including the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe, have shown that lowering blood pressure with pharmacologic interventions in older patients can reduce the risk of cardiovascular events and possibly dementia.⁶

Beta-blockers have been a mainstay of hypertension treatment for many decades and we suspect continue to be widely used as first-line therapy in patients for whom the evidence now indicates they are inferior.

Heart failure and angina are indications for beta-blockers

New evidence does not alter the 2003 JNC 7 recommendations to use beta-blockers as first-line therapy in patients with “compelling indications” such as ischemic heart disease and heart failure.

Study summaries

Two well-done reviews of beta-blocker trials show that they are inferior for first-line hypertension treatment in the elderly who do not have heart failure or angina.

2007 Cochrane review

The 2007 Cochrane review² analyzed randomized trials that compared beta-blockers for hypertension in adults 18 years of age and older to each of the other major classes of antihypertensives.

Conclusion. This meta-analysis showed a “relatively weak effect of beta-blockers to reduce stroke, and the absence of effect on coronary heart disease when compared with placebo or no treatment” and a “trend toward worse outcomes in comparison with calcium channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics.”

This meta-analysis included all adults and did not make any conclusions based on age.

2006 CMAJ meta-analysis

The Kahn and McAlister meta-analysis¹ pooled data from 21 randomized hyper-tension trials (including 6 placebo-controlled trials) that evaluated the efficacy of beta-blockers as first-line therapy for hypertension in preventing major cardiovascular outcomes (death, nonfatal MI, or nonfatal stroke).

The results were analyzed by age group: trials enrolling patients with a mean age of 60 years or older at baseline vs trials enrolling patients with a mean age of under 60 years.

Conclusion. They concluded that in trials comparing other antihypertensive medications with beta-blockers, all agents showed similar efficacy in younger patients, while in older patients, beta-blockers were associated with a higher risk of both composite events and strokes ( TABLE ).

TABLE
Adverse outcomes more likely in seniors taking a beta-blocker vs other antihypertensives¹

What’s new?: The age distinction

These 2 meta-analyses^1,2 help overturn a long-held belief about the value of beta-blockers for the treatment of hypertension. Beta-blockers may not be a good first-line choice for any hypertensive patient—and the evidence clearly shows they are not a good first-line choice for patients over 60 years old.

Two earlier systematic reviews did raise the concern about using beta-blockers as first-line treatment for hypertension (even when thiazides are not contraindicated).

The first systematic review to raise this concern was a 1998 study of 10 hypertension trials in more than 16,000 patients, ages 60 and older. This review showed that diuretics were superior to beta-blockers in reducing cardiovascular and all-cause mortality—which supports the JNC 7 recommendation to choose a thiazide diuretic as the first-line drug of choice.⁷

The second study, a meta-analysis published in 2005, also concluded that beta-blockers should no longer be considered first-line therapy for hypertension, due to a 16% increase in the relative risk of stroke compared with other agents. This meta-analysis, however, did not report outcomes by patient age.⁸

Beta-blockers are not 1st-line, even if thiazides are contraindicated

What is new about the Kahn and McAlister evidence is that beta-blockers should not be the first-line drug of choice even when thiazide diuretics are contraindicated. Their study included a larger number of trials (21 trials vs 13 in the 2005 meta-analysis), which allowed the investigators to examine outcomes in patients younger than 60 and in those 60 years and older.

Caveats: Continue beta-blockers for the right reasons

Patients over 60 with ischemic heart disease or heart failure should still be prescribed beta-blockers for heart failure and angina. Also, in older patients with hypertension who need multiple agents to control their blood pressure, a beta-blocker could be added as a third or fourth agent in addition to a diuretic, ACE inhibitor, ARB, or calcium-channel blocker. Metoprolol is a good choice, as it is inexpensive and proven to reduce mortality in patients with a history of MI or heart failure.

Atenolol may underperform

In a meta-analysis of 31 trials, Freemantle⁹ found that after MI, acebutolol, metoprolol, propranolol, and timolol significantly reduced mortality, while there was no mortality reduction with atenolol. Similarly, in heart failure, only bisoprolol, metoprolol, and carvedilol have evidence to support a reduction in mortality.¹⁰

Although atenolol is one of the most commonly prescribed beta-blockers due to its low cost and once-daily dosing, it may be the least effective. In a systematic review of 9 hypertension studies, Carlberg¹¹ showed that atenolol was no more effective than placebo at reducing MI, cardiovascular mortality, or all-cause mortality, and that patients on atenolol had significantly higher mortality than those taking other antihypertensives. Khan and McAlister do not differentiate between atenolol and other beta-blockers in their meta-analysis.¹

Challenges to implementation: Letting go

The evidence supporting this change in practice has been accumulating over time. The change itself represents a significant reversal of long-standing belief in the value of beta-blockers as an antihypertensive agent. For each individual patient, the risk is not dramatic even though the cumulative “harm” from using a beta-blocker compared to other options is potentially staggering because so many people over 60 have hypertension.

We suspect that the main challenge will be changing the beliefs of both physicians and patients. Once doctors are convinced that beta-blockers are not indicated for uncomplicated hypertension in patients over 60, changing medications in the millions of older patients who have been taking a beta-blocker for some time and have become comfortable with it will take tact and excellent communication skills.

Providing patient information may help. Sources for patients are available free or at low cost at www.nhlbi.nih.gov/health/public/heart/index.htm#hbp. These materials explain that diuretics are inexpensive and are the preferred drugs for initial treatment of hypertension.

PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Illustrative case

A 70-year-old man with newly diagnosed hypertension comes to your office. You don’t want to prescribe a diuretic due to his history of gout. He has no history of coronary artery disease or heart failure.

What is the best antihypertensive agent for him?

Background: Guidelines do not reflect new evidence

Guidelines for the use of beta-blockers in the elderly do not reflect current evidence.

JNC recommendations

The 2003 JNC 7 Report recommended the same antihypertensive medications for adults of all ages.³ (JNC 7 is the most recent report from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.)

JNC 7 recommends thiazide diuretics for first-line treatment of hypertension, and recommends other drugs—including beta-blockers, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs)—for first-line therapy if a thiazide is contraindicated, or in combination with thiazides for higher initial blood pressure.

Compelling indications. Beta-blockers are recommended in the JNC 7 Report as first-line therapy in patients with “compelling indications” such as ischemic heart disease and heart failure.

Clinical context: Seniors taking beta-blockers to their detriment?

