Clinical Care Conundrums

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Case

A 52-year-old white woman presents to the ED after a motor vehicle accident with a fractured left femur. After surgical repair of the fracture, she is treated with enoxaparin 40 mg daily for VTE prophylaxis. Upon admission to the hospital, her platelet count is 180x109/L. On postoperative day three, it is 140x109/L; on postoperative day six, it is 78x109/L. Because of persistent swelling of the left leg, a venous ultrasound is obtained; results are negative for DVT. Is the decrease in the platelet count concerning for heparin-induced thrombocytopenia?

Overview

Approximately one-third of hospitalized patients are exposed to heparin each year.¹ A well-described, life-threatening adverse effect of heparin use is thrombocytopenia, also called heparin-induced thrombocytopenia (HIT). Studies suggest that the frequency of HIT in the U.S. is as high as 1% to 5% in patients exposed to unfractionated heparin.^1,2

There are two types of HIT. Type 2 HIT is more serious, with risk for life- or limb-threatening complications. Type 1 HIT is a nonimmune disorder caused by the direct effect of heparin on platelet activation, which is characterized by a drop in thrombocyte count within the first 48 hours of heparin exposure. The platelet count is expected to normalize with continued heparin exposure in Type 1 HIT. Type 2 HIT is an immune-mediated disorder in which heparin-dependent IgG recognizes complexes of heparin and platelet factor 4 (PF4), which subsequently induce platelet activation via the platelet Fc gammaRIIa receptor. A positive feedback loop occurs, causing further release of PF4 and platelet activation, which can lead to devastating prothrombotic complications.

Individuals affected by Type 2 HIT have a 20% to 50% risk of developing new thrombotic events, and also have a 10% rate of major morbidity, including limb ischemia requiring amputation, cerebrovascular events, myocardial infarction, DVT, or pulmonary embolus.^1,2

Until recently, the mortality rate in HIT has been reported as high as 20%; however, earlier diagnosis and treatment have resulted in a better prognosis, with mortality and major morbidity of 6% to 10%.² Low-molecular-weight heparin (LMWH) carries a lower risk for development of HIT; as such, one measure to reduce the risk of HIT is to use LMWH in place of unfractionated heparin.³

Review of the Data

When to suspect HIT. HIT should be considered as a potential diagnosis anytime there is a drop in platelet count, either during or shortly following heparin exposure. The differential diagnosis for thrombocytopenia during heparin exposure is broad and includes:

• Disseminated intravascular coagulation;
• Drug-induced thrombocytopenia;
• Hemolytic-uremic syndrome;
• Immune thrombocytopenic purpura;
• Post-transfusion thrombocytopenia;
• Systemic lupus erythematosus; and
• Thrombotic thrombocytopenic purpura.

click for large version

The 2009 Clinical Practice Guideline on Evaluation and Management of HIT provided by the American Society of Hematology recommends the use of Warkentin’s 4Ts clinical probability scoring system as a guide in determining the probability of HIT in patients with thrombocytopenia who are exposed to heparin.⁴ The 4Ts scoring system is detailed in Table 1.

In patients with intermediate to high clinical probability of HIT (4-5 points and 6-8 points, respectively, on the 4Ts scoring system), immunologic and functional assays could further guide management. In patients with a low probability of HIT (4Ts score <3), the diagnosis is unlikely and an alternative diagnoses should be considered. Immunologic and functional assays are not recommended for these patients, and heparin can be continued.

Laboratory and diagnostic workups. Immunologic assays (polyspecific ELISA, IgG-specific ELISA, and particle gel immunoassay) detect antibodies against the PF4 heparin complexes regardless of their capacity to activate platelets. These tests are highly sensitive but less specific for HIT because they also detect PF4-heparin antibodies in patients who do not have HIT; therefore, immunoassays have a lower positive predictive value but a high negative predictive value (>95%).⁵

Functional assays (serotonin release assay, heparin-induced platelet activation assay, and platelet aggregation test) detect antibodies that induce heparin-dependent platelet activation. These assays are highly sensitive and specific but are not available at many medical centers. The positive predictive value of these assays is higher (89% to 100%).⁵

Figure 1 provides a diagnostic and initial treatment algorithm for suspected HIT. Immunoassays to detect PF4-heparin antibodies are recommended when clinical probability of HIT is intermediate to high. In these patients, a negative result on serologic testing has a high negative predictive value and suggests that an alternative diagnosis is more likely. In patients with a positive serologic test and intermediate probability of HIT, a functional assay might be beneficial, as a positive result increases the probability of HIT. For patients with high probability of HIT and a positive immunologic assay, functional assays might not be indicated as the diagnosis is likely.

click for large version

Treatment. If the probability of HIT is intermediate to high based on the 4Ts scoring system, all heparin products, including heparin flushes, should be immediately discontinued and a laboratory investigation for HIT antibodies should be undertaken. An investigation for lower-limb DVT also should be pursued in patients with high probability of HIT, as the risk of thrombosis is more than 30-fold higher than controls, and studies show that approximately 25% of patients with HIT present with both thrombocytopenia and thrombosis.⁵ In addition, the presence of thrombosis might influence duration of anticoagulation.

Avoid platelet transfusions, as this might propagate thrombosis.

Anticoagulation. With a significant risk of thrombosis associated with this disorder, treatment with an alternative anticoagulant should be started. Vitamin K antagonists, such as warfarin, cannot be given in acute HIT because of the high risk of inducing skin necrosis and venous limb gangrene. Such anticoagulation should not be used until the platelet count increases to greater than 150x109/L. If warfarin already has been given, reversal with vitamin K is indicated.

Consequently, an alternative anticoagulant bridge to warfarin therapy must be used. Usually, the bridging agent will be one of two intravenous direct thrombin inhibitors (argatroban and lepirudin) approved for this purpose.⁶ Both are associated with a higher risk of bleeding. Argatroban is hepatically cleared; lepirudin is renally cleared. Table 2 summarizes dosing information for these agents. A third direct thrombin inhibitor, bivalirudin, is approved for treatment of HIT, but only during percutaneous coronary intervention.⁶

Finally, the recently FDA-approved oral direct thrombin inhibitor dabigatrin has not been studied in or approved for HIT.

Other rational therapies include the factor Xa inhibitors danaparoid and fondaparinux. However, only danaparoid is FDA-approved for use in the treatment of HIT. It can, in cases of low or moderate suspicion of HIT, be given in prophylactic doses, lowering the risk of major bleeding.

Duration of treatment. Whichever bridging anticoagulant is chosen, it should be continued until the platelet count has fully recovered. Further, prior to discontinuation, warfarin therapy should be administered for at least five days and the international normalized ratio (INR) should be therapeutic for approximately 48 hours.

click for large version

The subsequent length of warfarin therapy is dependent upon the presence or absence of an associated thrombosis. With the presence of a thrombus, the duration should be as defined for other provoked thromboses (three to six months). With no thrombus, the duration should be at least 30 days.

Future anticoagulation in patients with a prior diagnosis of HIT. A history of HIT does not appear to be a risk factor for a higher frequency of forming heparin antibodies upon re-exposure to heparin.⁷ Therefore, in patients with an important indication for heparin (i.e. cardiac or vascular surgery) and a remote history of HIT (>100 days), heparin can be used. In patients with a subacute history of HIT in whom surgery cannot be delayed, heparin products should be avoided and laboratory investigation should be pursued.

If the immunoassay is positive but the functional assay is negative, it is reasonable to use heparin. If both the immunologic and the functional assays are positive, the patient should be considered as having acute HIT, and bivalirudin is recommended.⁴

Back to the Case

Our patient has acute thrombocytopenia with a fall in platelets greater than 50% from baseline. The decrease is within the appropriate time frame for HIT. No thrombosis is found, but no alternate explanation for the thrombocytopenia is apparent. The 4Ts score of 6 indicates high risk for HIT. Heparin was discontinued, and argatroban at a rate of 2 mcg/kg/min was initiated. The immunoassay was positive.

Argatroban was continued until the platelet count reached 150x109/L, at which point warfarin therapy, 5 mg daily, was started. After four days, the INR was 2.2. After another 24 hours, argatroban was discontinued. She was instructed to continue warfarin for another 30 days.

Bottom Line

Evaluation for HIT combines clinical judgment, summarized in the 4Ts, with laboratory evaluation including an immunoassay and possibly a functional assay. Treatment requires immediate discontinuation of heparin, early initiation of a direct thrombin inhibitor, and bridging to warfarin to continue treatment for at least 30 days. TH

Drs. Smith and Rice are members of the Section of Hospital Medicine at Vanderbilt University in Nashville, Tenn.

References

1. Heparin-Induced Thrombocytopenia. MedScape Reference website. Available at: http://emedicine.medscape.com/article/1357846. Accessed Aug. 31, 2010.
2. Heparin-Induced Thrombocytopenia. Orpha.net website. Available at: http://www.orpha.net/data/patho/GB/uk-HIT.pdf. Accessed Aug. 31, 2010.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335.
4. American Society of Hematology Guidelines: Immune Thrombocytopenia (HIT). American Society of Hematology website. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 28, 2011.
5. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61:77-90.
6. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S.
7. Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin N Am. 2010;24:755-775.

click for large version

Case

A 52-year-old white woman presents to the ED after a motor vehicle accident with a fractured left femur. After surgical repair of the fracture, she is treated with enoxaparin 40 mg daily for VTE prophylaxis. Upon admission to the hospital, her platelet count is 180x109/L. On postoperative day three, it is 140x109/L; on postoperative day six, it is 78x109/L. Because of persistent swelling of the left leg, a venous ultrasound is obtained; results are negative for DVT. Is the decrease in the platelet count concerning for heparin-induced thrombocytopenia?

Overview

Approximately one-third of hospitalized patients are exposed to heparin each year.¹ A well-described, life-threatening adverse effect of heparin use is thrombocytopenia, also called heparin-induced thrombocytopenia (HIT). Studies suggest that the frequency of HIT in the U.S. is as high as 1% to 5% in patients exposed to unfractionated heparin.^1,2

There are two types of HIT. Type 2 HIT is more serious, with risk for life- or limb-threatening complications. Type 1 HIT is a nonimmune disorder caused by the direct effect of heparin on platelet activation, which is characterized by a drop in thrombocyte count within the first 48 hours of heparin exposure. The platelet count is expected to normalize with continued heparin exposure in Type 1 HIT. Type 2 HIT is an immune-mediated disorder in which heparin-dependent IgG recognizes complexes of heparin and platelet factor 4 (PF4), which subsequently induce platelet activation via the platelet Fc gammaRIIa receptor. A positive feedback loop occurs, causing further release of PF4 and platelet activation, which can lead to devastating prothrombotic complications.

Individuals affected by Type 2 HIT have a 20% to 50% risk of developing new thrombotic events, and also have a 10% rate of major morbidity, including limb ischemia requiring amputation, cerebrovascular events, myocardial infarction, DVT, or pulmonary embolus.^1,2

Until recently, the mortality rate in HIT has been reported as high as 20%; however, earlier diagnosis and treatment have resulted in a better prognosis, with mortality and major morbidity of 6% to 10%.² Low-molecular-weight heparin (LMWH) carries a lower risk for development of HIT; as such, one measure to reduce the risk of HIT is to use LMWH in place of unfractionated heparin.³

Review of the Data

When to suspect HIT. HIT should be considered as a potential diagnosis anytime there is a drop in platelet count, either during or shortly following heparin exposure. The differential diagnosis for thrombocytopenia during heparin exposure is broad and includes:

• Disseminated intravascular coagulation;
• Drug-induced thrombocytopenia;
• Hemolytic-uremic syndrome;
• Immune thrombocytopenic purpura;
• Post-transfusion thrombocytopenia;
• Systemic lupus erythematosus; and
• Thrombotic thrombocytopenic purpura.

click for large version

The 2009 Clinical Practice Guideline on Evaluation and Management of HIT provided by the American Society of Hematology recommends the use of Warkentin’s 4Ts clinical probability scoring system as a guide in determining the probability of HIT in patients with thrombocytopenia who are exposed to heparin.⁴ The 4Ts scoring system is detailed in Table 1.

In patients with intermediate to high clinical probability of HIT (4-5 points and 6-8 points, respectively, on the 4Ts scoring system), immunologic and functional assays could further guide management. In patients with a low probability of HIT (4Ts score <3), the diagnosis is unlikely and an alternative diagnoses should be considered. Immunologic and functional assays are not recommended for these patients, and heparin can be continued.

Laboratory and diagnostic workups. Immunologic assays (polyspecific ELISA, IgG-specific ELISA, and particle gel immunoassay) detect antibodies against the PF4 heparin complexes regardless of their capacity to activate platelets. These tests are highly sensitive but less specific for HIT because they also detect PF4-heparin antibodies in patients who do not have HIT; therefore, immunoassays have a lower positive predictive value but a high negative predictive value (>95%).⁵

Functional assays (serotonin release assay, heparin-induced platelet activation assay, and platelet aggregation test) detect antibodies that induce heparin-dependent platelet activation. These assays are highly sensitive and specific but are not available at many medical centers. The positive predictive value of these assays is higher (89% to 100%).⁵

Figure 1 provides a diagnostic and initial treatment algorithm for suspected HIT. Immunoassays to detect PF4-heparin antibodies are recommended when clinical probability of HIT is intermediate to high. In these patients, a negative result on serologic testing has a high negative predictive value and suggests that an alternative diagnosis is more likely. In patients with a positive serologic test and intermediate probability of HIT, a functional assay might be beneficial, as a positive result increases the probability of HIT. For patients with high probability of HIT and a positive immunologic assay, functional assays might not be indicated as the diagnosis is likely.

click for large version

Treatment. If the probability of HIT is intermediate to high based on the 4Ts scoring system, all heparin products, including heparin flushes, should be immediately discontinued and a laboratory investigation for HIT antibodies should be undertaken. An investigation for lower-limb DVT also should be pursued in patients with high probability of HIT, as the risk of thrombosis is more than 30-fold higher than controls, and studies show that approximately 25% of patients with HIT present with both thrombocytopenia and thrombosis.⁵ In addition, the presence of thrombosis might influence duration of anticoagulation.

Avoid platelet transfusions, as this might propagate thrombosis.

Anticoagulation. With a significant risk of thrombosis associated with this disorder, treatment with an alternative anticoagulant should be started. Vitamin K antagonists, such as warfarin, cannot be given in acute HIT because of the high risk of inducing skin necrosis and venous limb gangrene. Such anticoagulation should not be used until the platelet count increases to greater than 150x109/L. If warfarin already has been given, reversal with vitamin K is indicated.

Consequently, an alternative anticoagulant bridge to warfarin therapy must be used. Usually, the bridging agent will be one of two intravenous direct thrombin inhibitors (argatroban and lepirudin) approved for this purpose.⁶ Both are associated with a higher risk of bleeding. Argatroban is hepatically cleared; lepirudin is renally cleared. Table 2 summarizes dosing information for these agents. A third direct thrombin inhibitor, bivalirudin, is approved for treatment of HIT, but only during percutaneous coronary intervention.⁶

Finally, the recently FDA-approved oral direct thrombin inhibitor dabigatrin has not been studied in or approved for HIT.

Other rational therapies include the factor Xa inhibitors danaparoid and fondaparinux. However, only danaparoid is FDA-approved for use in the treatment of HIT. It can, in cases of low or moderate suspicion of HIT, be given in prophylactic doses, lowering the risk of major bleeding.

Duration of treatment. Whichever bridging anticoagulant is chosen, it should be continued until the platelet count has fully recovered. Further, prior to discontinuation, warfarin therapy should be administered for at least five days and the international normalized ratio (INR) should be therapeutic for approximately 48 hours.

click for large version

The subsequent length of warfarin therapy is dependent upon the presence or absence of an associated thrombosis. With the presence of a thrombus, the duration should be as defined for other provoked thromboses (three to six months). With no thrombus, the duration should be at least 30 days.

Future anticoagulation in patients with a prior diagnosis of HIT. A history of HIT does not appear to be a risk factor for a higher frequency of forming heparin antibodies upon re-exposure to heparin.⁷ Therefore, in patients with an important indication for heparin (i.e. cardiac or vascular surgery) and a remote history of HIT (>100 days), heparin can be used. In patients with a subacute history of HIT in whom surgery cannot be delayed, heparin products should be avoided and laboratory investigation should be pursued.

If the immunoassay is positive but the functional assay is negative, it is reasonable to use heparin. If both the immunologic and the functional assays are positive, the patient should be considered as having acute HIT, and bivalirudin is recommended.⁴

Back to the Case

Our patient has acute thrombocytopenia with a fall in platelets greater than 50% from baseline. The decrease is within the appropriate time frame for HIT. No thrombosis is found, but no alternate explanation for the thrombocytopenia is apparent. The 4Ts score of 6 indicates high risk for HIT. Heparin was discontinued, and argatroban at a rate of 2 mcg/kg/min was initiated. The immunoassay was positive.