Many elderly patients are on beta-blockers, perhaps to their detriment. Treatment choices for hypertension can have an enormous impact on outcomes among older patients:

Two thirds of US adults 60 years of age and older have hypertension, mostly isolated systolic hypertension.^4,5

Multiple studies, including the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe, have shown that lowering blood pressure with pharmacologic interventions in older patients can reduce the risk of cardiovascular events and possibly dementia.⁶

Beta-blockers have been a mainstay of hypertension treatment for many decades and we suspect continue to be widely used as first-line therapy in patients for whom the evidence now indicates they are inferior.

Heart failure and angina are indications for beta-blockers

New evidence does not alter the 2003 JNC 7 recommendations to use beta-blockers as first-line therapy in patients with “compelling indications” such as ischemic heart disease and heart failure.

Study summaries

Two well-done reviews of beta-blocker trials show that they are inferior for first-line hypertension treatment in the elderly who do not have heart failure or angina.

2007 Cochrane review

The 2007 Cochrane review² analyzed randomized trials that compared beta-blockers for hypertension in adults 18 years of age and older to each of the other major classes of antihypertensives.

Conclusion. This meta-analysis showed a “relatively weak effect of beta-blockers to reduce stroke, and the absence of effect on coronary heart disease when compared with placebo or no treatment” and a “trend toward worse outcomes in comparison with calcium channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics.”

This meta-analysis included all adults and did not make any conclusions based on age.

2006 CMAJ meta-analysis

The Kahn and McAlister meta-analysis¹ pooled data from 21 randomized hyper-tension trials (including 6 placebo-controlled trials) that evaluated the efficacy of beta-blockers as first-line therapy for hypertension in preventing major cardiovascular outcomes (death, nonfatal MI, or nonfatal stroke).

The results were analyzed by age group: trials enrolling patients with a mean age of 60 years or older at baseline vs trials enrolling patients with a mean age of under 60 years.

Conclusion. They concluded that in trials comparing other antihypertensive medications with beta-blockers, all agents showed similar efficacy in younger patients, while in older patients, beta-blockers were associated with a higher risk of both composite events and strokes ( TABLE ).

TABLE
Adverse outcomes more likely in seniors taking a beta-blocker vs other antihypertensives¹

What’s new?: The age distinction

These 2 meta-analyses^1,2 help overturn a long-held belief about the value of beta-blockers for the treatment of hypertension. Beta-blockers may not be a good first-line choice for any hypertensive patient—and the evidence clearly shows they are not a good first-line choice for patients over 60 years old.

Two earlier systematic reviews did raise the concern about using beta-blockers as first-line treatment for hypertension (even when thiazides are not contraindicated).

The first systematic review to raise this concern was a 1998 study of 10 hypertension trials in more than 16,000 patients, ages 60 and older. This review showed that diuretics were superior to beta-blockers in reducing cardiovascular and all-cause mortality—which supports the JNC 7 recommendation to choose a thiazide diuretic as the first-line drug of choice.⁷

The second study, a meta-analysis published in 2005, also concluded that beta-blockers should no longer be considered first-line therapy for hypertension, due to a 16% increase in the relative risk of stroke compared with other agents. This meta-analysis, however, did not report outcomes by patient age.⁸

Beta-blockers are not 1st-line, even if thiazides are contraindicated

What is new about the Kahn and McAlister evidence is that beta-blockers should not be the first-line drug of choice even when thiazide diuretics are contraindicated. Their study included a larger number of trials (21 trials vs 13 in the 2005 meta-analysis), which allowed the investigators to examine outcomes in patients younger than 60 and in those 60 years and older.

Caveats: Continue beta-blockers for the right reasons

Patients over 60 with ischemic heart disease or heart failure should still be prescribed beta-blockers for heart failure and angina. Also, in older patients with hypertension who need multiple agents to control their blood pressure, a beta-blocker could be added as a third or fourth agent in addition to a diuretic, ACE inhibitor, ARB, or calcium-channel blocker. Metoprolol is a good choice, as it is inexpensive and proven to reduce mortality in patients with a history of MI or heart failure.

Atenolol may underperform

In a meta-analysis of 31 trials, Freemantle⁹ found that after MI, acebutolol, metoprolol, propranolol, and timolol significantly reduced mortality, while there was no mortality reduction with atenolol. Similarly, in heart failure, only bisoprolol, metoprolol, and carvedilol have evidence to support a reduction in mortality.¹⁰

Although atenolol is one of the most commonly prescribed beta-blockers due to its low cost and once-daily dosing, it may be the least effective. In a systematic review of 9 hypertension studies, Carlberg¹¹ showed that atenolol was no more effective than placebo at reducing MI, cardiovascular mortality, or all-cause mortality, and that patients on atenolol had significantly higher mortality than those taking other antihypertensives. Khan and McAlister do not differentiate between atenolol and other beta-blockers in their meta-analysis.¹

Challenges to implementation: Letting go

The evidence supporting this change in practice has been accumulating over time. The change itself represents a significant reversal of long-standing belief in the value of beta-blockers as an antihypertensive agent. For each individual patient, the risk is not dramatic even though the cumulative “harm” from using a beta-blocker compared to other options is potentially staggering because so many people over 60 have hypertension.

We suspect that the main challenge will be changing the beliefs of both physicians and patients. Once doctors are convinced that beta-blockers are not indicated for uncomplicated hypertension in patients over 60, changing medications in the millions of older patients who have been taking a beta-blocker for some time and have become comfortable with it will take tact and excellent communication skills.

Providing patient information may help. Sources for patients are available free or at low cost at www.nhlbi.nih.gov/health/public/heart/index.htm#hbp. These materials explain that diuretics are inexpensive and are the preferred drugs for initial treatment of hypertension.

PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Illustrative case

A 70-year-old man with newly diagnosed hypertension comes to your office. You don’t want to prescribe a diuretic due to his history of gout. He has no history of coronary artery disease or heart failure.

What is the best antihypertensive agent for him?

Background: Guidelines do not reflect new evidence

Guidelines for the use of beta-blockers in the elderly do not reflect current evidence.

JNC recommendations

The 2003 JNC 7 Report recommended the same antihypertensive medications for adults of all ages.³ (JNC 7 is the most recent report from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.)

JNC 7 recommends thiazide diuretics for first-line treatment of hypertension, and recommends other drugs—including beta-blockers, calcium-channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs)—for first-line therapy if a thiazide is contraindicated, or in combination with thiazides for higher initial blood pressure.

Compelling indications. Beta-blockers are recommended in the JNC 7 Report as first-line therapy in patients with “compelling indications” such as ischemic heart disease and heart failure.

Clinical context: Seniors taking beta-blockers to their detriment?