Argatroban was continued until the platelet count reached 150x109/L, at which point warfarin therapy, 5 mg daily, was started. After four days, the INR was 2.2. After another 24 hours, argatroban was discontinued. She was instructed to continue warfarin for another 30 days.

Bottom Line

Evaluation for HIT combines clinical judgment, summarized in the 4Ts, with laboratory evaluation including an immunoassay and possibly a functional assay. Treatment requires immediate discontinuation of heparin, early initiation of a direct thrombin inhibitor, and bridging to warfarin to continue treatment for at least 30 days. TH

Drs. Smith and Rice are members of the Section of Hospital Medicine at Vanderbilt University in Nashville, Tenn.

References

1. Heparin-Induced Thrombocytopenia. MedScape Reference website. Available at: http://emedicine.medscape.com/article/1357846. Accessed Aug. 31, 2010.
2. Heparin-Induced Thrombocytopenia. Orpha.net website. Available at: http://www.orpha.net/data/patho/GB/uk-HIT.pdf. Accessed Aug. 31, 2010.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335.
4. American Society of Hematology Guidelines: Immune Thrombocytopenia (HIT). American Society of Hematology website. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 28, 2011.
5. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61:77-90.
6. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S.
7. Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin N Am. 2010;24:755-775.

click for large version

Case

A 52-year-old white woman presents to the ED after a motor vehicle accident with a fractured left femur. After surgical repair of the fracture, she is treated with enoxaparin 40 mg daily for VTE prophylaxis. Upon admission to the hospital, her platelet count is 180x109/L. On postoperative day three, it is 140x109/L; on postoperative day six, it is 78x109/L. Because of persistent swelling of the left leg, a venous ultrasound is obtained; results are negative for DVT. Is the decrease in the platelet count concerning for heparin-induced thrombocytopenia?

Overview

Approximately one-third of hospitalized patients are exposed to heparin each year.¹ A well-described, life-threatening adverse effect of heparin use is thrombocytopenia, also called heparin-induced thrombocytopenia (HIT). Studies suggest that the frequency of HIT in the U.S. is as high as 1% to 5% in patients exposed to unfractionated heparin.^1,2

There are two types of HIT. Type 2 HIT is more serious, with risk for life- or limb-threatening complications. Type 1 HIT is a nonimmune disorder caused by the direct effect of heparin on platelet activation, which is characterized by a drop in thrombocyte count within the first 48 hours of heparin exposure. The platelet count is expected to normalize with continued heparin exposure in Type 1 HIT. Type 2 HIT is an immune-mediated disorder in which heparin-dependent IgG recognizes complexes of heparin and platelet factor 4 (PF4), which subsequently induce platelet activation via the platelet Fc gammaRIIa receptor. A positive feedback loop occurs, causing further release of PF4 and platelet activation, which can lead to devastating prothrombotic complications.

Individuals affected by Type 2 HIT have a 20% to 50% risk of developing new thrombotic events, and also have a 10% rate of major morbidity, including limb ischemia requiring amputation, cerebrovascular events, myocardial infarction, DVT, or pulmonary embolus.^1,2

Until recently, the mortality rate in HIT has been reported as high as 20%; however, earlier diagnosis and treatment have resulted in a better prognosis, with mortality and major morbidity of 6% to 10%.² Low-molecular-weight heparin (LMWH) carries a lower risk for development of HIT; as such, one measure to reduce the risk of HIT is to use LMWH in place of unfractionated heparin.³

Review of the Data

When to suspect HIT. HIT should be considered as a potential diagnosis anytime there is a drop in platelet count, either during or shortly following heparin exposure. The differential diagnosis for thrombocytopenia during heparin exposure is broad and includes:

• Disseminated intravascular coagulation;
• Drug-induced thrombocytopenia;
• Hemolytic-uremic syndrome;
• Immune thrombocytopenic purpura;
• Post-transfusion thrombocytopenia;
• Systemic lupus erythematosus; and
• Thrombotic thrombocytopenic purpura.

click for large version

The 2009 Clinical Practice Guideline on Evaluation and Management of HIT provided by the American Society of Hematology recommends the use of Warkentin’s 4Ts clinical probability scoring system as a guide in determining the probability of HIT in patients with thrombocytopenia who are exposed to heparin.⁴ The 4Ts scoring system is detailed in Table 1.

In patients with intermediate to high clinical probability of HIT (4-5 points and 6-8 points, respectively, on the 4Ts scoring system), immunologic and functional assays could further guide management. In patients with a low probability of HIT (4Ts score <3), the diagnosis is unlikely and an alternative diagnoses should be considered. Immunologic and functional assays are not recommended for these patients, and heparin can be continued.

Laboratory and diagnostic workups. Immunologic assays (polyspecific ELISA, IgG-specific ELISA, and particle gel immunoassay) detect antibodies against the PF4 heparin complexes regardless of their capacity to activate platelets. These tests are highly sensitive but less specific for HIT because they also detect PF4-heparin antibodies in patients who do not have HIT; therefore, immunoassays have a lower positive predictive value but a high negative predictive value (>95%).⁵

Functional assays (serotonin release assay, heparin-induced platelet activation assay, and platelet aggregation test) detect antibodies that induce heparin-dependent platelet activation. These assays are highly sensitive and specific but are not available at many medical centers. The positive predictive value of these assays is higher (89% to 100%).⁵

Figure 1 provides a diagnostic and initial treatment algorithm for suspected HIT. Immunoassays to detect PF4-heparin antibodies are recommended when clinical probability of HIT is intermediate to high. In these patients, a negative result on serologic testing has a high negative predictive value and suggests that an alternative diagnosis is more likely. In patients with a positive serologic test and intermediate probability of HIT, a functional assay might be beneficial, as a positive result increases the probability of HIT. For patients with high probability of HIT and a positive immunologic assay, functional assays might not be indicated as the diagnosis is likely.

click for large version

Treatment. If the probability of HIT is intermediate to high based on the 4Ts scoring system, all heparin products, including heparin flushes, should be immediately discontinued and a laboratory investigation for HIT antibodies should be undertaken. An investigation for lower-limb DVT also should be pursued in patients with high probability of HIT, as the risk of thrombosis is more than 30-fold higher than controls, and studies show that approximately 25% of patients with HIT present with both thrombocytopenia and thrombosis.⁵ In addition, the presence of thrombosis might influence duration of anticoagulation.

Avoid platelet transfusions, as this might propagate thrombosis.

Anticoagulation. With a significant risk of thrombosis associated with this disorder, treatment with an alternative anticoagulant should be started. Vitamin K antagonists, such as warfarin, cannot be given in acute HIT because of the high risk of inducing skin necrosis and venous limb gangrene. Such anticoagulation should not be used until the platelet count increases to greater than 150x109/L. If warfarin already has been given, reversal with vitamin K is indicated.

Consequently, an alternative anticoagulant bridge to warfarin therapy must be used. Usually, the bridging agent will be one of two intravenous direct thrombin inhibitors (argatroban and lepirudin) approved for this purpose.⁶ Both are associated with a higher risk of bleeding. Argatroban is hepatically cleared; lepirudin is renally cleared. Table 2 summarizes dosing information for these agents. A third direct thrombin inhibitor, bivalirudin, is approved for treatment of HIT, but only during percutaneous coronary intervention.⁶

Finally, the recently FDA-approved oral direct thrombin inhibitor dabigatrin has not been studied in or approved for HIT.

Other rational therapies include the factor Xa inhibitors danaparoid and fondaparinux. However, only danaparoid is FDA-approved for use in the treatment of HIT. It can, in cases of low or moderate suspicion of HIT, be given in prophylactic doses, lowering the risk of major bleeding.

Duration of treatment. Whichever bridging anticoagulant is chosen, it should be continued until the platelet count has fully recovered. Further, prior to discontinuation, warfarin therapy should be administered for at least five days and the international normalized ratio (INR) should be therapeutic for approximately 48 hours.

click for large version

The subsequent length of warfarin therapy is dependent upon the presence or absence of an associated thrombosis. With the presence of a thrombus, the duration should be as defined for other provoked thromboses (three to six months). With no thrombus, the duration should be at least 30 days.

Future anticoagulation in patients with a prior diagnosis of HIT. A history of HIT does not appear to be a risk factor for a higher frequency of forming heparin antibodies upon re-exposure to heparin.⁷ Therefore, in patients with an important indication for heparin (i.e. cardiac or vascular surgery) and a remote history of HIT (>100 days), heparin can be used. In patients with a subacute history of HIT in whom surgery cannot be delayed, heparin products should be avoided and laboratory investigation should be pursued.

If the immunoassay is positive but the functional assay is negative, it is reasonable to use heparin. If both the immunologic and the functional assays are positive, the patient should be considered as having acute HIT, and bivalirudin is recommended.⁴

Back to the Case

Our patient has acute thrombocytopenia with a fall in platelets greater than 50% from baseline. The decrease is within the appropriate time frame for HIT. No thrombosis is found, but no alternate explanation for the thrombocytopenia is apparent. The 4Ts score of 6 indicates high risk for HIT. Heparin was discontinued, and argatroban at a rate of 2 mcg/kg/min was initiated. The immunoassay was positive.

Argatroban was continued until the platelet count reached 150x109/L, at which point warfarin therapy, 5 mg daily, was started. After four days, the INR was 2.2. After another 24 hours, argatroban was discontinued. She was instructed to continue warfarin for another 30 days.

Bottom Line

Evaluation for HIT combines clinical judgment, summarized in the 4Ts, with laboratory evaluation including an immunoassay and possibly a functional assay. Treatment requires immediate discontinuation of heparin, early initiation of a direct thrombin inhibitor, and bridging to warfarin to continue treatment for at least 30 days. TH

Drs. Smith and Rice are members of the Section of Hospital Medicine at Vanderbilt University in Nashville, Tenn.

References

1. Heparin-Induced Thrombocytopenia. MedScape Reference website. Available at: http://emedicine.medscape.com/article/1357846. Accessed Aug. 31, 2010.
2. Heparin-Induced Thrombocytopenia. Orpha.net website. Available at: http://www.orpha.net/data/patho/GB/uk-HIT.pdf. Accessed Aug. 31, 2010.
3. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335.
4. American Society of Hematology Guidelines: Immune Thrombocytopenia (HIT). American Society of Hematology website. Available at: www.hematology.org/Practice/Guidelines/2934.aspx. Accessed Jan. 28, 2011.
5. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. Annu Rev Med. 2010;61:77-90.
6. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:340S-380S.
7. Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin N Am. 2010;24:755-775.

Case

A 79-year-old male with coronary artery disease, hypertension, non-insulin-dependent mellitus, moderate dementia, and chronic renal insufficiency is admitted after a fall evaluation. He is widowed and lives in an assisted living facility. He’s accompanied by his niece, is alert, and oriented to person. He thinks he is in a clinic and is unable to state the year, but the remainder of the examination is unremarkable. His labs are notable for potassium of 6.3 mmol/L, BUN of 78 mg/dL, and Cr of 3.7 mg/dL. The niece reports that the patient is not fond of medical care, thus the most recent labs are from two years ago (and indicate a BUN of 39 and Cr of 2.8, with an upward trend over the past decade). You discuss possible long-term need for dialysis with the patient and niece, and the patient clearly states "no." However, he also states that it is 1988. How do you determine if he has the capacity to make decisions?

Overview

Hospitalists are familiar with the doctrine of informed consent—describing a disease, treatment options, associated risks and benefits, potential for complications, and alternatives, including no treatment. Not only must the patient be informed, and the decision free from any coercion, but the patient also must have capacity to make the decision.

Hospitalists often care for patients in whom decision-making capacity comes into question. This includes populations with depression, psychosis, dementia, stroke, severe personality disorders, developmental delay, comatose patients, as well as those with impaired attentional capacity (e.g. acute pain) or general debility (e.g. metastatic cancer).^1,2

ave for the comatose patient, whether the patient has capacity might not be obvious. However, addressing the components of capacity (communication, understanding, appreciation, and rationalization) by using a validated clinical tool, such as the MacCAT-T, or more simply by systematically applying those four components to the clinical scenario under consideration, hospitalists can make this determination.

Review of the Literature

It is important to differentiate capacity from competency. Competency is a global assessment and a legal determination made by a judge in court. Capacity, on the other hand, is a functional assessment regarding a particular decision. Capacity is not static, and it can be performed by any clinician familiar with the patient. A hospitalist often is well positioned to make a capacity determination given established rapport with the patient and familiarity with the details of the case.

To make this determination, a hospitalist needs to know how to assess capacity. Although capacity usually is defined by state law and varies by jurisdiction, clinicians generally can assume it includes one or more of the four key components:

• Communication. The patient needs to be able to express a treatment choice, and this decision needs to be stable enough for the treatment to be implemented. Changing one’s decision in itself would not bring a patient’s capacity into question, so long as the patient was able to explain the rationale behind the switch. Frequent changes back and forth in the decision-making, however, could be indicative of an underlying psychiatric disorder or extreme indecision, which could bring capacity into question.
• Understanding. The patient needs to recall conversations about treatment, to make the link between causal relationships, and to process probabilities for outcomes. Problems with memory, attention span, and intelligence can affect one’s understanding.
• Appreciation. The patient should be able to identify the illness, treatment options, and likely outcomes as things that will affect him or her directly. A lack of appreciation usually stems from a denial based on intelligence (lack of a capability to understand) or emotion, or a delusion that the patient is not affected by this situation the same way and will have a different outcome.
• Rationalization or reasoning. The patient needs to be able to weigh the risks and benefits of the treatment options presented to come to a conclusion in keeping with their goals and best interests, as defined by their personal set of values. This often is affected in psychosis, depression, anxiety, phobias, delirium, and dementia.³

Several clinical capacity tools have been developed to assess these components:

Clinical tools.

The Mini-Mental Status Examination (MMSE) is a bedside test of a patient’s cognitive function, with scores ranging from 0 to 30.⁴ Although it wasn’t developed for assessing decision-making capacity, it has been compared with expert evaluation for assessment of capacity; the test performs reasonably well, particularly with high and low scores. Specifically, a MMSE >24 has a negative likelihood ratio (LR) of 0.05 for lack of capacity, while a MMSE <16 has a positive LR of 15.⁵ Scores from 17 to 23 do not correlate well with capacity, and further testing would be necessary. It is easy to administer, requires no formal training, and is familiar to most hospitalists. However, it does not address any specific aspects of informed consent, such as understanding or choice, and has not been validated in patients with mental illness.

The MacArthur Competence Assessment Tools for Treatment (MacCAT-T) is regarded as the gold standard for capacity assessment aids. It utilizes hospital chart review followed by a semi-structured interview to address clinical issues relevant to the patient being assessed; it takes 15 to 20 minutes to complete.⁶ The test provides scores in each of the four domains (choice, understanding, appreciation, and reasoning) of capacity. It has been validated in patients with dementia, schizophrenia, and depression. Limiting its clinical applicability is the fact that the MacCAT-T requires training to administer and interpret the results, though this is a relatively brief process.

The Capacity to Consent to Treatment Instrument (CCTI) uses hypothetical clinical vignettes in a structured interview to assess capacity across all four domains. The tool was developed and validated in patients with dementia and Parkinson’s disease, and takes 20 to 25 minutes to complete.⁷ A potential limitation is the CCTI’s use of vignettes as opposed to a patient-specific discussion, which could lead to different patient answers and a false assessment of the patient’s capacity.

The Hopemont Capacity Assessment Interview (HCAI) utilizes hypothetical vignettes in a semi-structured interview format to assess understanding, appreciation, choice, and likely reasoning.^8,9 Similar to CCTI, HCAI is not modified for individual patients. Rather, it uses clinical vignettes to gauge a patient’s ability to make decisions. The test takes 30 to 60 minutes to administer and performs less well in assessing appreciation and reasoning than the MacCAT-T and CCTI.¹⁰

It is not necessary to perform a formal assessment of capacity on every inpatient. For most, there is no reasonable concern for impaired capacity, obviating the need for formal testing. Likewise, in patients who clearly lack capacity, such as those with end-stage dementia or established guardians, formal reassessment usually is not required. Formal testing is most useful in situations in which capacity is unclear, disagreement amongst surrogate decision-makers exists, or judicial involvement is anticipated.

The MacCAT-T has been validated in the broadest population and is probably the most clinically useful tool currently available. The MMSE is an attractive alternative because of its widespread use and familiarity; however, it is imprecise with scores from 17 to 23, limiting its applicability.

click for large version

At a minimum, familiarity with the core legal standards of capacity (communication of choice, understanding, appreciation, and reasoning) will improve a hospitalist’s ability to identify patients who lack capacity. Understanding and applying the defined markers most often provides a sufficient capacity evaluation in itself. As capacity is not static, the decision usually requires more than one assessment.

Equally, deciding that a patient lacks capacity is not an end in itself, and the underlying cause should be addressed. Certain factors, such as infection, medication, time of day, and relationship with the clinician doing the assessment, can affect a patient’s capacity. These should be addressed through treatment, education, and social support whenever possible in order to optimize a patient’s performance during the capacity evaluation. If the decision can be delayed until a time when the patient can regain capacity, this should be done in order to maximize the patient’s autonomy.¹¹

Risk-related standards of capacity.

Although some question the notion, given our desire to facilitate management beneficial to the patient, the general consensus is that we have a lower threshold for capacity for consent to treatments that are low-risk and high-benefit.^12,13 We would then have a somewhat higher threshold for capacity to refuse that same treatment. Stemming from a desire to protect patients from harm, we have a relatively higher threshold for capacity to make decisions regarding high-risk, low-benefit treatments. For the remainder of cases (low risk/low benefit; high risk/high benefit), as well as treatments that significantly impact a patient’s lifestyle (e.g. dialysis, amputation), we have a low capacity to let patients decide for themselves.^11,14

Other considerations.

Clinicians should be thorough in documenting details in coming to a capacity determination, both as a means to formalize the thought process running through the four determinants of capacity, and in order to document for future reference. Cases in which it could be reasonable to call a consultant for those familiar with the assessment basics include:

• Cases in which a determination of lack of capacity could adversely affect the hospitalist’s relationship with the patient;
• Cases in which the hospitalist lacks the time to properly perform the evaluation;
• Particularly difficult or high-stakes cases (e.g. cases that might involve legal proceedings); and
• Cases in which significant mental illness affects a patient’s capacity.¹¹

Early involvement of potential surrogate decision-makers is wise for patients in whom capacity is questioned, both for obtaining collateral history as well as initiating dialogue as to the patient’s wishes. When a patient is found to lack capacity, resources to utilize to help make a treatment decision include existing advance directives and substitute decision-makers, such as durable power of attorneys (DPOAs) and family members. In those rare cases in which clinicians are unable to reach a consensus about a patient’s capacity, an ethics consult should be considered.

click for large version

Back to the Case.

Following the patient’s declaration that dialysis is not something he is interested in, his niece reports that he is a minimalist when it comes to interventions, and that he had similarly refused a cardiac catheterization in the 1990s. You review with the patient and niece that dialysis would be a procedure to replace his failing kidney function, and that failure to pursue this would ultimately be life-threatening and likely result in death, especially in regard to electrolyte abnormalities and his lack of any other terminal illness.

The consulting nephrologist reviews their recommendations with the patient and niece as well, and the patient consistently refuses. Having clearly communicated his choice, you ask the patient if he understands the situation. He says, "My kidneys are failing. That’s how I got the high potassium." You ask him what that means. "They aren’t going to function on their own much longer," he says. "I could die from it."

You confirm his ideas, and ask him why he doesn’t want dialysis. "I don’t want dialysis because I don’t want to spend my life hooked up to machines three times a week," the patient explains. "I just want to let things run their natural course." The niece says her uncle wouldn’t have wanted dialysis even if it were 10 years ago, so she’s not surprised he is refusing now.

Following this discussion, you feel comfortable that the patient has capacity to make this decision. Having documented this discussion, you discharge him to a subacute rehabilitation facility.

Bottom Line.

In cases in which capacity is in question, a hospitalist’s case-by-case review of the four components of capacity—communicating a choice, understanding, appreciation, and rationalization and reasoning—is warranted to help determine whether a patient has capacity. In cases in which a second opinion is warranted, psychiatry, geriatrics, or ethics consults could be utilized.

Drs. Dastidar and Odden are hospitalists at the University of Michigan in Ann Arbor.

References

1. Buchanan A, Brock DW. Deciding for others. Milbank Q. 1986;64(Suppl. 2):17-94.
2. Guidelines for assessing the decision-making capacities of potential research subjects with cognitive impairment. American Psychiatric Association. Am J Psychiatry. 1998;155(11):1649-50.
3. Appelbaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med. 1988;319(25):1635-1638.
4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
5. Etchells E, Darzins P, Silberfeld M, et al. Assessment of patient capacity to consent to treatment. J Gen Intern Med. 1999;14:27-34.
6. Grisso T, Appelbaum PS, Hill-Fotouhi C. The MacCAT-T: a clinical tool to assess patients’ capacities to make treatment decisions. Psychiatr Serv. 1997;48:1415- 1419.
7. Marson DC, Ingram KK, Cody HA, Harrell LE. Assessing the competency of patients with Alzheimer’s disease under different legal standards. A prototype instrument. Arch Neurol. 1995;52:949-954.
8. Edelstein B. Hopemont Capacity Assessment Interview Manual and Scoring Guide. 1999: Morgantown, W.V.: West Virginia University.
9. Pruchno RA, Smyer MA, Rose MS, Hartman-Stein PE, Henderson-Laribee DL. Competence of long-term care residents to participate in decisions about their medical care: a brief, objective assessment. Gerontologist. 1995;35:622-629.
10. Moye J, Karel M, Azar AR, Gurrera R. Capacity to consent to treatment: empirical comparison of three instruments in older adults with and without dementia. Gerontologist. 2004;44:166-175.
11. Grisso T, Appelbaum PS. Assessing competence to consent to treatment: a guide for physicians and other health professionals. 1998; New York: Oxford University Press, 211.
12. Cale GS. Risk-related standards of competence: continuing the debate over risk-related standards of competence. Bioethics. 1999;13(2):131-148.
13. Checkland D. On risk and decisional capacity. J Med Philos. 2001;26(1):35-59.
14. Wilks I. The debate over risk-related standards of competence. Bioethics. 1997;11(5):413-426.
15. Ganzini L, Volicer L, Nelson WA, Fox E, Derse AR. Ten myths about decision-making capacity. J Am Med Dir Assoc. 2004;5(4):263-267.

Acknowledgements:The authors would like to thank Dr. Jeff Rohde for reviewing a copy of the manuscript, and Dr. Amy Rosinski for providing direction from the psychiatry standpoint

Case

A 79-year-old male with coronary artery disease, hypertension, non-insulin-dependent mellitus, moderate dementia, and chronic renal insufficiency is admitted after a fall evaluation. He is widowed and lives in an assisted living facility. He’s accompanied by his niece, is alert, and oriented to person. He thinks he is in a clinic and is unable to state the year, but the remainder of the examination is unremarkable. His labs are notable for potassium of 6.3 mmol/L, BUN of 78 mg/dL, and Cr of 3.7 mg/dL. The niece reports that the patient is not fond of medical care, thus the most recent labs are from two years ago (and indicate a BUN of 39 and Cr of 2.8, with an upward trend over the past decade). You discuss possible long-term need for dialysis with the patient and niece, and the patient clearly states "no." However, he also states that it is 1988. How do you determine if he has the capacity to make decisions?

Overview

Hospitalists are familiar with the doctrine of informed consent—describing a disease, treatment options, associated risks and benefits, potential for complications, and alternatives, including no treatment. Not only must the patient be informed, and the decision free from any coercion, but the patient also must have capacity to make the decision.

Hospitalists often care for patients in whom decision-making capacity comes into question. This includes populations with depression, psychosis, dementia, stroke, severe personality disorders, developmental delay, comatose patients, as well as those with impaired attentional capacity (e.g. acute pain) or general debility (e.g. metastatic cancer).^1,2

ave for the comatose patient, whether the patient has capacity might not be obvious. However, addressing the components of capacity (communication, understanding, appreciation, and rationalization) by using a validated clinical tool, such as the MacCAT-T, or more simply by systematically applying those four components to the clinical scenario under consideration, hospitalists can make this determination.

Review of the Literature

It is important to differentiate capacity from competency. Competency is a global assessment and a legal determination made by a judge in court. Capacity, on the other hand, is a functional assessment regarding a particular decision. Capacity is not static, and it can be performed by any clinician familiar with the patient. A hospitalist often is well positioned to make a capacity determination given established rapport with the patient and familiarity with the details of the case.

To make this determination, a hospitalist needs to know how to assess capacity. Although capacity usually is defined by state law and varies by jurisdiction, clinicians generally can assume it includes one or more of the four key components:

• Communication. The patient needs to be able to express a treatment choice, and this decision needs to be stable enough for the treatment to be implemented. Changing one’s decision in itself would not bring a patient’s capacity into question, so long as the patient was able to explain the rationale behind the switch. Frequent changes back and forth in the decision-making, however, could be indicative of an underlying psychiatric disorder or extreme indecision, which could bring capacity into question.
• Understanding. The patient needs to recall conversations about treatment, to make the link between causal relationships, and to process probabilities for outcomes. Problems with memory, attention span, and intelligence can affect one’s understanding.
• Appreciation. The patient should be able to identify the illness, treatment options, and likely outcomes as things that will affect him or her directly. A lack of appreciation usually stems from a denial based on intelligence (lack of a capability to understand) or emotion, or a delusion that the patient is not affected by this situation the same way and will have a different outcome.
• Rationalization or reasoning. The patient needs to be able to weigh the risks and benefits of the treatment options presented to come to a conclusion in keeping with their goals and best interests, as defined by their personal set of values. This often is affected in psychosis, depression, anxiety, phobias, delirium, and dementia.³

Several clinical capacity tools have been developed to assess these components:

Clinical tools.

The Mini-Mental Status Examination (MMSE) is a bedside test of a patient’s cognitive function, with scores ranging from 0 to 30.⁴ Although it wasn’t developed for assessing decision-making capacity, it has been compared with expert evaluation for assessment of capacity; the test performs reasonably well, particularly with high and low scores. Specifically, a MMSE >24 has a negative likelihood ratio (LR) of 0.05 for lack of capacity, while a MMSE <16 has a positive LR of 15.⁵ Scores from 17 to 23 do not correlate well with capacity, and further testing would be necessary. It is easy to administer, requires no formal training, and is familiar to most hospitalists. However, it does not address any specific aspects of informed consent, such as understanding or choice, and has not been validated in patients with mental illness.

The MacArthur Competence Assessment Tools for Treatment (MacCAT-T) is regarded as the gold standard for capacity assessment aids. It utilizes hospital chart review followed by a semi-structured interview to address clinical issues relevant to the patient being assessed; it takes 15 to 20 minutes to complete.⁶ The test provides scores in each of the four domains (choice, understanding, appreciation, and reasoning) of capacity. It has been validated in patients with dementia, schizophrenia, and depression. Limiting its clinical applicability is the fact that the MacCAT-T requires training to administer and interpret the results, though this is a relatively brief process.

The Capacity to Consent to Treatment Instrument (CCTI) uses hypothetical clinical vignettes in a structured interview to assess capacity across all four domains. The tool was developed and validated in patients with dementia and Parkinson’s disease, and takes 20 to 25 minutes to complete.⁷ A potential limitation is the CCTI’s use of vignettes as opposed to a patient-specific discussion, which could lead to different patient answers and a false assessment of the patient’s capacity.

The Hopemont Capacity Assessment Interview (HCAI) utilizes hypothetical vignettes in a semi-structured interview format to assess understanding, appreciation, choice, and likely reasoning.^8,9 Similar to CCTI, HCAI is not modified for individual patients. Rather, it uses clinical vignettes to gauge a patient’s ability to make decisions. The test takes 30 to 60 minutes to administer and performs less well in assessing appreciation and reasoning than the MacCAT-T and CCTI.¹⁰

It is not necessary to perform a formal assessment of capacity on every inpatient. For most, there is no reasonable concern for impaired capacity, obviating the need for formal testing. Likewise, in patients who clearly lack capacity, such as those with end-stage dementia or established guardians, formal reassessment usually is not required. Formal testing is most useful in situations in which capacity is unclear, disagreement amongst surrogate decision-makers exists, or judicial involvement is anticipated.

The MacCAT-T has been validated in the broadest population and is probably the most clinically useful tool currently available. The MMSE is an attractive alternative because of its widespread use and familiarity; however, it is imprecise with scores from 17 to 23, limiting its applicability.

click for large version

At a minimum, familiarity with the core legal standards of capacity (communication of choice, understanding, appreciation, and reasoning) will improve a hospitalist’s ability to identify patients who lack capacity. Understanding and applying the defined markers most often provides a sufficient capacity evaluation in itself. As capacity is not static, the decision usually requires more than one assessment.

Equally, deciding that a patient lacks capacity is not an end in itself, and the underlying cause should be addressed. Certain factors, such as infection, medication, time of day, and relationship with the clinician doing the assessment, can affect a patient’s capacity. These should be addressed through treatment, education, and social support whenever possible in order to optimize a patient’s performance during the capacity evaluation. If the decision can be delayed until a time when the patient can regain capacity, this should be done in order to maximize the patient’s autonomy.¹¹

Risk-related standards of capacity.

Although some question the notion, given our desire to facilitate management beneficial to the patient, the general consensus is that we have a lower threshold for capacity for consent to treatments that are low-risk and high-benefit.^12,13 We would then have a somewhat higher threshold for capacity to refuse that same treatment. Stemming from a desire to protect patients from harm, we have a relatively higher threshold for capacity to make decisions regarding high-risk, low-benefit treatments. For the remainder of cases (low risk/low benefit; high risk/high benefit), as well as treatments that significantly impact a patient’s lifestyle (e.g. dialysis, amputation), we have a low capacity to let patients decide for themselves.^11,14

Other considerations.

Clinicians should be thorough in documenting details in coming to a capacity determination, both as a means to formalize the thought process running through the four determinants of capacity, and in order to document for future reference. Cases in which it could be reasonable to call a consultant for those familiar with the assessment basics include:

• Cases in which a determination of lack of capacity could adversely affect the hospitalist’s relationship with the patient;
• Cases in which the hospitalist lacks the time to properly perform the evaluation;
• Particularly difficult or high-stakes cases (e.g. cases that might involve legal proceedings); and
• Cases in which significant mental illness affects a patient’s capacity.¹¹

Early involvement of potential surrogate decision-makers is wise for patients in whom capacity is questioned, both for obtaining collateral history as well as initiating dialogue as to the patient’s wishes. When a patient is found to lack capacity, resources to utilize to help make a treatment decision include existing advance directives and substitute decision-makers, such as durable power of attorneys (DPOAs) and family members. In those rare cases in which clinicians are unable to reach a consensus about a patient’s capacity, an ethics consult should be considered.

click for large version

Back to the Case.

Following the patient’s declaration that dialysis is not something he is interested in, his niece reports that he is a minimalist when it comes to interventions, and that he had similarly refused a cardiac catheterization in the 1990s. You review with the patient and niece that dialysis would be a procedure to replace his failing kidney function, and that failure to pursue this would ultimately be life-threatening and likely result in death, especially in regard to electrolyte abnormalities and his lack of any other terminal illness.

The consulting nephrologist reviews their recommendations with the patient and niece as well, and the patient consistently refuses. Having clearly communicated his choice, you ask the patient if he understands the situation. He says, "My kidneys are failing. That’s how I got the high potassium." You ask him what that means. "They aren’t going to function on their own much longer," he says. "I could die from it."

You confirm his ideas, and ask him why he doesn’t want dialysis. "I don’t want dialysis because I don’t want to spend my life hooked up to machines three times a week," the patient explains. "I just want to let things run their natural course." The niece says her uncle wouldn’t have wanted dialysis even if it were 10 years ago, so she’s not surprised he is refusing now.

Following this discussion, you feel comfortable that the patient has capacity to make this decision. Having documented this discussion, you discharge him to a subacute rehabilitation facility.

Bottom Line.

In cases in which capacity is in question, a hospitalist’s case-by-case review of the four components of capacity—communicating a choice, understanding, appreciation, and rationalization and reasoning—is warranted to help determine whether a patient has capacity. In cases in which a second opinion is warranted, psychiatry, geriatrics, or ethics consults could be utilized.

Drs. Dastidar and Odden are hospitalists at the University of Michigan in Ann Arbor.