Many elderly patients are on beta-blockers, perhaps to their detriment. Treatment choices for hypertension can have an enormous impact on outcomes among older patients:

Two thirds of US adults 60 years of age and older have hypertension, mostly isolated systolic hypertension.^4,5

Multiple studies, including the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe, have shown that lowering blood pressure with pharmacologic interventions in older patients can reduce the risk of cardiovascular events and possibly dementia.⁶

Beta-blockers have been a mainstay of hypertension treatment for many decades and we suspect continue to be widely used as first-line therapy in patients for whom the evidence now indicates they are inferior.

Heart failure and angina are indications for beta-blockers

New evidence does not alter the 2003 JNC 7 recommendations to use beta-blockers as first-line therapy in patients with “compelling indications” such as ischemic heart disease and heart failure.

Study summaries

Two well-done reviews of beta-blocker trials show that they are inferior for first-line hypertension treatment in the elderly who do not have heart failure or angina.

2007 Cochrane review

The 2007 Cochrane review² analyzed randomized trials that compared beta-blockers for hypertension in adults 18 years of age and older to each of the other major classes of antihypertensives.

Conclusion. This meta-analysis showed a “relatively weak effect of beta-blockers to reduce stroke, and the absence of effect on coronary heart disease when compared with placebo or no treatment” and a “trend toward worse outcomes in comparison with calcium channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics.”

This meta-analysis included all adults and did not make any conclusions based on age.

2006 CMAJ meta-analysis

The Kahn and McAlister meta-analysis¹ pooled data from 21 randomized hyper-tension trials (including 6 placebo-controlled trials) that evaluated the efficacy of beta-blockers as first-line therapy for hypertension in preventing major cardiovascular outcomes (death, nonfatal MI, or nonfatal stroke).

The results were analyzed by age group: trials enrolling patients with a mean age of 60 years or older at baseline vs trials enrolling patients with a mean age of under 60 years.

Conclusion. They concluded that in trials comparing other antihypertensive medications with beta-blockers, all agents showed similar efficacy in younger patients, while in older patients, beta-blockers were associated with a higher risk of both composite events and strokes ( TABLE ).

TABLE
Adverse outcomes more likely in seniors taking a beta-blocker vs other antihypertensives¹

What’s new?: The age distinction

These 2 meta-analyses^1,2 help overturn a long-held belief about the value of beta-blockers for the treatment of hypertension. Beta-blockers may not be a good first-line choice for any hypertensive patient—and the evidence clearly shows they are not a good first-line choice for patients over 60 years old.

Two earlier systematic reviews did raise the concern about using beta-blockers as first-line treatment for hypertension (even when thiazides are not contraindicated).

The first systematic review to raise this concern was a 1998 study of 10 hypertension trials in more than 16,000 patients, ages 60 and older. This review showed that diuretics were superior to beta-blockers in reducing cardiovascular and all-cause mortality—which supports the JNC 7 recommendation to choose a thiazide diuretic as the first-line drug of choice.⁷

The second study, a meta-analysis published in 2005, also concluded that beta-blockers should no longer be considered first-line therapy for hypertension, due to a 16% increase in the relative risk of stroke compared with other agents. This meta-analysis, however, did not report outcomes by patient age.⁸

Beta-blockers are not 1st-line, even if thiazides are contraindicated

What is new about the Kahn and McAlister evidence is that beta-blockers should not be the first-line drug of choice even when thiazide diuretics are contraindicated. Their study included a larger number of trials (21 trials vs 13 in the 2005 meta-analysis), which allowed the investigators to examine outcomes in patients younger than 60 and in those 60 years and older.

Caveats: Continue beta-blockers for the right reasons

Patients over 60 with ischemic heart disease or heart failure should still be prescribed beta-blockers for heart failure and angina. Also, in older patients with hypertension who need multiple agents to control their blood pressure, a beta-blocker could be added as a third or fourth agent in addition to a diuretic, ACE inhibitor, ARB, or calcium-channel blocker. Metoprolol is a good choice, as it is inexpensive and proven to reduce mortality in patients with a history of MI or heart failure.

Atenolol may underperform

In a meta-analysis of 31 trials, Freemantle⁹ found that after MI, acebutolol, metoprolol, propranolol, and timolol significantly reduced mortality, while there was no mortality reduction with atenolol. Similarly, in heart failure, only bisoprolol, metoprolol, and carvedilol have evidence to support a reduction in mortality.¹⁰

Although atenolol is one of the most commonly prescribed beta-blockers due to its low cost and once-daily dosing, it may be the least effective. In a systematic review of 9 hypertension studies, Carlberg¹¹ showed that atenolol was no more effective than placebo at reducing MI, cardiovascular mortality, or all-cause mortality, and that patients on atenolol had significantly higher mortality than those taking other antihypertensives. Khan and McAlister do not differentiate between atenolol and other beta-blockers in their meta-analysis.¹

Challenges to implementation: Letting go

The evidence supporting this change in practice has been accumulating over time. The change itself represents a significant reversal of long-standing belief in the value of beta-blockers as an antihypertensive agent. For each individual patient, the risk is not dramatic even though the cumulative “harm” from using a beta-blocker compared to other options is potentially staggering because so many people over 60 have hypertension.

We suspect that the main challenge will be changing the beliefs of both physicians and patients. Once doctors are convinced that beta-blockers are not indicated for uncomplicated hypertension in patients over 60, changing medications in the millions of older patients who have been taking a beta-blocker for some time and have become comfortable with it will take tact and excellent communication skills.

Providing patient information may help. Sources for patients are available free or at low cost at www.nhlbi.nih.gov/health/public/heart/index.htm#hbp. These materials explain that diuretics are inexpensive and are the preferred drugs for initial treatment of hypertension.

PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

In studies of older patients, the prevalence of subjective memory complaints in community-based populations varies from 11% to 56%,^1,2 depending on sample selection and on how the complaints are assessed.¹ Subjective memory complaints may be associated with psychiatric symptoms—in particular, depression^3,4 and anxiety—as well as older age, lower education, and female gender.¹ In these studies, some association has been found between memory complaints and cognitive impairment on testing, even after adjustment for depressive symptoms.^4,5

Researchers have suggested that subjective memory complaints may be an early indicator for dementia,¹ and could therefore be considered as a marker for identification of dementia in general practice. However, these complaints may be the result of a wide range of conditions; longitudinal studies assessing the value of memory complaints in predicting dementia or cognitive decline have shown varying results.^6-8

The prevalence of subjective memory complaints among elderly patients consulting their GP is not known, and the clinical implication of these complaints is not well established. We conducted this study in order to investigate the prevalence and potential clinical implications of subjective memory complaints among elderly patients in general practice.