References

1. Buchanan A, Brock DW. Deciding for others. Milbank Q. 1986;64(Suppl. 2):17-94.
2. Guidelines for assessing the decision-making capacities of potential research subjects with cognitive impairment. American Psychiatric Association. Am J Psychiatry. 1998;155(11):1649-50.
3. Appelbaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med. 1988;319(25):1635-1638.
4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
5. Etchells E, Darzins P, Silberfeld M, et al. Assessment of patient capacity to consent to treatment. J Gen Intern Med. 1999;14:27-34.
6. Grisso T, Appelbaum PS, Hill-Fotouhi C. The MacCAT-T: a clinical tool to assess patients’ capacities to make treatment decisions. Psychiatr Serv. 1997;48:1415- 1419.
7. Marson DC, Ingram KK, Cody HA, Harrell LE. Assessing the competency of patients with Alzheimer’s disease under different legal standards. A prototype instrument. Arch Neurol. 1995;52:949-954.
8. Edelstein B. Hopemont Capacity Assessment Interview Manual and Scoring Guide. 1999: Morgantown, W.V.: West Virginia University.
9. Pruchno RA, Smyer MA, Rose MS, Hartman-Stein PE, Henderson-Laribee DL. Competence of long-term care residents to participate in decisions about their medical care: a brief, objective assessment. Gerontologist. 1995;35:622-629.
10. Moye J, Karel M, Azar AR, Gurrera R. Capacity to consent to treatment: empirical comparison of three instruments in older adults with and without dementia. Gerontologist. 2004;44:166-175.
11. Grisso T, Appelbaum PS. Assessing competence to consent to treatment: a guide for physicians and other health professionals. 1998; New York: Oxford University Press, 211.
12. Cale GS. Risk-related standards of competence: continuing the debate over risk-related standards of competence. Bioethics. 1999;13(2):131-148.
13. Checkland D. On risk and decisional capacity. J Med Philos. 2001;26(1):35-59.
14. Wilks I. The debate over risk-related standards of competence. Bioethics. 1997;11(5):413-426.
15. Ganzini L, Volicer L, Nelson WA, Fox E, Derse AR. Ten myths about decision-making capacity. J Am Med Dir Assoc. 2004;5(4):263-267.

Acknowledgements:The authors would like to thank Dr. Jeff Rohde for reviewing a copy of the manuscript, and Dr. Amy Rosinski for providing direction from the psychiatry standpoint

Case

A 79-year-old male with coronary artery disease, hypertension, non-insulin-dependent mellitus, moderate dementia, and chronic renal insufficiency is admitted after a fall evaluation. He is widowed and lives in an assisted living facility. He’s accompanied by his niece, is alert, and oriented to person. He thinks he is in a clinic and is unable to state the year, but the remainder of the examination is unremarkable. His labs are notable for potassium of 6.3 mmol/L, BUN of 78 mg/dL, and Cr of 3.7 mg/dL. The niece reports that the patient is not fond of medical care, thus the most recent labs are from two years ago (and indicate a BUN of 39 and Cr of 2.8, with an upward trend over the past decade). You discuss possible long-term need for dialysis with the patient and niece, and the patient clearly states "no." However, he also states that it is 1988. How do you determine if he has the capacity to make decisions?

Overview

Hospitalists are familiar with the doctrine of informed consent—describing a disease, treatment options, associated risks and benefits, potential for complications, and alternatives, including no treatment. Not only must the patient be informed, and the decision free from any coercion, but the patient also must have capacity to make the decision.

Hospitalists often care for patients in whom decision-making capacity comes into question. This includes populations with depression, psychosis, dementia, stroke, severe personality disorders, developmental delay, comatose patients, as well as those with impaired attentional capacity (e.g. acute pain) or general debility (e.g. metastatic cancer).^1,2

ave for the comatose patient, whether the patient has capacity might not be obvious. However, addressing the components of capacity (communication, understanding, appreciation, and rationalization) by using a validated clinical tool, such as the MacCAT-T, or more simply by systematically applying those four components to the clinical scenario under consideration, hospitalists can make this determination.

Review of the Literature

It is important to differentiate capacity from competency. Competency is a global assessment and a legal determination made by a judge in court. Capacity, on the other hand, is a functional assessment regarding a particular decision. Capacity is not static, and it can be performed by any clinician familiar with the patient. A hospitalist often is well positioned to make a capacity determination given established rapport with the patient and familiarity with the details of the case.

To make this determination, a hospitalist needs to know how to assess capacity. Although capacity usually is defined by state law and varies by jurisdiction, clinicians generally can assume it includes one or more of the four key components:

• Communication. The patient needs to be able to express a treatment choice, and this decision needs to be stable enough for the treatment to be implemented. Changing one’s decision in itself would not bring a patient’s capacity into question, so long as the patient was able to explain the rationale behind the switch. Frequent changes back and forth in the decision-making, however, could be indicative of an underlying psychiatric disorder or extreme indecision, which could bring capacity into question.
• Understanding. The patient needs to recall conversations about treatment, to make the link between causal relationships, and to process probabilities for outcomes. Problems with memory, attention span, and intelligence can affect one’s understanding.
• Appreciation. The patient should be able to identify the illness, treatment options, and likely outcomes as things that will affect him or her directly. A lack of appreciation usually stems from a denial based on intelligence (lack of a capability to understand) or emotion, or a delusion that the patient is not affected by this situation the same way and will have a different outcome.
• Rationalization or reasoning. The patient needs to be able to weigh the risks and benefits of the treatment options presented to come to a conclusion in keeping with their goals and best interests, as defined by their personal set of values. This often is affected in psychosis, depression, anxiety, phobias, delirium, and dementia.³

Several clinical capacity tools have been developed to assess these components:

Clinical tools.

The Mini-Mental Status Examination (MMSE) is a bedside test of a patient’s cognitive function, with scores ranging from 0 to 30.⁴ Although it wasn’t developed for assessing decision-making capacity, it has been compared with expert evaluation for assessment of capacity; the test performs reasonably well, particularly with high and low scores. Specifically, a MMSE >24 has a negative likelihood ratio (LR) of 0.05 for lack of capacity, while a MMSE <16 has a positive LR of 15.⁵ Scores from 17 to 23 do not correlate well with capacity, and further testing would be necessary. It is easy to administer, requires no formal training, and is familiar to most hospitalists. However, it does not address any specific aspects of informed consent, such as understanding or choice, and has not been validated in patients with mental illness.

The MacArthur Competence Assessment Tools for Treatment (MacCAT-T) is regarded as the gold standard for capacity assessment aids. It utilizes hospital chart review followed by a semi-structured interview to address clinical issues relevant to the patient being assessed; it takes 15 to 20 minutes to complete.⁶ The test provides scores in each of the four domains (choice, understanding, appreciation, and reasoning) of capacity. It has been validated in patients with dementia, schizophrenia, and depression. Limiting its clinical applicability is the fact that the MacCAT-T requires training to administer and interpret the results, though this is a relatively brief process.

The Capacity to Consent to Treatment Instrument (CCTI) uses hypothetical clinical vignettes in a structured interview to assess capacity across all four domains. The tool was developed and validated in patients with dementia and Parkinson’s disease, and takes 20 to 25 minutes to complete.⁷ A potential limitation is the CCTI’s use of vignettes as opposed to a patient-specific discussion, which could lead to different patient answers and a false assessment of the patient’s capacity.

The Hopemont Capacity Assessment Interview (HCAI) utilizes hypothetical vignettes in a semi-structured interview format to assess understanding, appreciation, choice, and likely reasoning.^8,9 Similar to CCTI, HCAI is not modified for individual patients. Rather, it uses clinical vignettes to gauge a patient’s ability to make decisions. The test takes 30 to 60 minutes to administer and performs less well in assessing appreciation and reasoning than the MacCAT-T and CCTI.¹⁰

It is not necessary to perform a formal assessment of capacity on every inpatient. For most, there is no reasonable concern for impaired capacity, obviating the need for formal testing. Likewise, in patients who clearly lack capacity, such as those with end-stage dementia or established guardians, formal reassessment usually is not required. Formal testing is most useful in situations in which capacity is unclear, disagreement amongst surrogate decision-makers exists, or judicial involvement is anticipated.

The MacCAT-T has been validated in the broadest population and is probably the most clinically useful tool currently available. The MMSE is an attractive alternative because of its widespread use and familiarity; however, it is imprecise with scores from 17 to 23, limiting its applicability.

click for large version

At a minimum, familiarity with the core legal standards of capacity (communication of choice, understanding, appreciation, and reasoning) will improve a hospitalist’s ability to identify patients who lack capacity. Understanding and applying the defined markers most often provides a sufficient capacity evaluation in itself. As capacity is not static, the decision usually requires more than one assessment.

Equally, deciding that a patient lacks capacity is not an end in itself, and the underlying cause should be addressed. Certain factors, such as infection, medication, time of day, and relationship with the clinician doing the assessment, can affect a patient’s capacity. These should be addressed through treatment, education, and social support whenever possible in order to optimize a patient’s performance during the capacity evaluation. If the decision can be delayed until a time when the patient can regain capacity, this should be done in order to maximize the patient’s autonomy.¹¹

Risk-related standards of capacity.

Although some question the notion, given our desire to facilitate management beneficial to the patient, the general consensus is that we have a lower threshold for capacity for consent to treatments that are low-risk and high-benefit.^12,13 We would then have a somewhat higher threshold for capacity to refuse that same treatment. Stemming from a desire to protect patients from harm, we have a relatively higher threshold for capacity to make decisions regarding high-risk, low-benefit treatments. For the remainder of cases (low risk/low benefit; high risk/high benefit), as well as treatments that significantly impact a patient’s lifestyle (e.g. dialysis, amputation), we have a low capacity to let patients decide for themselves.^11,14

Other considerations.

Clinicians should be thorough in documenting details in coming to a capacity determination, both as a means to formalize the thought process running through the four determinants of capacity, and in order to document for future reference. Cases in which it could be reasonable to call a consultant for those familiar with the assessment basics include:

• Cases in which a determination of lack of capacity could adversely affect the hospitalist’s relationship with the patient;
• Cases in which the hospitalist lacks the time to properly perform the evaluation;
• Particularly difficult or high-stakes cases (e.g. cases that might involve legal proceedings); and
• Cases in which significant mental illness affects a patient’s capacity.¹¹

Early involvement of potential surrogate decision-makers is wise for patients in whom capacity is questioned, both for obtaining collateral history as well as initiating dialogue as to the patient’s wishes. When a patient is found to lack capacity, resources to utilize to help make a treatment decision include existing advance directives and substitute decision-makers, such as durable power of attorneys (DPOAs) and family members. In those rare cases in which clinicians are unable to reach a consensus about a patient’s capacity, an ethics consult should be considered.

click for large version

Back to the Case.

Following the patient’s declaration that dialysis is not something he is interested in, his niece reports that he is a minimalist when it comes to interventions, and that he had similarly refused a cardiac catheterization in the 1990s. You review with the patient and niece that dialysis would be a procedure to replace his failing kidney function, and that failure to pursue this would ultimately be life-threatening and likely result in death, especially in regard to electrolyte abnormalities and his lack of any other terminal illness.

The consulting nephrologist reviews their recommendations with the patient and niece as well, and the patient consistently refuses. Having clearly communicated his choice, you ask the patient if he understands the situation. He says, "My kidneys are failing. That’s how I got the high potassium." You ask him what that means. "They aren’t going to function on their own much longer," he says. "I could die from it."

You confirm his ideas, and ask him why he doesn’t want dialysis. "I don’t want dialysis because I don’t want to spend my life hooked up to machines three times a week," the patient explains. "I just want to let things run their natural course." The niece says her uncle wouldn’t have wanted dialysis even if it were 10 years ago, so she’s not surprised he is refusing now.

Following this discussion, you feel comfortable that the patient has capacity to make this decision. Having documented this discussion, you discharge him to a subacute rehabilitation facility.

Bottom Line.

In cases in which capacity is in question, a hospitalist’s case-by-case review of the four components of capacity—communicating a choice, understanding, appreciation, and rationalization and reasoning—is warranted to help determine whether a patient has capacity. In cases in which a second opinion is warranted, psychiatry, geriatrics, or ethics consults could be utilized.

Drs. Dastidar and Odden are hospitalists at the University of Michigan in Ann Arbor.

References

1. Buchanan A, Brock DW. Deciding for others. Milbank Q. 1986;64(Suppl. 2):17-94.
2. Guidelines for assessing the decision-making capacities of potential research subjects with cognitive impairment. American Psychiatric Association. Am J Psychiatry. 1998;155(11):1649-50.
3. Appelbaum PS, Grisso T. Assessing patients’ capacities to consent to treatment. N Engl J Med. 1988;319(25):1635-1638.
4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
5. Etchells E, Darzins P, Silberfeld M, et al. Assessment of patient capacity to consent to treatment. J Gen Intern Med. 1999;14:27-34.
6. Grisso T, Appelbaum PS, Hill-Fotouhi C. The MacCAT-T: a clinical tool to assess patients’ capacities to make treatment decisions. Psychiatr Serv. 1997;48:1415- 1419.
7. Marson DC, Ingram KK, Cody HA, Harrell LE. Assessing the competency of patients with Alzheimer’s disease under different legal standards. A prototype instrument. Arch Neurol. 1995;52:949-954.
8. Edelstein B. Hopemont Capacity Assessment Interview Manual and Scoring Guide. 1999: Morgantown, W.V.: West Virginia University.
9. Pruchno RA, Smyer MA, Rose MS, Hartman-Stein PE, Henderson-Laribee DL. Competence of long-term care residents to participate in decisions about their medical care: a brief, objective assessment. Gerontologist. 1995;35:622-629.
10. Moye J, Karel M, Azar AR, Gurrera R. Capacity to consent to treatment: empirical comparison of three instruments in older adults with and without dementia. Gerontologist. 2004;44:166-175.
11. Grisso T, Appelbaum PS. Assessing competence to consent to treatment: a guide for physicians and other health professionals. 1998; New York: Oxford University Press, 211.
12. Cale GS. Risk-related standards of competence: continuing the debate over risk-related standards of competence. Bioethics. 1999;13(2):131-148.
13. Checkland D. On risk and decisional capacity. J Med Philos. 2001;26(1):35-59.
14. Wilks I. The debate over risk-related standards of competence. Bioethics. 1997;11(5):413-426.
15. Ganzini L, Volicer L, Nelson WA, Fox E, Derse AR. Ten myths about decision-making capacity. J Am Med Dir Assoc. 2004;5(4):263-267.

Acknowledgements:The authors would like to thank Dr. Jeff Rohde for reviewing a copy of the manuscript, and Dr. Amy Rosinski for providing direction from the psychiatry standpoint

Case

A 70-year-old woman with hypertension presents after a fall. Her medications include hydrochlorothiazide. Her blood pressure is 130/70 mm/Hg, with heart rate of 86. She has normal orthostatic vital signs. Her mucus membranes are moist and she has no jugular venous distension, edema, or ascites. Her plasma sodium (P_Na) is 125 mmol/L, potassium 3.6 mmol/L, blood urea nitrogen (BUN) 30 mg/dL, and creatinine 0.8 mg/dL. Additional labs include serum thyroid stimulating hormone 1.12 mIU/L, cortisol 15 mcg/dL, serum osmolality 270 mOsm/kg, uric acid 4 mg/dL, urine osmolality 300 mOsm/kg, urine sodium (U_Na) 40 mmol/L, fractional excretion of sodium 1.0%, and fractional excretion of urate (FE_Urate) 13%. She receives 2 L isotonic saline intravenously over 24 hours, with resulting P_Na of 127.

What is the cause of her hyponatremia, and how should her hyponatremia be managed?

Overview

Hyponatremia is one of the most common electrolyte abnormalities; it has a prevalence as high as 30% upon admission to the hospital.¹ Hyponatremia is important clinically because of its high risk of mortality in the acute and symptomatic setting, and the risk of central pontine myelinolysis (CPM), or death with too rapid correction.² Even so-called “asymptomatic” mild hyponatremia is associated with increased falls and impairments in gait and attention in the elderly.³

Hyponatremia is a state of excess water compared with the amount of solute in the extracellular fluid. To aid in diagnosing the etiology of hypotonic hyponatremia, the differential is traditionally divided into categories based on extracellular fluid volume (ECV) status, as shown in Table 1 (below), with syndrome of inappropriate antidiuretic hormone secretion (SIADH) being the most common cause of euvolemic hyponatremia.² However, data show that clinical determination of volume status is often flawed,⁴ and an algorithmic approach to diagnosis and treatment yields improved results.⁵

Review of the Data

Diagnosis of SIADH. The original diagnostic criteria for SIADH, with minor modifications, are presented in Table 2, page 18).^6,7,8 However, applying these criteria in clinical settings presents several difficulties, most notably a determination of ECV. The gold standard for assessing ECV status is by radioisotope, which is not practically feasible.⁹ Therefore, clinicians must rely on surrogate clinical markers of ECV (orthostatic hypotension, skin turgor, mucus membrane dryness, central venous pressure, BUN, BUN-creatinine ratio, and serum uric acid levels), which lack both sensitivity and specificity.⁴ Astoundingly, clinical assessment of ECV has been demonstrated to be accurate only 50% of the time when differentiating euvolemic patients from those with hypovolemia.⁴

click for large version

Another challenge lies in the interpretation of U_Na, which frequently is used as a surrogate for extra-arterial blood volume (EABV) status.¹⁰ Unfortunately, in the setting of diuretic use, U_Na becomes inaccurate. The FE_Urate, however, is unaffected by diuretic use and can be helpful in distinguishing between etiologies of hyponatremia with U_Na greater than 30 mmol/L.¹¹ The FE_Urate is about 10% in normal euvolemic subjects and is reduced (usually <8%) in patients with low effective arterial blood volume.^11,12 A trial of 86 patients demonstrated that a FE_Urate of 12% had a specificity and positive predictive value of 100% in accurately identifying SIADH from diuretic-induced hyponatremia in patients on diuretics.^11,12 Therefore, the U_Na is a valid marker of EABV status when patients are not on diuretics; however, the FE_Urate should be used in the setting of diuretic use.

Yet another pitfall is differentiating patients with salt depletion from those with SIADH. In these situations, measurement of the change in P_Na concentration after a test infusion of isotonic saline is helpful. In salt depletion, P_Na usually increases ≥5 mmol/L after 2 L saline infusion, which is not the case with SIADH.¹³ Incorrectly diagnosing renal salt wasting (RSW) as SIADH results in fluid restriction and, consequently, ECV depletion and increased morbidity.¹⁴ The persistence of hypouricemia and elevated FE_Urate after correction of the hyponatremia in RSW differentiates it from SIADH.^{13, 14}

Given these challenges, recommendations to use an algorithmic approach for the evaluation and diagnosis of hyponatremia have surfaced. In a study of 121 patients admitted with hyponatremia, an algorithm-based approach to the diagnosis of hyponatremia yielded an overall diagnostic accuracy of 71%, compared with an accuracy of 32% by experienced clinicians.⁵ This study also highlighted SIADH as the most frequent false-positive diagnosis that was expected whenever the combination of euvolemia and a U_Na >30 mmol/L was present.⁵ Cases of diuretic-induced hyponatremia often were misclassified due to errors in the accurate assessment of ECV status, as most of these patients appeared clinically euvolemic or hypervolemic.⁵ Therefore, it is important to use an algorithm in identifying SIADH and to use one that does not rely solely on clinical estimation of ECV status (see Figure 1, below).

Management of acute and symptomatic hyponatremia. When hyponatremia develops acutely, urgent treatment is required (see Figure 2, below).¹⁵ Hyponatremia is considered acute when the onset is within 48 hours.¹⁵ Acute hyponatremia is most easily identified in the hospital and is commonly iatrogenic. Small case reviews in the 1980s began to associate postoperative deaths with the administration of hypotonic fluids.¹⁶ Asymptomatic patients with hyponatremia presenting from home should be considered chronic hyponatremias as the duration often is unclear.

click for large version

Acute hyponatremia or neurologically symptomatic hyponatremia regardless of duration requires the use of hypertonic saline.¹⁵ Traditional sodium correction algorithms are based on early case series, which were focused on limiting neurologic complications from sodium overcorrection.¹⁷ This resulted in protocols recommending a conservative rate of correction spread over a 24- to 48-hour period.¹⁷ Infusing 3% saline at a rate of 1 ml/kg/hr to 2 ml/kg/hr results in a 1 mmol/L/hr to 2 mmol/L/hr increase in P_Na.¹⁵ This simplified formula results in similar correction rates as more complex calculations.15 Correction should not exceed 8 mmol/L to 10 mmol/L within the first 24 hours, and 18 mmol/L to 25 mmol/L by 48 hours to avoid CPM.¹⁵ P_Na should be checked every two hours to ensure that the correction rate is not exceeding the predicted rate, as the formulas do not take into account oral intake and ongoing losses.¹⁵

Recent observations focused on the initial four hours from onset of hyponatremia suggest a higher rate of correction can be tolerated without complications.¹⁸ Rapid sodium correction of 4 mmol/L to 6 mmol/L often is enough to stop neurologic complications.¹⁸ This can be accomplished with a bolus infusion of 100 mL of 3% saline.¹⁹ This may be repeated twice at 10-minute intervals until there is neurologic improvement.¹⁹ This might sound aggressive, but this would correspond to a rise in P_Na of 5 mmol/L to 6 mmol/L in a 50 kg woman. Subsequent treatment with hypertonic fluid might not be needed if symptoms resolve.

Management of chronic hyponatremia. Hyponatremia secondary to SIADH improves with the treatment of the underlying cause, thus an active search for a causative medication or condition should be sought (see Table 1, p. 17).²⁰

click for large version

Water restriction. Restriction of fluid intake is the first-line treatment for SIADH in patients without hypovolemia. The severity of fluid restriction is guided by the concentration of the urinary solutes.¹⁵ Restriction of water intake to 500 ml/day to 1,000 ml/day is generally advised for many patients, as losses from the skin, lungs, and urine exceed this amount, leading to a gradual reduction in total body water.²¹ The main drawback of fluid restriction is poor compliance due to an intact thirst mechanism.

Saline infusion. The infusion of normal saline theoretically worsens hyponatremia due to SIADH because the water is retained while the salt is excreted. However, a trial of normal saline sometimes is attempted in patients in whom the differentiation between hypovolemia and euvolemia is difficult. From a study of a series of 17 patients with chronic SIADH, Musch and Decaux concluded that the infusion of intravenous normal (0.9%) saline raises P_Na when the urine osmolality is less than 530 mosm/L.²²

Oral solutes (urea and salt). The oral intake of salt augments water excretion²³, and salt tablets are used as a second-line agent in patients with persistent hyponatremia despite fluid restriction.²³ The oral administration of urea also results in increased free-water excretion via osmotic diuresis,²⁴ but its poor palatability, lack of availability in the U.S., and limited user experience has restricted its usage.²⁴

Demeclocycline. Demeclo-cycline is a tetracycline derivative that causes a partial nephrogenic diabetes insipidus.²⁵ Its limitations include a slow onset of action (two to five days) and an unpredictable treatment effect with the possibility of causing profound polyuria and hypernatremia. It is also associated with reversible azotemia and sometimes nephrotoxicity, especially in patients with cirrhosis.

Lithium. Lithium also causes nephrogenic diabetes insipidus by downregulating vasopressin-stimulated aquaporin-2 expression and thus improves hyponatremia in SIADH.²⁶ However, its use is significantly limited by its unpredictable response and the risks of interstitial nephritis and end-stage renal disease with chronic use. Therefore, it is no longer recommended for the treatment of SIADH.

Vasopressin receptor antagonists. Due to the role of excessive levels of vasopressin in the pathophysiology of most types of SIADH, antagonists of the vasopressin receptor were developed with the goal of preventing the excess water absorption that causes hyponatremia. Two vasopressin receptor antagonists, or vaptans, have been approved by the FDA for the treatment of nonemergent euvolemic and hypervolemic hyponatremia. Conivaptan is a nonselective vasopressin receptor antagonist that is for IV use only. Tolvaptan is a selective V2 receptor antagonist that is taken orally. Both conivaptan and tolvaptan successfully increase P_Na levels while the drugs are being taken.^27,28,29,30 Tolvaptan increases P_Na levels in hyponatremia due to SIADH and CHF, and modestly so in cirrhosis.³⁰

click for large version

The most common side effects of the vaptans include dry mouth, increased thirst, and increased urination, although serious side effects (hypernatremia or too-rapid rate of increase in P_Na) are possible.²⁹ It is unclear if treating stable, asymptomatic hyponatremia with vaptans has any reduction in morbidity or mortality. One study found that tolvaptan increased the patients’ self-evaluations of mental functioning, but a study of tolvaptan used in combination with diuretics in the setting of CHF did not result in decreased mortality.^29,31 Due to their expense, necessity of being started in the hospital, and unclear long-term benefit, the vaptans are only recommended when traditional measures such as fluid restriction and salt tablets have been unsuccessful.

Back to the Case

Our patient has hypotonic hyponatremia based on her low serum osmolality. The duration of her hyponatremia is unclear, but the patient is not experiencing seizures or coma. Therefore, her hyponatremia should be corrected slowly, and hypertonic saline is not indicated.

As is common in clinical practice, her true volume status is difficult to clinically ascertain. By physical exam, she appears euvolemic, but because she is on hydrochlorothiazide, she might be subtly hypovolemic. The U_Na of 40 mmol/L is not consistent with hypovolemia, but its accuracy is limited in the setting of diuretics. The failure to improve her sodium by at least 5 mmol/L after a 2 L normal saline infusion argues against low effective arterial blood volume and indicates that the hydrochlorothiazide is unlikely to be the cause of her hyponatremia.

Therefore, the most likely cause of the hyponatremia is SIADH, a diagnosis further corroborated by the elevated FE_Urate of 13%. Her chronic hyponatremia should be managed initially with fluid restriction while an investigation for an underlying cause of SIADH is initiated.

Bottom Line

The diagnosis of SIADH relies on the careful evaluation of laboratory values, use of an algorithm, and recognizing the limitations of clinically assessing volume status. The underlying cause of SIADH must also be sought and treated. TH

Dr. Grant is a clinical lecturer in internal medicine, Dr. Cho is a clinical instructor in internal medicine, and Dr. Nichani is an assistant professor of internal medicine at the University of Michigan Hospital and Health Systems in Ann Arbor.

References

1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 Suppl 1):S30-35.
2. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1-21.
3. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e71-78.
4. Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987;83(5):905-908.
5. Fenske W, Maier SK, Blechschmidt A, Allolio B, Störk S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010;123(7):652-657.
6. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42(5):790-806.
7. Smith DM, McKenna K, Thompson CJ. Hyponatraemia. Clin Endocrinol (Oxf). 2000;52(6):667-678.
8. Verbalis JG. Hyponatraemia. Baillieres Clin Endocrinol Metab. Aug 1989;3(2):499-530.
9. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or renal salt wasting? Kidney Int. 2009;76(9):934-938.
10. Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.
11. Fenske W, Störk S, Koschker AC, et al. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. J Clin Endocrinol Metab. 2008;93(8):2991-2997.
12. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis. 1998;32(6):917-933.
13. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056-1062.
14. Bitew S, Imbriano L, Miyawaki N, Fishbane S, Maesaka JK. More on renal salt wasting without cerebral disease: response to saline infusion. Clin J Am Soc Nephrol. 2009;4(2):309-315.
15. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072.
16. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. 1986;314(24):1529-1535.
17. Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med. 1987;317(19):1190-1195.
18. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282-299.
19. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med. 2008;18(2):111-121.
20. List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986;4(8):1191-1198.
21. Verbalis JG. Managing hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion. J Hosp Med. 2010;5 Suppl 3:S18-S26.
22. Musch W, Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline. QJM. 1998;91(11):749-753.
23. Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol. 2008;19(6):1076-1078.
24. Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. 1980;69(1):99-106.
25. Forrest JN Jr., Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1978;298(4):173-177.
26. Nielsen J, Hoffert JD, Knepper MA, Agre P, Nielsen S, Fenton RA. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci U S A. 2008;105(9):3634-3639.
27. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447-457.
28. Verbalis JG, Zeltser D, Smith N, Barve A, Andoh M. Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study. Clin Endocrinol (Oxf). 2008;69(1):159-168.
29. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112.
30. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705-712.
31. Konstam MA, Gheorghiade M, Burnett JC Jr., et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331.

Case

A 70-year-old woman with hypertension presents after a fall. Her medications include hydrochlorothiazide. Her blood pressure is 130/70 mm/Hg, with heart rate of 86. She has normal orthostatic vital signs. Her mucus membranes are moist and she has no jugular venous distension, edema, or ascites. Her plasma sodium (P_Na) is 125 mmol/L, potassium 3.6 mmol/L, blood urea nitrogen (BUN) 30 mg/dL, and creatinine 0.8 mg/dL. Additional labs include serum thyroid stimulating hormone 1.12 mIU/L, cortisol 15 mcg/dL, serum osmolality 270 mOsm/kg, uric acid 4 mg/dL, urine osmolality 300 mOsm/kg, urine sodium (U_Na) 40 mmol/L, fractional excretion of sodium 1.0%, and fractional excretion of urate (FE_Urate) 13%. She receives 2 L isotonic saline intravenously over 24 hours, with resulting P_Na of 127.

What is the cause of her hyponatremia, and how should her hyponatremia be managed?

Overview

Hyponatremia is one of the most common electrolyte abnormalities; it has a prevalence as high as 30% upon admission to the hospital.¹ Hyponatremia is important clinically because of its high risk of mortality in the acute and symptomatic setting, and the risk of central pontine myelinolysis (CPM), or death with too rapid correction.² Even so-called “asymptomatic” mild hyponatremia is associated with increased falls and impairments in gait and attention in the elderly.³

Hyponatremia is a state of excess water compared with the amount of solute in the extracellular fluid. To aid in diagnosing the etiology of hypotonic hyponatremia, the differential is traditionally divided into categories based on extracellular fluid volume (ECV) status, as shown in Table 1 (below), with syndrome of inappropriate antidiuretic hormone secretion (SIADH) being the most common cause of euvolemic hyponatremia.² However, data show that clinical determination of volume status is often flawed,⁴ and an algorithmic approach to diagnosis and treatment yields improved results.⁵

Review of the Data

Diagnosis of SIADH. The original diagnostic criteria for SIADH, with minor modifications, are presented in Table 2, page 18).^6,7,8 However, applying these criteria in clinical settings presents several difficulties, most notably a determination of ECV. The gold standard for assessing ECV status is by radioisotope, which is not practically feasible.⁹ Therefore, clinicians must rely on surrogate clinical markers of ECV (orthostatic hypotension, skin turgor, mucus membrane dryness, central venous pressure, BUN, BUN-creatinine ratio, and serum uric acid levels), which lack both sensitivity and specificity.⁴ Astoundingly, clinical assessment of ECV has been demonstrated to be accurate only 50% of the time when differentiating euvolemic patients from those with hypovolemia.⁴

click for large version

Another challenge lies in the interpretation of U_Na, which frequently is used as a surrogate for extra-arterial blood volume (EABV) status.¹⁰ Unfortunately, in the setting of diuretic use, U_Na becomes inaccurate. The FE_Urate, however, is unaffected by diuretic use and can be helpful in distinguishing between etiologies of hyponatremia with U_Na greater than 30 mmol/L.¹¹ The FE_Urate is about 10% in normal euvolemic subjects and is reduced (usually <8%) in patients with low effective arterial blood volume.^11,12 A trial of 86 patients demonstrated that a FE_Urate of 12% had a specificity and positive predictive value of 100% in accurately identifying SIADH from diuretic-induced hyponatremia in patients on diuretics.^11,12 Therefore, the U_Na is a valid marker of EABV status when patients are not on diuretics; however, the FE_Urate should be used in the setting of diuretic use.

Yet another pitfall is differentiating patients with salt depletion from those with SIADH. In these situations, measurement of the change in P_Na concentration after a test infusion of isotonic saline is helpful. In salt depletion, P_Na usually increases ≥5 mmol/L after 2 L saline infusion, which is not the case with SIADH.¹³ Incorrectly diagnosing renal salt wasting (RSW) as SIADH results in fluid restriction and, consequently, ECV depletion and increased morbidity.¹⁴ The persistence of hypouricemia and elevated FE_Urate after correction of the hyponatremia in RSW differentiates it from SIADH.^{13, 14}

Given these challenges, recommendations to use an algorithmic approach for the evaluation and diagnosis of hyponatremia have surfaced. In a study of 121 patients admitted with hyponatremia, an algorithm-based approach to the diagnosis of hyponatremia yielded an overall diagnostic accuracy of 71%, compared with an accuracy of 32% by experienced clinicians.⁵ This study also highlighted SIADH as the most frequent false-positive diagnosis that was expected whenever the combination of euvolemia and a U_Na >30 mmol/L was present.⁵ Cases of diuretic-induced hyponatremia often were misclassified due to errors in the accurate assessment of ECV status, as most of these patients appeared clinically euvolemic or hypervolemic.⁵ Therefore, it is important to use an algorithm in identifying SIADH and to use one that does not rely solely on clinical estimation of ECV status (see Figure 1, below).