Methods

Recruiting the subjects

Seventeen general medical practices with 24 GPs located in the central district of Copenhagen, Denmark, participated in this study. These practices served a total of 40,865 patients, 2934 of whom were 65 years of age or older.

We asked all patients 65 years of age or older who consulted their GP in October and November 2002 to participate in the study, regardless of the reason for the encounter. We excluded patients who were not able to read Danish or not able to sign an informed consent form. We also excluded those with severe acute or terminal illness or a diagnosis of dementia.

Assessment of the patients

Participant questionnaire. Before the visit with their GP, we asked all qualifying patients to complete a questionnaire with items about self-reported health and memory status, as well as demographic questions. The item regarding memory status was phrased: “How would you evaluate your memory?” The categories were “excellent,” “good,” “less good,” “poor,” and “miserable.” Patients rating their memory as “less good,” “poor,” or “miserable” were classified as patients with subjective memory complaints, whereas patients rating their memory as “excellent” or “good” were defined as patients without subjective memory complaints.

Quality-of-life assessment. During their visit, the patients also completed the Danish Validated Version of EuroQoL-5D, which includes a visual analogue scale (VAS). EuroQoL-5D is a standardized instrument for use as a measure of health outcomes.⁹ Patients are asked to assess their health—in regards to mobility, self-care, everyday activities, pain, and anxiety—by checking 1 of 3 boxes. They are then asked to assess their general state of health on a VAS ranging from 0 to 100.

GP questionnaire. A questionnaire dealing with the GP’s clinical impression of dementia was developed together with 2 of the GPs and tested in a pilot survey. This questionnaire was completed by the GP for each patient before they administered the Mini Mental State Examination (MMSE), with no information from the completed participant questionnaire. The GPs could complete the questionnaire before or during the office visit.

MMSE. The MMSE, recommended in GP guidelines as a cognitive screening test, was given to the patients after the GPs completed their own questionnaires.¹⁰ The test is a 30-point questionnaire that assesses cognition; it includes simple questions and problems in a number of areas: time and place of the test, repeating lists of words, math problems, language use and comprehension, and copying a drawing. An MMSE score <24 has been widely used as an indication of the presence of cognitive impairment in population-based studies.

Registry data and ethics

The Danish National Health Register provided the information regarding the physicians and their practices.¹¹ The municipality of Copenhagen provided information regarding the nursing home status of patients.

The Scientific Ethical Committee for Copenhagen and Frederiksberg Municipalities evaluated the project. The Danish Data Protection Agency and the Danish College of General Practitioners Study Committee approved the project.

How we analyzed the data

All statistical analyses were performed using SAS, version 9.1 (SAS Institute Inc, Cary, NC). To avoid a possible cluster effect between the 17 practices, probabilities and corresponding 95% confidence intervals were estimated using a Generalized Estimating Equation (GEE) regression model. We used this method so that we could compare participants to nonparticipants, as well as to patients with subjective memory complaints and those without them. A backward elimination and a significance level of 5% to stay in model were used. Pearson’s chi-square was used to evaluate Goodness of Fit for the reduced model.

In the hypothesis-generating analysis, the following variables were included: age, gender, living with partner, receiving home care, school education, MMSE score, and EuroQoL-5D-VAS score. The EuroQoL-5D results were categorized into 3 groups: severe impairment (0 to 49 points), mild to moderate impairment (50 to 74), and normal (75 to 100). The MMSE was adjusted for age and education.

Results

Only quality-of-life scores predicted memory complaints

A total of 1180 patients 65 years of age and older consulted their GPs in the study period. From this group, we excluded 133 patients. Of the eligible 1047 patients, 775 (74.0%) patients agreed to participate in the study. These patents had a mean age of 74.8 years (standard deviation [SD], 7.1), and an average relationship with their GP of 11 years. Those who refused to participate in the study were more likely to be female and were less likely to complain about memory problems, according to the GP surveys.

The average MMSE score for these 775 patients was 28.2 (SD, 2.0), and the average EuroQoL-5D-VAS score was 70.9 (SD, 18.9). A total of 758 patients responded to the patient questionnaire regarding memory. Of these 758 patients, 177 (23.4%) reported memory complaints (that is, indicated their memory was “less good,” “poor,” or “miserable”). Only 33 (18.6%) of these 177 patients had previously consulted their GP regarding memory problems. The TABLE shows the characteristics of participants based on self-reported memory complaints.

In a hypothesis-generating analysis, we found that the only predictor for subjective memory complaints, as compared with those patients with good memory (stated as “excellent” or “good”), was an impairment of EuroQoL-5D-VAS: for a score of 0–49 points, the odds ratio (OR) for subjective memory complaints was 4.8; for a score of 50–74 points, the OR was 4.1. The patients’ gender, education, MMSE score, whether they lived alone or with a partner, and whether they were receiving home care did not seem to be independent predictors.

TABLE
Quality-of-life score was the only predictor of self-reported memory problems

Discussion

Other predictors of memory problems remain to be discovered

Depression,¹² other psychiatric conditions,^3,4 as well as certain medications may be associated with self-reported memory problems in elderly patients. These associations may explain why we found a correlation between reports of a lower quality of life and subjective memory complaints. Advanced age, female gender, and a low level of education have also been associated with a higher prevalence of memory complaints in other studies, but our study did not confirm any of these findings.

Limitations of this study

This study had several limitations. It had some selection bias, which may decrease its generalizability. In addition, this study was not designed to clarify whether memory complaints could be an early indicator for onset of dementia, or whether these complaints are associated with mild cognitive impairment or existing dementia.

The collection of data was monitored on a weekly basis by site visits from a study nurse. However, we did not monitor the actual exams.

An MMSE score of <24 has been widely used as an indication of the presence of cognitive impairment in population-based studies.¹² However, research has shown that MMSE scores are affected by age, education, and cultural background; this may explain why the MMSE by itself is not sufficient to diagnose dementia.¹²

Future studies should focus on clinically relevant outcomes

Further prospective studies in GP settings are needed to examine the potential implications of subjective memory complaints. We suggest that in future studies, clinically relevant outcomes—such as death, nursing home placement, medication usage, or health care usage—be used as possible correlating factors.