Management of acute and symptomatic hyponatremia. When hyponatremia develops acutely, urgent treatment is required (see Figure 2, below).¹⁵ Hyponatremia is considered acute when the onset is within 48 hours.¹⁵ Acute hyponatremia is most easily identified in the hospital and is commonly iatrogenic. Small case reviews in the 1980s began to associate postoperative deaths with the administration of hypotonic fluids.¹⁶ Asymptomatic patients with hyponatremia presenting from home should be considered chronic hyponatremias as the duration often is unclear.

click for large version

Acute hyponatremia or neurologically symptomatic hyponatremia regardless of duration requires the use of hypertonic saline.¹⁵ Traditional sodium correction algorithms are based on early case series, which were focused on limiting neurologic complications from sodium overcorrection.¹⁷ This resulted in protocols recommending a conservative rate of correction spread over a 24- to 48-hour period.¹⁷ Infusing 3% saline at a rate of 1 ml/kg/hr to 2 ml/kg/hr results in a 1 mmol/L/hr to 2 mmol/L/hr increase in P_Na.¹⁵ This simplified formula results in similar correction rates as more complex calculations.15 Correction should not exceed 8 mmol/L to 10 mmol/L within the first 24 hours, and 18 mmol/L to 25 mmol/L by 48 hours to avoid CPM.¹⁵ P_Na should be checked every two hours to ensure that the correction rate is not exceeding the predicted rate, as the formulas do not take into account oral intake and ongoing losses.¹⁵

Recent observations focused on the initial four hours from onset of hyponatremia suggest a higher rate of correction can be tolerated without complications.¹⁸ Rapid sodium correction of 4 mmol/L to 6 mmol/L often is enough to stop neurologic complications.¹⁸ This can be accomplished with a bolus infusion of 100 mL of 3% saline.¹⁹ This may be repeated twice at 10-minute intervals until there is neurologic improvement.¹⁹ This might sound aggressive, but this would correspond to a rise in P_Na of 5 mmol/L to 6 mmol/L in a 50 kg woman. Subsequent treatment with hypertonic fluid might not be needed if symptoms resolve.

Management of chronic hyponatremia. Hyponatremia secondary to SIADH improves with the treatment of the underlying cause, thus an active search for a causative medication or condition should be sought (see Table 1, p. 17).²⁰

click for large version

Water restriction. Restriction of fluid intake is the first-line treatment for SIADH in patients without hypovolemia. The severity of fluid restriction is guided by the concentration of the urinary solutes.¹⁵ Restriction of water intake to 500 ml/day to 1,000 ml/day is generally advised for many patients, as losses from the skin, lungs, and urine exceed this amount, leading to a gradual reduction in total body water.²¹ The main drawback of fluid restriction is poor compliance due to an intact thirst mechanism.

Saline infusion. The infusion of normal saline theoretically worsens hyponatremia due to SIADH because the water is retained while the salt is excreted. However, a trial of normal saline sometimes is attempted in patients in whom the differentiation between hypovolemia and euvolemia is difficult. From a study of a series of 17 patients with chronic SIADH, Musch and Decaux concluded that the infusion of intravenous normal (0.9%) saline raises P_Na when the urine osmolality is less than 530 mosm/L.²²

Oral solutes (urea and salt). The oral intake of salt augments water excretion²³, and salt tablets are used as a second-line agent in patients with persistent hyponatremia despite fluid restriction.²³ The oral administration of urea also results in increased free-water excretion via osmotic diuresis,²⁴ but its poor palatability, lack of availability in the U.S., and limited user experience has restricted its usage.²⁴

Demeclocycline. Demeclo-cycline is a tetracycline derivative that causes a partial nephrogenic diabetes insipidus.²⁵ Its limitations include a slow onset of action (two to five days) and an unpredictable treatment effect with the possibility of causing profound polyuria and hypernatremia. It is also associated with reversible azotemia and sometimes nephrotoxicity, especially in patients with cirrhosis.

Lithium. Lithium also causes nephrogenic diabetes insipidus by downregulating vasopressin-stimulated aquaporin-2 expression and thus improves hyponatremia in SIADH.²⁶ However, its use is significantly limited by its unpredictable response and the risks of interstitial nephritis and end-stage renal disease with chronic use. Therefore, it is no longer recommended for the treatment of SIADH.

Vasopressin receptor antagonists. Due to the role of excessive levels of vasopressin in the pathophysiology of most types of SIADH, antagonists of the vasopressin receptor were developed with the goal of preventing the excess water absorption that causes hyponatremia. Two vasopressin receptor antagonists, or vaptans, have been approved by the FDA for the treatment of nonemergent euvolemic and hypervolemic hyponatremia. Conivaptan is a nonselective vasopressin receptor antagonist that is for IV use only. Tolvaptan is a selective V2 receptor antagonist that is taken orally. Both conivaptan and tolvaptan successfully increase P_Na levels while the drugs are being taken.^27,28,29,30 Tolvaptan increases P_Na levels in hyponatremia due to SIADH and CHF, and modestly so in cirrhosis.³⁰

click for large version

The most common side effects of the vaptans include dry mouth, increased thirst, and increased urination, although serious side effects (hypernatremia or too-rapid rate of increase in P_Na) are possible.²⁹ It is unclear if treating stable, asymptomatic hyponatremia with vaptans has any reduction in morbidity or mortality. One study found that tolvaptan increased the patients’ self-evaluations of mental functioning, but a study of tolvaptan used in combination with diuretics in the setting of CHF did not result in decreased mortality.^29,31 Due to their expense, necessity of being started in the hospital, and unclear long-term benefit, the vaptans are only recommended when traditional measures such as fluid restriction and salt tablets have been unsuccessful.

Back to the Case

Our patient has hypotonic hyponatremia based on her low serum osmolality. The duration of her hyponatremia is unclear, but the patient is not experiencing seizures or coma. Therefore, her hyponatremia should be corrected slowly, and hypertonic saline is not indicated.

As is common in clinical practice, her true volume status is difficult to clinically ascertain. By physical exam, she appears euvolemic, but because she is on hydrochlorothiazide, she might be subtly hypovolemic. The U_Na of 40 mmol/L is not consistent with hypovolemia, but its accuracy is limited in the setting of diuretics. The failure to improve her sodium by at least 5 mmol/L after a 2 L normal saline infusion argues against low effective arterial blood volume and indicates that the hydrochlorothiazide is unlikely to be the cause of her hyponatremia.

Therefore, the most likely cause of the hyponatremia is SIADH, a diagnosis further corroborated by the elevated FE_Urate of 13%. Her chronic hyponatremia should be managed initially with fluid restriction while an investigation for an underlying cause of SIADH is initiated.

Bottom Line

The diagnosis of SIADH relies on the careful evaluation of laboratory values, use of an algorithm, and recognizing the limitations of clinically assessing volume status. The underlying cause of SIADH must also be sought and treated. TH

Dr. Grant is a clinical lecturer in internal medicine, Dr. Cho is a clinical instructor in internal medicine, and Dr. Nichani is an assistant professor of internal medicine at the University of Michigan Hospital and Health Systems in Ann Arbor.

References

1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 Suppl 1):S30-35.
2. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1-21.
3. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e71-78.
4. Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987;83(5):905-908.
5. Fenske W, Maier SK, Blechschmidt A, Allolio B, Störk S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010;123(7):652-657.
6. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42(5):790-806.
7. Smith DM, McKenna K, Thompson CJ. Hyponatraemia. Clin Endocrinol (Oxf). 2000;52(6):667-678.
8. Verbalis JG. Hyponatraemia. Baillieres Clin Endocrinol Metab. Aug 1989;3(2):499-530.
9. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or renal salt wasting? Kidney Int. 2009;76(9):934-938.
10. Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.
11. Fenske W, Störk S, Koschker AC, et al. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. J Clin Endocrinol Metab. 2008;93(8):2991-2997.
12. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis. 1998;32(6):917-933.
13. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056-1062.
14. Bitew S, Imbriano L, Miyawaki N, Fishbane S, Maesaka JK. More on renal salt wasting without cerebral disease: response to saline infusion. Clin J Am Soc Nephrol. 2009;4(2):309-315.
15. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072.
16. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. 1986;314(24):1529-1535.
17. Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med. 1987;317(19):1190-1195.
18. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282-299.
19. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med. 2008;18(2):111-121.
20. List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986;4(8):1191-1198.
21. Verbalis JG. Managing hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion. J Hosp Med. 2010;5 Suppl 3:S18-S26.
22. Musch W, Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline. QJM. 1998;91(11):749-753.
23. Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol. 2008;19(6):1076-1078.
24. Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. 1980;69(1):99-106.
25. Forrest JN Jr., Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1978;298(4):173-177.
26. Nielsen J, Hoffert JD, Knepper MA, Agre P, Nielsen S, Fenton RA. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci U S A. 2008;105(9):3634-3639.
27. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447-457.
28. Verbalis JG, Zeltser D, Smith N, Barve A, Andoh M. Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study. Clin Endocrinol (Oxf). 2008;69(1):159-168.
29. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112.
30. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705-712.
31. Konstam MA, Gheorghiade M, Burnett JC Jr., et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331.

Case

A 70-year-old woman with hypertension presents after a fall. Her medications include hydrochlorothiazide. Her blood pressure is 130/70 mm/Hg, with heart rate of 86. She has normal orthostatic vital signs. Her mucus membranes are moist and she has no jugular venous distension, edema, or ascites. Her plasma sodium (P_Na) is 125 mmol/L, potassium 3.6 mmol/L, blood urea nitrogen (BUN) 30 mg/dL, and creatinine 0.8 mg/dL. Additional labs include serum thyroid stimulating hormone 1.12 mIU/L, cortisol 15 mcg/dL, serum osmolality 270 mOsm/kg, uric acid 4 mg/dL, urine osmolality 300 mOsm/kg, urine sodium (U_Na) 40 mmol/L, fractional excretion of sodium 1.0%, and fractional excretion of urate (FE_Urate) 13%. She receives 2 L isotonic saline intravenously over 24 hours, with resulting P_Na of 127.

What is the cause of her hyponatremia, and how should her hyponatremia be managed?

Overview

Hyponatremia is one of the most common electrolyte abnormalities; it has a prevalence as high as 30% upon admission to the hospital.¹ Hyponatremia is important clinically because of its high risk of mortality in the acute and symptomatic setting, and the risk of central pontine myelinolysis (CPM), or death with too rapid correction.² Even so-called “asymptomatic” mild hyponatremia is associated with increased falls and impairments in gait and attention in the elderly.³

Hyponatremia is a state of excess water compared with the amount of solute in the extracellular fluid. To aid in diagnosing the etiology of hypotonic hyponatremia, the differential is traditionally divided into categories based on extracellular fluid volume (ECV) status, as shown in Table 1 (below), with syndrome of inappropriate antidiuretic hormone secretion (SIADH) being the most common cause of euvolemic hyponatremia.² However, data show that clinical determination of volume status is often flawed,⁴ and an algorithmic approach to diagnosis and treatment yields improved results.⁵

Review of the Data

Diagnosis of SIADH. The original diagnostic criteria for SIADH, with minor modifications, are presented in Table 2, page 18).^6,7,8 However, applying these criteria in clinical settings presents several difficulties, most notably a determination of ECV. The gold standard for assessing ECV status is by radioisotope, which is not practically feasible.⁹ Therefore, clinicians must rely on surrogate clinical markers of ECV (orthostatic hypotension, skin turgor, mucus membrane dryness, central venous pressure, BUN, BUN-creatinine ratio, and serum uric acid levels), which lack both sensitivity and specificity.⁴ Astoundingly, clinical assessment of ECV has been demonstrated to be accurate only 50% of the time when differentiating euvolemic patients from those with hypovolemia.⁴

click for large version

Another challenge lies in the interpretation of U_Na, which frequently is used as a surrogate for extra-arterial blood volume (EABV) status.¹⁰ Unfortunately, in the setting of diuretic use, U_Na becomes inaccurate. The FE_Urate, however, is unaffected by diuretic use and can be helpful in distinguishing between etiologies of hyponatremia with U_Na greater than 30 mmol/L.¹¹ The FE_Urate is about 10% in normal euvolemic subjects and is reduced (usually <8%) in patients with low effective arterial blood volume.^11,12 A trial of 86 patients demonstrated that a FE_Urate of 12% had a specificity and positive predictive value of 100% in accurately identifying SIADH from diuretic-induced hyponatremia in patients on diuretics.^11,12 Therefore, the U_Na is a valid marker of EABV status when patients are not on diuretics; however, the FE_Urate should be used in the setting of diuretic use.

Yet another pitfall is differentiating patients with salt depletion from those with SIADH. In these situations, measurement of the change in P_Na concentration after a test infusion of isotonic saline is helpful. In salt depletion, P_Na usually increases ≥5 mmol/L after 2 L saline infusion, which is not the case with SIADH.¹³ Incorrectly diagnosing renal salt wasting (RSW) as SIADH results in fluid restriction and, consequently, ECV depletion and increased morbidity.¹⁴ The persistence of hypouricemia and elevated FE_Urate after correction of the hyponatremia in RSW differentiates it from SIADH.^{13, 14}

Given these challenges, recommendations to use an algorithmic approach for the evaluation and diagnosis of hyponatremia have surfaced. In a study of 121 patients admitted with hyponatremia, an algorithm-based approach to the diagnosis of hyponatremia yielded an overall diagnostic accuracy of 71%, compared with an accuracy of 32% by experienced clinicians.⁵ This study also highlighted SIADH as the most frequent false-positive diagnosis that was expected whenever the combination of euvolemia and a U_Na >30 mmol/L was present.⁵ Cases of diuretic-induced hyponatremia often were misclassified due to errors in the accurate assessment of ECV status, as most of these patients appeared clinically euvolemic or hypervolemic.⁵ Therefore, it is important to use an algorithm in identifying SIADH and to use one that does not rely solely on clinical estimation of ECV status (see Figure 1, below).

Management of acute and symptomatic hyponatremia. When hyponatremia develops acutely, urgent treatment is required (see Figure 2, below).¹⁵ Hyponatremia is considered acute when the onset is within 48 hours.¹⁵ Acute hyponatremia is most easily identified in the hospital and is commonly iatrogenic. Small case reviews in the 1980s began to associate postoperative deaths with the administration of hypotonic fluids.¹⁶ Asymptomatic patients with hyponatremia presenting from home should be considered chronic hyponatremias as the duration often is unclear.

click for large version

Acute hyponatremia or neurologically symptomatic hyponatremia regardless of duration requires the use of hypertonic saline.¹⁵ Traditional sodium correction algorithms are based on early case series, which were focused on limiting neurologic complications from sodium overcorrection.¹⁷ This resulted in protocols recommending a conservative rate of correction spread over a 24- to 48-hour period.¹⁷ Infusing 3% saline at a rate of 1 ml/kg/hr to 2 ml/kg/hr results in a 1 mmol/L/hr to 2 mmol/L/hr increase in P_Na.¹⁵ This simplified formula results in similar correction rates as more complex calculations.15 Correction should not exceed 8 mmol/L to 10 mmol/L within the first 24 hours, and 18 mmol/L to 25 mmol/L by 48 hours to avoid CPM.¹⁵ P_Na should be checked every two hours to ensure that the correction rate is not exceeding the predicted rate, as the formulas do not take into account oral intake and ongoing losses.¹⁵

Recent observations focused on the initial four hours from onset of hyponatremia suggest a higher rate of correction can be tolerated without complications.¹⁸ Rapid sodium correction of 4 mmol/L to 6 mmol/L often is enough to stop neurologic complications.¹⁸ This can be accomplished with a bolus infusion of 100 mL of 3% saline.¹⁹ This may be repeated twice at 10-minute intervals until there is neurologic improvement.¹⁹ This might sound aggressive, but this would correspond to a rise in P_Na of 5 mmol/L to 6 mmol/L in a 50 kg woman. Subsequent treatment with hypertonic fluid might not be needed if symptoms resolve.

Management of chronic hyponatremia. Hyponatremia secondary to SIADH improves with the treatment of the underlying cause, thus an active search for a causative medication or condition should be sought (see Table 1, p. 17).²⁰

click for large version

Water restriction. Restriction of fluid intake is the first-line treatment for SIADH in patients without hypovolemia. The severity of fluid restriction is guided by the concentration of the urinary solutes.¹⁵ Restriction of water intake to 500 ml/day to 1,000 ml/day is generally advised for many patients, as losses from the skin, lungs, and urine exceed this amount, leading to a gradual reduction in total body water.²¹ The main drawback of fluid restriction is poor compliance due to an intact thirst mechanism.

Saline infusion. The infusion of normal saline theoretically worsens hyponatremia due to SIADH because the water is retained while the salt is excreted. However, a trial of normal saline sometimes is attempted in patients in whom the differentiation between hypovolemia and euvolemia is difficult. From a study of a series of 17 patients with chronic SIADH, Musch and Decaux concluded that the infusion of intravenous normal (0.9%) saline raises P_Na when the urine osmolality is less than 530 mosm/L.²²

Oral solutes (urea and salt). The oral intake of salt augments water excretion²³, and salt tablets are used as a second-line agent in patients with persistent hyponatremia despite fluid restriction.²³ The oral administration of urea also results in increased free-water excretion via osmotic diuresis,²⁴ but its poor palatability, lack of availability in the U.S., and limited user experience has restricted its usage.²⁴

Demeclocycline. Demeclo-cycline is a tetracycline derivative that causes a partial nephrogenic diabetes insipidus.²⁵ Its limitations include a slow onset of action (two to five days) and an unpredictable treatment effect with the possibility of causing profound polyuria and hypernatremia. It is also associated with reversible azotemia and sometimes nephrotoxicity, especially in patients with cirrhosis.