Correspondence
Frans Boch Waldorff, MD, PhD, Research Unit of General Practice, Kommunehospitalet, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark; [email protected]

In studies of older patients, the prevalence of subjective memory complaints in community-based populations varies from 11% to 56%,^1,2 depending on sample selection and on how the complaints are assessed.¹ Subjective memory complaints may be associated with psychiatric symptoms—in particular, depression^3,4 and anxiety—as well as older age, lower education, and female gender.¹ In these studies, some association has been found between memory complaints and cognitive impairment on testing, even after adjustment for depressive symptoms.^4,5

Researchers have suggested that subjective memory complaints may be an early indicator for dementia,¹ and could therefore be considered as a marker for identification of dementia in general practice. However, these complaints may be the result of a wide range of conditions; longitudinal studies assessing the value of memory complaints in predicting dementia or cognitive decline have shown varying results.^6-8

The prevalence of subjective memory complaints among elderly patients consulting their GP is not known, and the clinical implication of these complaints is not well established. We conducted this study in order to investigate the prevalence and potential clinical implications of subjective memory complaints among elderly patients in general practice.

Methods

Recruiting the subjects

Seventeen general medical practices with 24 GPs located in the central district of Copenhagen, Denmark, participated in this study. These practices served a total of 40,865 patients, 2934 of whom were 65 years of age or older.

We asked all patients 65 years of age or older who consulted their GP in October and November 2002 to participate in the study, regardless of the reason for the encounter. We excluded patients who were not able to read Danish or not able to sign an informed consent form. We also excluded those with severe acute or terminal illness or a diagnosis of dementia.

Assessment of the patients

Participant questionnaire. Before the visit with their GP, we asked all qualifying patients to complete a questionnaire with items about self-reported health and memory status, as well as demographic questions. The item regarding memory status was phrased: “How would you evaluate your memory?” The categories were “excellent,” “good,” “less good,” “poor,” and “miserable.” Patients rating their memory as “less good,” “poor,” or “miserable” were classified as patients with subjective memory complaints, whereas patients rating their memory as “excellent” or “good” were defined as patients without subjective memory complaints.

Quality-of-life assessment. During their visit, the patients also completed the Danish Validated Version of EuroQoL-5D, which includes a visual analogue scale (VAS). EuroQoL-5D is a standardized instrument for use as a measure of health outcomes.⁹ Patients are asked to assess their health—in regards to mobility, self-care, everyday activities, pain, and anxiety—by checking 1 of 3 boxes. They are then asked to assess their general state of health on a VAS ranging from 0 to 100.

GP questionnaire. A questionnaire dealing with the GP’s clinical impression of dementia was developed together with 2 of the GPs and tested in a pilot survey. This questionnaire was completed by the GP for each patient before they administered the Mini Mental State Examination (MMSE), with no information from the completed participant questionnaire. The GPs could complete the questionnaire before or during the office visit.

MMSE. The MMSE, recommended in GP guidelines as a cognitive screening test, was given to the patients after the GPs completed their own questionnaires.¹⁰ The test is a 30-point questionnaire that assesses cognition; it includes simple questions and problems in a number of areas: time and place of the test, repeating lists of words, math problems, language use and comprehension, and copying a drawing. An MMSE score <24 has been widely used as an indication of the presence of cognitive impairment in population-based studies.

Registry data and ethics

The Danish National Health Register provided the information regarding the physicians and their practices.¹¹ The municipality of Copenhagen provided information regarding the nursing home status of patients.

The Scientific Ethical Committee for Copenhagen and Frederiksberg Municipalities evaluated the project. The Danish Data Protection Agency and the Danish College of General Practitioners Study Committee approved the project.

How we analyzed the data

All statistical analyses were performed using SAS, version 9.1 (SAS Institute Inc, Cary, NC). To avoid a possible cluster effect between the 17 practices, probabilities and corresponding 95% confidence intervals were estimated using a Generalized Estimating Equation (GEE) regression model. We used this method so that we could compare participants to nonparticipants, as well as to patients with subjective memory complaints and those without them. A backward elimination and a significance level of 5% to stay in model were used. Pearson’s chi-square was used to evaluate Goodness of Fit for the reduced model.

In the hypothesis-generating analysis, the following variables were included: age, gender, living with partner, receiving home care, school education, MMSE score, and EuroQoL-5D-VAS score. The EuroQoL-5D results were categorized into 3 groups: severe impairment (0 to 49 points), mild to moderate impairment (50 to 74), and normal (75 to 100). The MMSE was adjusted for age and education.

Results

Only quality-of-life scores predicted memory complaints

A total of 1180 patients 65 years of age and older consulted their GPs in the study period. From this group, we excluded 133 patients. Of the eligible 1047 patients, 775 (74.0%) patients agreed to participate in the study. These patents had a mean age of 74.8 years (standard deviation [SD], 7.1), and an average relationship with their GP of 11 years. Those who refused to participate in the study were more likely to be female and were less likely to complain about memory problems, according to the GP surveys.

The average MMSE score for these 775 patients was 28.2 (SD, 2.0), and the average EuroQoL-5D-VAS score was 70.9 (SD, 18.9). A total of 758 patients responded to the patient questionnaire regarding memory. Of these 758 patients, 177 (23.4%) reported memory complaints (that is, indicated their memory was “less good,” “poor,” or “miserable”). Only 33 (18.6%) of these 177 patients had previously consulted their GP regarding memory problems. The TABLE shows the characteristics of participants based on self-reported memory complaints.

In a hypothesis-generating analysis, we found that the only predictor for subjective memory complaints, as compared with those patients with good memory (stated as “excellent” or “good”), was an impairment of EuroQoL-5D-VAS: for a score of 0–49 points, the odds ratio (OR) for subjective memory complaints was 4.8; for a score of 50–74 points, the OR was 4.1. The patients’ gender, education, MMSE score, whether they lived alone or with a partner, and whether they were receiving home care did not seem to be independent predictors.

TABLE
Quality-of-life score was the only predictor of self-reported memory problems

Discussion

Other predictors of memory problems remain to be discovered

Depression,¹² other psychiatric conditions,^3,4 as well as certain medications may be associated with self-reported memory problems in elderly patients. These associations may explain why we found a correlation between reports of a lower quality of life and subjective memory complaints. Advanced age, female gender, and a low level of education have also been associated with a higher prevalence of memory complaints in other studies, but our study did not confirm any of these findings.

Limitations of this study

This study had several limitations. It had some selection bias, which may decrease its generalizability. In addition, this study was not designed to clarify whether memory complaints could be an early indicator for onset of dementia, or whether these complaints are associated with mild cognitive impairment or existing dementia.

The collection of data was monitored on a weekly basis by site visits from a study nurse. However, we did not monitor the actual exams.