Lithium. Lithium also causes nephrogenic diabetes insipidus by downregulating vasopressin-stimulated aquaporin-2 expression and thus improves hyponatremia in SIADH.²⁶ However, its use is significantly limited by its unpredictable response and the risks of interstitial nephritis and end-stage renal disease with chronic use. Therefore, it is no longer recommended for the treatment of SIADH.

Vasopressin receptor antagonists. Due to the role of excessive levels of vasopressin in the pathophysiology of most types of SIADH, antagonists of the vasopressin receptor were developed with the goal of preventing the excess water absorption that causes hyponatremia. Two vasopressin receptor antagonists, or vaptans, have been approved by the FDA for the treatment of nonemergent euvolemic and hypervolemic hyponatremia. Conivaptan is a nonselective vasopressin receptor antagonist that is for IV use only. Tolvaptan is a selective V2 receptor antagonist that is taken orally. Both conivaptan and tolvaptan successfully increase P_Na levels while the drugs are being taken.^27,28,29,30 Tolvaptan increases P_Na levels in hyponatremia due to SIADH and CHF, and modestly so in cirrhosis.³⁰

click for large version

The most common side effects of the vaptans include dry mouth, increased thirst, and increased urination, although serious side effects (hypernatremia or too-rapid rate of increase in P_Na) are possible.²⁹ It is unclear if treating stable, asymptomatic hyponatremia with vaptans has any reduction in morbidity or mortality. One study found that tolvaptan increased the patients’ self-evaluations of mental functioning, but a study of tolvaptan used in combination with diuretics in the setting of CHF did not result in decreased mortality.^29,31 Due to their expense, necessity of being started in the hospital, and unclear long-term benefit, the vaptans are only recommended when traditional measures such as fluid restriction and salt tablets have been unsuccessful.

Back to the Case

Our patient has hypotonic hyponatremia based on her low serum osmolality. The duration of her hyponatremia is unclear, but the patient is not experiencing seizures or coma. Therefore, her hyponatremia should be corrected slowly, and hypertonic saline is not indicated.

As is common in clinical practice, her true volume status is difficult to clinically ascertain. By physical exam, she appears euvolemic, but because she is on hydrochlorothiazide, she might be subtly hypovolemic. The U_Na of 40 mmol/L is not consistent with hypovolemia, but its accuracy is limited in the setting of diuretics. The failure to improve her sodium by at least 5 mmol/L after a 2 L normal saline infusion argues against low effective arterial blood volume and indicates that the hydrochlorothiazide is unlikely to be the cause of her hyponatremia.

Therefore, the most likely cause of the hyponatremia is SIADH, a diagnosis further corroborated by the elevated FE_Urate of 13%. Her chronic hyponatremia should be managed initially with fluid restriction while an investigation for an underlying cause of SIADH is initiated.

Bottom Line

The diagnosis of SIADH relies on the careful evaluation of laboratory values, use of an algorithm, and recognizing the limitations of clinically assessing volume status. The underlying cause of SIADH must also be sought and treated. TH

Dr. Grant is a clinical lecturer in internal medicine, Dr. Cho is a clinical instructor in internal medicine, and Dr. Nichani is an assistant professor of internal medicine at the University of Michigan Hospital and Health Systems in Ann Arbor.

References

1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med. 2006;119(7 Suppl 1):S30-35.
2. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1-21.
3. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e71-78.
4. Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med. 1987;83(5):905-908.
5. Fenske W, Maier SK, Blechschmidt A, Allolio B, Störk S. Utility and limitations of the traditional diagnostic approach to hyponatremia: a diagnostic study. Am J Med. 2010;123(7):652-657.
6. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med. 1967;42(5):790-806.
7. Smith DM, McKenna K, Thompson CJ. Hyponatraemia. Clin Endocrinol (Oxf). 2000;52(6):667-678.
8. Verbalis JG. Hyponatraemia. Baillieres Clin Endocrinol Metab. Aug 1989;3(2):499-530.
9. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E. Is it cerebral or renal salt wasting? Kidney Int. 2009;76(9):934-938.
10. Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.
11. Fenske W, Störk S, Koschker AC, et al. Value of fractional uric acid excretion in differential diagnosis of hyponatremic patients on diuretics. J Clin Endocrinol Metab. 2008;93(8):2991-2997.
12. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis. 1998;32(6):917-933.
13. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166(8):1056-1062.
14. Bitew S, Imbriano L, Miyawaki N, Fishbane S, Maesaka JK. More on renal salt wasting without cerebral disease: response to saline infusion. Clin J Am Soc Nephrol. 2009;4(2):309-315.
15. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064-2072.
16. Arieff AI. Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med. 1986;314(24):1529-1535.
17. Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med. 1987;317(19):1190-1195.
18. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Semin Nephrol. 2009;29(3):282-299.
19. Hew-Butler T, Ayus JC, Kipps C, et al. Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med. 2008;18(2):111-121.
20. List AF, Hainsworth JD, Davis BW, Hande KR, Greco FA, Johnson DH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in small-cell lung cancer. J Clin Oncol. 1986;4(8):1191-1198.
21. Verbalis JG. Managing hyponatremia in patients with syndrome of inappropriate antidiuretic hormone secretion. J Hosp Med. 2010;5 Suppl 3:S18-S26.
22. Musch W, Decaux G. Treating the syndrome of inappropriate ADH secretion with isotonic saline. QJM. 1998;91(11):749-753.
23. Berl T. Impact of solute intake on urine flow and water excretion. J Am Soc Nephrol. 2008;19(6):1076-1078.
24. Decaux G, Brimioulle S, Genette F, Mockel J. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med. 1980;69(1):99-106.
25. Forrest JN Jr., Cox M, Hong C, Morrison G, Bia M, Singer I. Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med. 1978;298(4):173-177.
26. Nielsen J, Hoffert JD, Knepper MA, Agre P, Nielsen S, Fenton RA. Proteomic analysis of lithium-induced nephrogenic diabetes insipidus: mechanisms for aquaporin 2 down-regulation and cellular proliferation. Proc Natl Acad Sci U S A. 2008;105(9):3634-3639.
27. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol. 2007;27(5):447-457.
28. Verbalis JG, Zeltser D, Smith N, Barve A, Andoh M. Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study. Clin Endocrinol (Oxf). 2008;69(1):159-168.
29. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099-2112.
30. Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705-712.
31. Konstam MA, Gheorghiade M, Burnett JC Jr., et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319-1331.

click for large version

Case

A 66-year-old Caucasian female with moderate chronic obstructive pulmonary disease (COPD) (FEV1 55% predicted), obesity, hypertension, and Type 2 diabetes mellitus on insulin therapy presents to the ED with four days of increased cough productive of yellow sputum and progressive shortness of breath. Her physical exam is notable for an oxygen saturation of 87% on room air, along with diffuse expiratory wheezing with use of accessory muscles; her chest X-ray is unchanged from previous. The patient is given oxygen, nebulized bronchodilators, and one dose of IV methylprednisolone. Her symptoms do not improve significantly, and she is admitted for further management. What regimen of corticosteroids is most appropriate to treat her acute exacerbation of COPD?

Overview

COPD is the fourth-leading cause of death in the United States and continues to increase in prevalence.1 Acute exacerbations of COPD (AECOPD) contribute significantly to this high mortality rate, which approaches 40% at one year in those patients requiring mechanical support.¹ An exacerbation of COPD has been defined as an acute change in a patient’s baseline dyspnea, cough, and/or sputum beyond day-to-day variability sufficient to warrant a change in therapy.² Exacerbations commonly occur in COPD patients and often necessitate hospital admission. In fact, COPD consistently is one of the 10 most common reasons for hospitalization, with billions of dollars in associated healthcare costs.³

The goals for inpatient management of AECOPD are to provide acute symptom relief and to minimize the potential for subsequent exacerbations. These are accomplished via a multifaceted approach, including the use of bronchodilators, antibiotics, supplemental oxygen, noninvasive positive pressure ventilation in certain circumstances, and systemic corticosteroids.

The administration of systemic steroids in AECOPD has been prevalent for several decades, with initial studies showing positive effects on lung function, specifically FEV1.⁴ Studies have demonstrated the benefit of steroids in prolonging the time to subsequent exacerbation, reducing the rate of treatment failure, and reducing length of stay (LOS).⁵ Corticosteroids have since become an essential component of the standard of care in AECOPD management.

Despite consensus that systemic steroids should be used in COPD exacerbations, a great deal of controversy still surrounds the optimal steroid regimen.⁶ Steroid use is not without risk, as steroids can lead to adverse outcomes in medically complex hospitalized patients (see Table 1, below). Current guidelines provide limited guidance as to the optimal route of administration, dosing regimen, or length of therapy; clinical practice varies widely.

Review of the Data

Administration route: intravenous (IV) vs. oral. The use of steroids in AECOPD began with such IV formulations as methylprednisolone, and this became the typical method of treating hospitalized patients. This practice was validated in a multicenter Veterans Affairs trial, which demonstrated decreased risk of treatment failure (defined as all-cause mortality, need for intubation, readmission for COPD, or intensification of pharmacologic therapy) for patients randomized to receive an IV-to-oral steroid regimen compared with those randomized to placebo.5 Patients receiving steroids also had shorter LOS and improvements in FEV1 after the first day of treatment. Subsequent randomized controlled trials in patients with AECOPD demonstrated the benefit of oral regimens compared with placebo with regard to FEV1, LOS, and risk of treatment failure.^6,7,8

Similarities in the bioavailability of oral and IV steroids have been known for a long time.⁹ Comparisons in efficacy initially were completed in the management of acute asthma exacerbations, with increasing evidence, including a meta-analysis, demonstrating no difference in improvement in pulmonary function and in preventing relapse of exacerbations for oral compared with IV steroids.¹⁰ However, only recently have oral and IV steroids been compared in the treatment of AECOPD. De Jong et al randomized more than 200 patients hospitalized for AECOPD to 60 mg of either IV or oral prednisolone for five days, followed by a week of an oral taper.¹¹ There were no significant differences in treatment failure between the IV and oral groups (62% vs. 56%, respectively, at 90 days; one-sided lower bound of the 95% confidence interval [CI], −5.8%).

click for large version

A large observational study by Lindenauer et al, including nearly 80,000 AECOPD patients admitted at more than 400 hospitals, added further support to the idea that oral and IV steroids were comparable in efficacy.¹² In this study, multivariate analysis found no difference in treatment failure between oral and IV groups (odds ratio [OR] 0.93; 95% CI, 0.84-1.02). The authors also found, however, that current clinical practice still overwhelmingly favors intravenous steroids, with 92% of study patients initially being administered IV steroids.¹²

Based on the evidence from de Jong and Lindenauer, it appears that there is no significant benefit to the use of IV over oral steroids. Additionally, there is evidence for oral administration being associated with beneficial effects on cost and hospital LOS.¹² Oral steroids, therefore, are the preferred route of administration to treat a hospitalized patient with AECOPD, unless the patient is unable to tolerate oral medications. Current guidelines support the practice of giving oral steroids as first-line treatment for AECOPD (see Table 2, above).

High dose vs. low dose. Another important clinical issue concerns the dosing of steroids. The randomized trials examining the use of corticosteroids in AECOPD vary widely in the dosages studied. Further, the majority of these trials have compared steroids to placebo, rather than comparing different dosage regimens. The agents studied have included prednisone, prednisolone, methylprednisolone, and hydrocortisone, or combinations thereof. In order to compare regimens of these different drugs, steroid doses often are converted into prednisone equivalents (see Table 3, below). Though no guidelines define “high dose” and “low dose,” some studies have designated doses of >80 mg prednisone equivalents daily as high-dose and prednisone equivalents of ≤80 mg daily as low-dose.^13,14

click for large version

Starting doses of systemic corticosteroids in the treatment of AECOPD in clinical studies range from prednisone equivalents of 30 mg daily to 625 mg on the first day of treatment.^5,8 No randomized studies of high- versus low-dose steroid regimens have been conducted. One retrospective chart review of 145 AECOPD admissions evaluated outcomes among patients who were given higher (mean daily dose >80 mg prednisone equivalent) and lower (mean daily dose of ≤80 mg prednisone) doses.¹⁴ The authors found that patients who received higher doses of steroids had significantly longer LOS compared with those who received lower doses, especially among the subset of patients who were admitted to the floor rather than the ICU, though this analysis did not adjust for severity of illness. In this study, the most striking finding noted by the authors was the wide variability in the steroid doses prescribed for the inpatient treatment of AECOPD.

More recently, the study by Lindenauer et al examined outcomes between patients treated with high-dose IV steroids (equivalent of 120 mg-800 mg of prednisone on the first or second day of treatment) compared to low-dose oral steroids (prednisone equivalents of 20 mg-80 mg per day).¹² The authors found no differences between the two groups regarding the rate of treatment failure, defined by initiation of mechanical ventilation after the second hospital day, in-hospital mortality, or readmission for COPD within 30 days of discharge. After multivariate adjustment, including the propensity for oral treatment, the low-dose oral therapy group was found to have lower risk of treatment failure, shorter LOS, and lower total hospital cost.

Despite the heterogeneity of the published data and the lack of randomized trials, the existing evidence suggests that low-dose prednisone (or equivalent) is similar in efficacy to higher doses and generally is associated with shorter hospital stays. Recognizing these benefits, guidelines do favor initiating treatment with low-dose steroids in patients admitted with AECOPD. The most recent publications from the American Thoracic Society/European Respiratory Society Task Force (ATS/ERS), the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the National Clinical Guidelines Centre in the United Kingdom, and the Canadian Thoracic Society all recommend equivalent dosing of prednisone in patients admitted with AECOPD who are able to tolerate oral intake (see Table 2).^1,2,15,16

Duration. As with the dosing of systemic corticosteroids in AECOPD, the optimal duration of treatment is not well-established. National and international consensus panels vary in their recommendations, as outlined in Table 2. This may be related to the variability in length of treatment found in the literature.

Treatment durations ranging from one day to eight weeks have been studied in inpatients with AECOPD. The landmark randomized controlled trial by Niewoehner and colleagues compared two-week and eight-week courses of systemic corticosteroids and found no difference in the rates of treatment failure, which included death, need for mechanical ventilation, readmission for COPD, and intensification of pharmacologic therapy.⁵ Based on these results, many experts have concluded that there is no benefit to steroid courses lasting beyond two weeks.

Although improvements in outcomes have been demonstrated with corticosteroid regimens as short as three days compared with placebo, most of the randomized controlled trials have included courses of seven to 14 days.⁴ Given the risks of adverse events (e.g. hyperglycemia) that are associated with systemic administration of steroids, the shortest effective duration should be considered.

click for large version

In both clinical practice and clinical studies, steroid regimens often include a taper. A study by Vondracek and Hemstreet found that 79% of hospital discharges for AECOPD included a tapered corticosteroid regimen.¹⁴ From a physiologic standpoint, durations of corticosteroid treatment approximately three weeks or less, regardless of dosage, should not lead to adrenal suppression.¹⁷ There also is no evidence to suggest that abrupt discontinuation of steroids leads to clinical worsening of disease, and complicated steroid tapers are a potential source of medication errors after hospital discharge.¹⁸ Furthermore, the clinical guidelines do not address the tapering of corticosteroids. Therefore, there is a lack of evidence advocating for or against the use of tapered steroid regimens in AECOPD.

Back to the Case

In addition to standard treatment modalities for AECOPD, our patient was administered oral prednisone 40 mg daily. She experienced steroid-induced hyperglycemia, which was corrected with adjustment of her insulin regimen. The patient’s pulmonary symptoms improved within 72 hours, and she was discharged home on hospital day four to complete a seven-day steroid course. At hospital discharge, she was administered influenza and pneumococcal vaccinations, and she was instructed to resume her usual insulin dosing once she finished her prednisone course.

Overview

In the management of AECOPD, there remains a lack of consensus in defining the ideal steroid regimen. Based on current literature, the use of low-dose oral corticosteroids, such as prednisone 40 mg daily, for a seven- to 14-day course is recommended. TH

Dr. Cunningham is an assistant professor of internal medicine and academic hospitalist in the section of hospital medicine at Vanderbilt University School of Medicine in Nashville, Tenn. Dr. LaBrin is an assistant professor of internal medicine and pediatrics and academic hospitalist at Vanderbilt University School of Medicine.