An MMSE score of <24 has been widely used as an indication of the presence of cognitive impairment in population-based studies.¹² However, research has shown that MMSE scores are affected by age, education, and cultural background; this may explain why the MMSE by itself is not sufficient to diagnose dementia.¹²

Future studies should focus on clinically relevant outcomes

Further prospective studies in GP settings are needed to examine the potential implications of subjective memory complaints. We suggest that in future studies, clinically relevant outcomes—such as death, nursing home placement, medication usage, or health care usage—be used as possible correlating factors.

Correspondence
Frans Boch Waldorff, MD, PhD, Research Unit of General Practice, Kommunehospitalet, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark; [email protected]

In studies of older patients, the prevalence of subjective memory complaints in community-based populations varies from 11% to 56%,^1,2 depending on sample selection and on how the complaints are assessed.¹ Subjective memory complaints may be associated with psychiatric symptoms—in particular, depression^3,4 and anxiety—as well as older age, lower education, and female gender.¹ In these studies, some association has been found between memory complaints and cognitive impairment on testing, even after adjustment for depressive symptoms.^4,5

Researchers have suggested that subjective memory complaints may be an early indicator for dementia,¹ and could therefore be considered as a marker for identification of dementia in general practice. However, these complaints may be the result of a wide range of conditions; longitudinal studies assessing the value of memory complaints in predicting dementia or cognitive decline have shown varying results.^6-8

The prevalence of subjective memory complaints among elderly patients consulting their GP is not known, and the clinical implication of these complaints is not well established. We conducted this study in order to investigate the prevalence and potential clinical implications of subjective memory complaints among elderly patients in general practice.

Methods

Recruiting the subjects

Seventeen general medical practices with 24 GPs located in the central district of Copenhagen, Denmark, participated in this study. These practices served a total of 40,865 patients, 2934 of whom were 65 years of age or older.

We asked all patients 65 years of age or older who consulted their GP in October and November 2002 to participate in the study, regardless of the reason for the encounter. We excluded patients who were not able to read Danish or not able to sign an informed consent form. We also excluded those with severe acute or terminal illness or a diagnosis of dementia.

Assessment of the patients

Participant questionnaire. Before the visit with their GP, we asked all qualifying patients to complete a questionnaire with items about self-reported health and memory status, as well as demographic questions. The item regarding memory status was phrased: “How would you evaluate your memory?” The categories were “excellent,” “good,” “less good,” “poor,” and “miserable.” Patients rating their memory as “less good,” “poor,” or “miserable” were classified as patients with subjective memory complaints, whereas patients rating their memory as “excellent” or “good” were defined as patients without subjective memory complaints.

Quality-of-life assessment. During their visit, the patients also completed the Danish Validated Version of EuroQoL-5D, which includes a visual analogue scale (VAS). EuroQoL-5D is a standardized instrument for use as a measure of health outcomes.⁹ Patients are asked to assess their health—in regards to mobility, self-care, everyday activities, pain, and anxiety—by checking 1 of 3 boxes. They are then asked to assess their general state of health on a VAS ranging from 0 to 100.

GP questionnaire. A questionnaire dealing with the GP’s clinical impression of dementia was developed together with 2 of the GPs and tested in a pilot survey. This questionnaire was completed by the GP for each patient before they administered the Mini Mental State Examination (MMSE), with no information from the completed participant questionnaire. The GPs could complete the questionnaire before or during the office visit.

MMSE. The MMSE, recommended in GP guidelines as a cognitive screening test, was given to the patients after the GPs completed their own questionnaires.¹⁰ The test is a 30-point questionnaire that assesses cognition; it includes simple questions and problems in a number of areas: time and place of the test, repeating lists of words, math problems, language use and comprehension, and copying a drawing. An MMSE score <24 has been widely used as an indication of the presence of cognitive impairment in population-based studies.

Registry data and ethics

The Danish National Health Register provided the information regarding the physicians and their practices.¹¹ The municipality of Copenhagen provided information regarding the nursing home status of patients.

The Scientific Ethical Committee for Copenhagen and Frederiksberg Municipalities evaluated the project. The Danish Data Protection Agency and the Danish College of General Practitioners Study Committee approved the project.

How we analyzed the data

All statistical analyses were performed using SAS, version 9.1 (SAS Institute Inc, Cary, NC). To avoid a possible cluster effect between the 17 practices, probabilities and corresponding 95% confidence intervals were estimated using a Generalized Estimating Equation (GEE) regression model. We used this method so that we could compare participants to nonparticipants, as well as to patients with subjective memory complaints and those without them. A backward elimination and a significance level of 5% to stay in model were used. Pearson’s chi-square was used to evaluate Goodness of Fit for the reduced model.

In the hypothesis-generating analysis, the following variables were included: age, gender, living with partner, receiving home care, school education, MMSE score, and EuroQoL-5D-VAS score. The EuroQoL-5D results were categorized into 3 groups: severe impairment (0 to 49 points), mild to moderate impairment (50 to 74), and normal (75 to 100). The MMSE was adjusted for age and education.

Results

Only quality-of-life scores predicted memory complaints

A total of 1180 patients 65 years of age and older consulted their GPs in the study period. From this group, we excluded 133 patients. Of the eligible 1047 patients, 775 (74.0%) patients agreed to participate in the study. These patents had a mean age of 74.8 years (standard deviation [SD], 7.1), and an average relationship with their GP of 11 years. Those who refused to participate in the study were more likely to be female and were less likely to complain about memory problems, according to the GP surveys.

The average MMSE score for these 775 patients was 28.2 (SD, 2.0), and the average EuroQoL-5D-VAS score was 70.9 (SD, 18.9). A total of 758 patients responded to the patient questionnaire regarding memory. Of these 758 patients, 177 (23.4%) reported memory complaints (that is, indicated their memory was “less good,” “poor,” or “miserable”). Only 33 (18.6%) of these 177 patients had previously consulted their GP regarding memory problems. The TABLE shows the characteristics of participants based on self-reported memory complaints.

In a hypothesis-generating analysis, we found that the only predictor for subjective memory complaints, as compared with those patients with good memory (stated as “excellent” or “good”), was an impairment of EuroQoL-5D-VAS: for a score of 0–49 points, the odds ratio (OR) for subjective memory complaints was 4.8; for a score of 50–74 points, the OR was 4.1. The patients’ gender, education, MMSE score, whether they lived alone or with a partner, and whether they were receiving home care did not seem to be independent predictors.

TABLE
Quality-of-life score was the only predictor of self-reported memory problems

Discussion

Other predictors of memory problems remain to be discovered

Depression,¹² other psychiatric conditions,^3,4 as well as certain medications may be associated with self-reported memory problems in elderly patients. These associations may explain why we found a correlation between reports of a lower quality of life and subjective memory complaints. Advanced age, female gender, and a low level of education have also been associated with a higher prevalence of memory complaints in other studies, but our study did not confirm any of these findings.

Limitations of this study

This study had several limitations. It had some selection bias, which may decrease its generalizability. In addition, this study was not designed to clarify whether memory complaints could be an early indicator for onset of dementia, or whether these complaints are associated with mild cognitive impairment or existing dementia.

The collection of data was monitored on a weekly basis by site visits from a study nurse. However, we did not monitor the actual exams.

An MMSE score of <24 has been widely used as an indication of the presence of cognitive impairment in population-based studies.¹² However, research has shown that MMSE scores are affected by age, education, and cultural background; this may explain why the MMSE by itself is not sufficient to diagnose dementia.¹²

Future studies should focus on clinically relevant outcomes

Further prospective studies in GP settings are needed to examine the potential implications of subjective memory complaints. We suggest that in future studies, clinically relevant outcomes—such as death, nursing home placement, medication usage, or health care usage—be used as possible correlating factors.

Correspondence
Frans Boch Waldorff, MD, PhD, Research Unit of General Practice, Kommunehospitalet, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark; [email protected]

The varicella vaccine has had tremendous success over the last few years, but its success has stalled.

The widespread use of the varicella vaccine has led to a coverage rate of 88%, and the vaccine has proven to be 85% effective. As a result, between 1995 and 2001 there was an 87% decline in hospitalizations, 66% decline in deaths, and an 87% decline in costs attributed to varicella.

However, the number of varicella cases has remained at a constant level over the past few years and sporadic outbreaks continue to occur in schools—even where high rates of immunization are achieved.^1,2

Varicella outbreaks involve both infections in unvaccinated children and “breakthrough disease” in those who have been vaccinated. If a vaccinated person is exposed to varicella, the risk of suffering a breakthrough infection is about 15%.² A 2-dose series of varicella vaccine reduces the risk by about 75%¹ (Figure).

Breakthrough disease is usually milder than infection in the unvaccinated, with fewer skin lesions, milder symptoms, and fewer complications. Those affected, though, are still infectious to others.

It was this ongoing risk of varicella that prompted the Advisory Committee on Immunization Practices (ACIP) to recommend new control measures, reported on in 2007.¹

FIGURE
2 doses of varicella vaccine reduce risk of breakthrough infection by about 75%¹

ACIP now recommends 2 doses of the vaccine

ACIP recommends the following:

• Universal administration of 2 doses of varicella vaccine; the first at ages 12 to 15 months and the second at age 4 to 6 years. (This is the same schedule as immunization against mumps, measles, and rubella.)
• Two doses of varicella vaccine, 4 to 8 weeks apart, for all adolescents and adults without evidence of immunity. (See “New criteria to prove immunity” at right.)
• A catch-up second dose for everyone who received one dose previously.
• Screening for varicella immunity in pregnant women and postpartum vaccination for those who are not immune, with 2 doses 4 to 8 weeks apart. The first dose should be administered before discharge.

Which HIV patients can get the vaccine?

ACIP has also clarified when HIV patients can be vaccinated, noting that single antigen varicella vaccine can be administered to HIV positive children if their CD4+ Tlymphocyte % is ≥15%. HIV positive adolescents and adults can be vaccinated if their CD4+ T-lymphocyte count ≥200/μL and, if 2 doses are indicated, they should be separated by at least 3 months.

2 options: Varivax and ProQuad

Two varicella vaccines contain modified live varicella virus antigen. Varivax, a single antigen vaccine, is approved for use in adults, adolescents, and children ≥12 months of age. The second vaccine, ProQuad, is approved for use in patients who are between 12 months and 12 years of age, and contains 4 viral antigens: mumps, measles, rubella, and varicella.

The quadrivalent MMRV vaccine is currently unavailable, however, and isn’t expected to be available until early 2009.³ Once the supply is stabilized, though, it will facilitate vaccination of children by decreasing the number of injections needed to achieve full immunization status.

29-year-old patient with varicellaThese 2 varicella vaccines should not be confused with the varicella zoster vaccine, Zostavax, which is approved for use in adults who are 60 years of age and older for the prevention of shingles and postherpetic neuralgia.⁴

Pregnancy precludes vaccination

Varicella vaccine is contraindicated during pregnancy and in those who have had a severe allergic reaction to any vaccine component, including gelatin; have a malignancy of the blood, bone marrow, or lymphatic system; have a congenital or hereditary immunodeficiency; or are receiving systemic immunosuppressive therapy including those on the equivalent of 2 mg/kg, or >20 mg/day, of prednisone.

You should delay giving the vaccine to patients with an acute, severe illness. There is a potential for immune globulin containing products to interfere with the effectiveness of live virus vaccines. As a result, if a patient has received blood, plasma, or immune globulin, you should wait 3 to 11 months before giving the varicella vaccine. These products should also be avoided, if possible, for 2 weeks after the vaccine has been administered.

Avoid using quadrivalent MMRV in patients with HIV infection because it contains a higher quantity of varicella antigen than the single antigen product.

One final precaution: Patients should avoid taking salicylates for 6 weeks following vaccination because of the theoretical risk of Reye’s syndrome.

The varicella vaccine has had tremendous success over the last few years, but its success has stalled.

The widespread use of the varicella vaccine has led to a coverage rate of 88%, and the vaccine has proven to be 85% effective. As a result, between 1995 and 2001 there was an 87% decline in hospitalizations, 66% decline in deaths, and an 87% decline in costs attributed to varicella.

However, the number of varicella cases has remained at a constant level over the past few years and sporadic outbreaks continue to occur in schools—even where high rates of immunization are achieved.^1,2

Varicella outbreaks involve both infections in unvaccinated children and “breakthrough disease” in those who have been vaccinated. If a vaccinated person is exposed to varicella, the risk of suffering a breakthrough infection is about 15%.² A 2-dose series of varicella vaccine reduces the risk by about 75%¹ (Figure).

Breakthrough disease is usually milder than infection in the unvaccinated, with fewer skin lesions, milder symptoms, and fewer complications. Those affected, though, are still infectious to others.

It was this ongoing risk of varicella that prompted the Advisory Committee on Immunization Practices (ACIP) to recommend new control measures, reported on in 2007.¹

FIGURE
2 doses of varicella vaccine reduce risk of breakthrough infection by about 75%¹

ACIP now recommends 2 doses of the vaccine

ACIP recommends the following:

• Universal administration of 2 doses of varicella vaccine; the first at ages 12 to 15 months and the second at age 4 to 6 years. (This is the same schedule as immunization against mumps, measles, and rubella.)
• Two doses of varicella vaccine, 4 to 8 weeks apart, for all adolescents and adults without evidence of immunity. (See “New criteria to prove immunity” at right.)
• A catch-up second dose for everyone who received one dose previously.
• Screening for varicella immunity in pregnant women and postpartum vaccination for those who are not immune, with 2 doses 4 to 8 weeks apart. The first dose should be administered before discharge.

Which HIV patients can get the vaccine?

ACIP has also clarified when HIV patients can be vaccinated, noting that single antigen varicella vaccine can be administered to HIV positive children if their CD4+ Tlymphocyte % is ≥15%. HIV positive adolescents and adults can be vaccinated if their CD4+ T-lymphocyte count ≥200/μL and, if 2 doses are indicated, they should be separated by at least 3 months.

2 options: Varivax and ProQuad

Two varicella vaccines contain modified live varicella virus antigen. Varivax, a single antigen vaccine, is approved for use in adults, adolescents, and children ≥12 months of age. The second vaccine, ProQuad, is approved for use in patients who are between 12 months and 12 years of age, and contains 4 viral antigens: mumps, measles, rubella, and varicella.

The quadrivalent MMRV vaccine is currently unavailable, however, and isn’t expected to be available until early 2009.³ Once the supply is stabilized, though, it will facilitate vaccination of children by decreasing the number of injections needed to achieve full immunization status.

29-year-old patient with varicellaThese 2 varicella vaccines should not be confused with the varicella zoster vaccine, Zostavax, which is approved for use in adults who are 60 years of age and older for the prevention of shingles and postherpetic neuralgia.⁴

Pregnancy precludes vaccination

Varicella vaccine is contraindicated during pregnancy and in those who have had a severe allergic reaction to any vaccine component, including gelatin; have a malignancy of the blood, bone marrow, or lymphatic system; have a congenital or hereditary immunodeficiency; or are receiving systemic immunosuppressive therapy including those on the equivalent of 2 mg/kg, or >20 mg/day, of prednisone.

You should delay giving the vaccine to patients with an acute, severe illness. There is a potential for immune globulin containing products to interfere with the effectiveness of live virus vaccines. As a result, if a patient has received blood, plasma, or immune globulin, you should wait 3 to 11 months before giving the varicella vaccine. These products should also be avoided, if possible, for 2 weeks after the vaccine has been administered.

Avoid using quadrivalent MMRV in patients with HIV infection because it contains a higher quantity of varicella antigen than the single antigen product.

One final precaution: Patients should avoid taking salicylates for 6 weeks following vaccination because of the theoretical risk of Reye’s syndrome.

The varicella vaccine has had tremendous success over the last few years, but its success has stalled.

The widespread use of the varicella vaccine has led to a coverage rate of 88%, and the vaccine has proven to be 85% effective. As a result, between 1995 and 2001 there was an 87% decline in hospitalizations, 66% decline in deaths, and an 87% decline in costs attributed to varicella.

However, the number of varicella cases has remained at a constant level over the past few years and sporadic outbreaks continue to occur in schools—even where high rates of immunization are achieved.^1,2

Varicella outbreaks involve both infections in unvaccinated children and “breakthrough disease” in those who have been vaccinated. If a vaccinated person is exposed to varicella, the risk of suffering a breakthrough infection is about 15%.² A 2-dose series of varicella vaccine reduces the risk by about 75%¹ (Figure).

Breakthrough disease is usually milder than infection in the unvaccinated, with fewer skin lesions, milder symptoms, and fewer complications. Those affected, though, are still infectious to others.

It was this ongoing risk of varicella that prompted the Advisory Committee on Immunization Practices (ACIP) to recommend new control measures, reported on in 2007.¹

FIGURE
2 doses of varicella vaccine reduce risk of breakthrough infection by about 75%¹

ACIP now recommends 2 doses of the vaccine

ACIP recommends the following:

• Universal administration of 2 doses of varicella vaccine; the first at ages 12 to 15 months and the second at age 4 to 6 years. (This is the same schedule as immunization against mumps, measles, and rubella.)
• Two doses of varicella vaccine, 4 to 8 weeks apart, for all adolescents and adults without evidence of immunity. (See “New criteria to prove immunity” at right.)
• A catch-up second dose for everyone who received one dose previously.
• Screening for varicella immunity in pregnant women and postpartum vaccination for those who are not immune, with 2 doses 4 to 8 weeks apart. The first dose should be administered before discharge.

Which HIV patients can get the vaccine?

ACIP has also clarified when HIV patients can be vaccinated, noting that single antigen varicella vaccine can be administered to HIV positive children if their CD4+ Tlymphocyte % is ≥15%. HIV positive adolescents and adults can be vaccinated if their CD4+ T-lymphocyte count ≥200/μL and, if 2 doses are indicated, they should be separated by at least 3 months.

2 options: Varivax and ProQuad

Two varicella vaccines contain modified live varicella virus antigen. Varivax, a single antigen vaccine, is approved for use in adults, adolescents, and children ≥12 months of age. The second vaccine, ProQuad, is approved for use in patients who are between 12 months and 12 years of age, and contains 4 viral antigens: mumps, measles, rubella, and varicella.

The quadrivalent MMRV vaccine is currently unavailable, however, and isn’t expected to be available until early 2009.³ Once the supply is stabilized, though, it will facilitate vaccination of children by decreasing the number of injections needed to achieve full immunization status.

29-year-old patient with varicellaThese 2 varicella vaccines should not be confused with the varicella zoster vaccine, Zostavax, which is approved for use in adults who are 60 years of age and older for the prevention of shingles and postherpetic neuralgia.⁴

Pregnancy precludes vaccination

Varicella vaccine is contraindicated during pregnancy and in those who have had a severe allergic reaction to any vaccine component, including gelatin; have a malignancy of the blood, bone marrow, or lymphatic system; have a congenital or hereditary immunodeficiency; or are receiving systemic immunosuppressive therapy including those on the equivalent of 2 mg/kg, or >20 mg/day, of prednisone.

You should delay giving the vaccine to patients with an acute, severe illness. There is a potential for immune globulin containing products to interfere with the effectiveness of live virus vaccines. As a result, if a patient has received blood, plasma, or immune globulin, you should wait 3 to 11 months before giving the varicella vaccine. These products should also be avoided, if possible, for 2 weeks after the vaccine has been administered.

Avoid using quadrivalent MMRV in patients with HIV infection because it contains a higher quantity of varicella antigen than the single antigen product.

One final precaution: Patients should avoid taking salicylates for 6 weeks following vaccination because of the theoretical risk of Reye’s syndrome.