References

1. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Global Initiative for Chronic Obstructive Lung Disease website. Available at: www.goldcopd.org/GuidelineItem.asp?intId=989. Accessed Feb. 21, 2011.
2. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946.
3. Morbidity and mortality: 2009 chart book on cardiovascular, lung, and blood diseases. National Institutes of Health’s National Heart, Lung, and Blood Institute website. Available at: www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf. Accessed Feb. 24, 2011.
4. Albert RK, Martin TR, Lewis SW. Controlled trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med. 1980;92(6):753-758.
5. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340(25):1941-1947.
6. Thompson WH, Nielson C, Carvalho P, Charan NB, Crowley JJ. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med. 1996;154:407-412.
7. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1608-1613.
8. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet. 1999;354(9177):456-460.
9. Al-Habet S, Rogers HJ. Pharmacokinetics of intravenous and oral prednisolone. Br J Clin Pharmacol. 1980;10(5):503-508.
10. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J Emerg Med. 1992;10:301-310.
11. De Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: A randomized, controlled, double-blind study. Chest. 2007;132(6):1741-1747.
12. Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB. Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303(23):2359-2367.
13. Manser R, Reid D, Abramsom MJ. Corticosteroids for acute severe asthma in hospitalized patients. Cochrane Database Syst Rev. 2000;(2):CD001740.
14. Vondracek SF, Hemstreet BA. Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations of chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2006;63:645-652.
15. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. National Institute for Health and Clinical Excellence website. Available at: guidance.nice.org.uk/CG101/Guidance/pdf/English. Accessed Feb. 21, 2011.
16. O’Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2007 update. Can Respir J. 2007;14 Suppl B:5B-32B.
17. Webb J, Clark TJ. Recovery of plasma corticotrophin and cortisol levels after three-week course of prednisolone. Thorax. 1981;36:22-24.
18. O’Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Double-blind trial of steroid tapering in acute asthma. Lancet. 1993; 341:324-7.

click for large version

Case

A 66-year-old Caucasian female with moderate chronic obstructive pulmonary disease (COPD) (FEV1 55% predicted), obesity, hypertension, and Type 2 diabetes mellitus on insulin therapy presents to the ED with four days of increased cough productive of yellow sputum and progressive shortness of breath. Her physical exam is notable for an oxygen saturation of 87% on room air, along with diffuse expiratory wheezing with use of accessory muscles; her chest X-ray is unchanged from previous. The patient is given oxygen, nebulized bronchodilators, and one dose of IV methylprednisolone. Her symptoms do not improve significantly, and she is admitted for further management. What regimen of corticosteroids is most appropriate to treat her acute exacerbation of COPD?

Overview

COPD is the fourth-leading cause of death in the United States and continues to increase in prevalence.1 Acute exacerbations of COPD (AECOPD) contribute significantly to this high mortality rate, which approaches 40% at one year in those patients requiring mechanical support.¹ An exacerbation of COPD has been defined as an acute change in a patient’s baseline dyspnea, cough, and/or sputum beyond day-to-day variability sufficient to warrant a change in therapy.² Exacerbations commonly occur in COPD patients and often necessitate hospital admission. In fact, COPD consistently is one of the 10 most common reasons for hospitalization, with billions of dollars in associated healthcare costs.³

The goals for inpatient management of AECOPD are to provide acute symptom relief and to minimize the potential for subsequent exacerbations. These are accomplished via a multifaceted approach, including the use of bronchodilators, antibiotics, supplemental oxygen, noninvasive positive pressure ventilation in certain circumstances, and systemic corticosteroids.

The administration of systemic steroids in AECOPD has been prevalent for several decades, with initial studies showing positive effects on lung function, specifically FEV1.⁴ Studies have demonstrated the benefit of steroids in prolonging the time to subsequent exacerbation, reducing the rate of treatment failure, and reducing length of stay (LOS).⁵ Corticosteroids have since become an essential component of the standard of care in AECOPD management.

Despite consensus that systemic steroids should be used in COPD exacerbations, a great deal of controversy still surrounds the optimal steroid regimen.⁶ Steroid use is not without risk, as steroids can lead to adverse outcomes in medically complex hospitalized patients (see Table 1, below). Current guidelines provide limited guidance as to the optimal route of administration, dosing regimen, or length of therapy; clinical practice varies widely.

Review of the Data

Administration route: intravenous (IV) vs. oral. The use of steroids in AECOPD began with such IV formulations as methylprednisolone, and this became the typical method of treating hospitalized patients. This practice was validated in a multicenter Veterans Affairs trial, which demonstrated decreased risk of treatment failure (defined as all-cause mortality, need for intubation, readmission for COPD, or intensification of pharmacologic therapy) for patients randomized to receive an IV-to-oral steroid regimen compared with those randomized to placebo.5 Patients receiving steroids also had shorter LOS and improvements in FEV1 after the first day of treatment. Subsequent randomized controlled trials in patients with AECOPD demonstrated the benefit of oral regimens compared with placebo with regard to FEV1, LOS, and risk of treatment failure.^6,7,8

Similarities in the bioavailability of oral and IV steroids have been known for a long time.⁹ Comparisons in efficacy initially were completed in the management of acute asthma exacerbations, with increasing evidence, including a meta-analysis, demonstrating no difference in improvement in pulmonary function and in preventing relapse of exacerbations for oral compared with IV steroids.¹⁰ However, only recently have oral and IV steroids been compared in the treatment of AECOPD. De Jong et al randomized more than 200 patients hospitalized for AECOPD to 60 mg of either IV or oral prednisolone for five days, followed by a week of an oral taper.¹¹ There were no significant differences in treatment failure between the IV and oral groups (62% vs. 56%, respectively, at 90 days; one-sided lower bound of the 95% confidence interval [CI], −5.8%).

click for large version

A large observational study by Lindenauer et al, including nearly 80,000 AECOPD patients admitted at more than 400 hospitals, added further support to the idea that oral and IV steroids were comparable in efficacy.¹² In this study, multivariate analysis found no difference in treatment failure between oral and IV groups (odds ratio [OR] 0.93; 95% CI, 0.84-1.02). The authors also found, however, that current clinical practice still overwhelmingly favors intravenous steroids, with 92% of study patients initially being administered IV steroids.¹²

Based on the evidence from de Jong and Lindenauer, it appears that there is no significant benefit to the use of IV over oral steroids. Additionally, there is evidence for oral administration being associated with beneficial effects on cost and hospital LOS.¹² Oral steroids, therefore, are the preferred route of administration to treat a hospitalized patient with AECOPD, unless the patient is unable to tolerate oral medications. Current guidelines support the practice of giving oral steroids as first-line treatment for AECOPD (see Table 2, above).

High dose vs. low dose. Another important clinical issue concerns the dosing of steroids. The randomized trials examining the use of corticosteroids in AECOPD vary widely in the dosages studied. Further, the majority of these trials have compared steroids to placebo, rather than comparing different dosage regimens. The agents studied have included prednisone, prednisolone, methylprednisolone, and hydrocortisone, or combinations thereof. In order to compare regimens of these different drugs, steroid doses often are converted into prednisone equivalents (see Table 3, below). Though no guidelines define “high dose” and “low dose,” some studies have designated doses of >80 mg prednisone equivalents daily as high-dose and prednisone equivalents of ≤80 mg daily as low-dose.^13,14

click for large version

Starting doses of systemic corticosteroids in the treatment of AECOPD in clinical studies range from prednisone equivalents of 30 mg daily to 625 mg on the first day of treatment.^5,8 No randomized studies of high- versus low-dose steroid regimens have been conducted. One retrospective chart review of 145 AECOPD admissions evaluated outcomes among patients who were given higher (mean daily dose >80 mg prednisone equivalent) and lower (mean daily dose of ≤80 mg prednisone) doses.¹⁴ The authors found that patients who received higher doses of steroids had significantly longer LOS compared with those who received lower doses, especially among the subset of patients who were admitted to the floor rather than the ICU, though this analysis did not adjust for severity of illness. In this study, the most striking finding noted by the authors was the wide variability in the steroid doses prescribed for the inpatient treatment of AECOPD.

More recently, the study by Lindenauer et al examined outcomes between patients treated with high-dose IV steroids (equivalent of 120 mg-800 mg of prednisone on the first or second day of treatment) compared to low-dose oral steroids (prednisone equivalents of 20 mg-80 mg per day).¹² The authors found no differences between the two groups regarding the rate of treatment failure, defined by initiation of mechanical ventilation after the second hospital day, in-hospital mortality, or readmission for COPD within 30 days of discharge. After multivariate adjustment, including the propensity for oral treatment, the low-dose oral therapy group was found to have lower risk of treatment failure, shorter LOS, and lower total hospital cost.

Despite the heterogeneity of the published data and the lack of randomized trials, the existing evidence suggests that low-dose prednisone (or equivalent) is similar in efficacy to higher doses and generally is associated with shorter hospital stays. Recognizing these benefits, guidelines do favor initiating treatment with low-dose steroids in patients admitted with AECOPD. The most recent publications from the American Thoracic Society/European Respiratory Society Task Force (ATS/ERS), the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the National Clinical Guidelines Centre in the United Kingdom, and the Canadian Thoracic Society all recommend equivalent dosing of prednisone in patients admitted with AECOPD who are able to tolerate oral intake (see Table 2).^1,2,15,16

Duration. As with the dosing of systemic corticosteroids in AECOPD, the optimal duration of treatment is not well-established. National and international consensus panels vary in their recommendations, as outlined in Table 2. This may be related to the variability in length of treatment found in the literature.

Treatment durations ranging from one day to eight weeks have been studied in inpatients with AECOPD. The landmark randomized controlled trial by Niewoehner and colleagues compared two-week and eight-week courses of systemic corticosteroids and found no difference in the rates of treatment failure, which included death, need for mechanical ventilation, readmission for COPD, and intensification of pharmacologic therapy.⁵ Based on these results, many experts have concluded that there is no benefit to steroid courses lasting beyond two weeks.

Although improvements in outcomes have been demonstrated with corticosteroid regimens as short as three days compared with placebo, most of the randomized controlled trials have included courses of seven to 14 days.⁴ Given the risks of adverse events (e.g. hyperglycemia) that are associated with systemic administration of steroids, the shortest effective duration should be considered.

click for large version

In both clinical practice and clinical studies, steroid regimens often include a taper. A study by Vondracek and Hemstreet found that 79% of hospital discharges for AECOPD included a tapered corticosteroid regimen.¹⁴ From a physiologic standpoint, durations of corticosteroid treatment approximately three weeks or less, regardless of dosage, should not lead to adrenal suppression.¹⁷ There also is no evidence to suggest that abrupt discontinuation of steroids leads to clinical worsening of disease, and complicated steroid tapers are a potential source of medication errors after hospital discharge.¹⁸ Furthermore, the clinical guidelines do not address the tapering of corticosteroids. Therefore, there is a lack of evidence advocating for or against the use of tapered steroid regimens in AECOPD.

Back to the Case

In addition to standard treatment modalities for AECOPD, our patient was administered oral prednisone 40 mg daily. She experienced steroid-induced hyperglycemia, which was corrected with adjustment of her insulin regimen. The patient’s pulmonary symptoms improved within 72 hours, and she was discharged home on hospital day four to complete a seven-day steroid course. At hospital discharge, she was administered influenza and pneumococcal vaccinations, and she was instructed to resume her usual insulin dosing once she finished her prednisone course.

Overview

In the management of AECOPD, there remains a lack of consensus in defining the ideal steroid regimen. Based on current literature, the use of low-dose oral corticosteroids, such as prednisone 40 mg daily, for a seven- to 14-day course is recommended. TH

Dr. Cunningham is an assistant professor of internal medicine and academic hospitalist in the section of hospital medicine at Vanderbilt University School of Medicine in Nashville, Tenn. Dr. LaBrin is an assistant professor of internal medicine and pediatrics and academic hospitalist at Vanderbilt University School of Medicine.

References

1. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Global Initiative for Chronic Obstructive Lung Disease website. Available at: www.goldcopd.org/GuidelineItem.asp?intId=989. Accessed Feb. 21, 2011.
2. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946.
3. Morbidity and mortality: 2009 chart book on cardiovascular, lung, and blood diseases. National Institutes of Health’s National Heart, Lung, and Blood Institute website. Available at: www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf. Accessed Feb. 24, 2011.
4. Albert RK, Martin TR, Lewis SW. Controlled trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med. 1980;92(6):753-758.
5. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340(25):1941-1947.
6. Thompson WH, Nielson C, Carvalho P, Charan NB, Crowley JJ. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med. 1996;154:407-412.
7. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1608-1613.
8. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet. 1999;354(9177):456-460.
9. Al-Habet S, Rogers HJ. Pharmacokinetics of intravenous and oral prednisolone. Br J Clin Pharmacol. 1980;10(5):503-508.
10. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J Emerg Med. 1992;10:301-310.
11. De Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: A randomized, controlled, double-blind study. Chest. 2007;132(6):1741-1747.
12. Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB. Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303(23):2359-2367.
13. Manser R, Reid D, Abramsom MJ. Corticosteroids for acute severe asthma in hospitalized patients. Cochrane Database Syst Rev. 2000;(2):CD001740.
14. Vondracek SF, Hemstreet BA. Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations of chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2006;63:645-652.
15. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. National Institute for Health and Clinical Excellence website. Available at: guidance.nice.org.uk/CG101/Guidance/pdf/English. Accessed Feb. 21, 2011.
16. O’Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2007 update. Can Respir J. 2007;14 Suppl B:5B-32B.
17. Webb J, Clark TJ. Recovery of plasma corticotrophin and cortisol levels after three-week course of prednisolone. Thorax. 1981;36:22-24.
18. O’Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Double-blind trial of steroid tapering in acute asthma. Lancet. 1993; 341:324-7.

click for large version

Case

A 66-year-old Caucasian female with moderate chronic obstructive pulmonary disease (COPD) (FEV1 55% predicted), obesity, hypertension, and Type 2 diabetes mellitus on insulin therapy presents to the ED with four days of increased cough productive of yellow sputum and progressive shortness of breath. Her physical exam is notable for an oxygen saturation of 87% on room air, along with diffuse expiratory wheezing with use of accessory muscles; her chest X-ray is unchanged from previous. The patient is given oxygen, nebulized bronchodilators, and one dose of IV methylprednisolone. Her symptoms do not improve significantly, and she is admitted for further management. What regimen of corticosteroids is most appropriate to treat her acute exacerbation of COPD?

Overview

COPD is the fourth-leading cause of death in the United States and continues to increase in prevalence.1 Acute exacerbations of COPD (AECOPD) contribute significantly to this high mortality rate, which approaches 40% at one year in those patients requiring mechanical support.¹ An exacerbation of COPD has been defined as an acute change in a patient’s baseline dyspnea, cough, and/or sputum beyond day-to-day variability sufficient to warrant a change in therapy.² Exacerbations commonly occur in COPD patients and often necessitate hospital admission. In fact, COPD consistently is one of the 10 most common reasons for hospitalization, with billions of dollars in associated healthcare costs.³

The goals for inpatient management of AECOPD are to provide acute symptom relief and to minimize the potential for subsequent exacerbations. These are accomplished via a multifaceted approach, including the use of bronchodilators, antibiotics, supplemental oxygen, noninvasive positive pressure ventilation in certain circumstances, and systemic corticosteroids.

The administration of systemic steroids in AECOPD has been prevalent for several decades, with initial studies showing positive effects on lung function, specifically FEV1.⁴ Studies have demonstrated the benefit of steroids in prolonging the time to subsequent exacerbation, reducing the rate of treatment failure, and reducing length of stay (LOS).⁵ Corticosteroids have since become an essential component of the standard of care in AECOPD management.

Despite consensus that systemic steroids should be used in COPD exacerbations, a great deal of controversy still surrounds the optimal steroid regimen.⁶ Steroid use is not without risk, as steroids can lead to adverse outcomes in medically complex hospitalized patients (see Table 1, below). Current guidelines provide limited guidance as to the optimal route of administration, dosing regimen, or length of therapy; clinical practice varies widely.

Review of the Data

Administration route: intravenous (IV) vs. oral. The use of steroids in AECOPD began with such IV formulations as methylprednisolone, and this became the typical method of treating hospitalized patients. This practice was validated in a multicenter Veterans Affairs trial, which demonstrated decreased risk of treatment failure (defined as all-cause mortality, need for intubation, readmission for COPD, or intensification of pharmacologic therapy) for patients randomized to receive an IV-to-oral steroid regimen compared with those randomized to placebo.5 Patients receiving steroids also had shorter LOS and improvements in FEV1 after the first day of treatment. Subsequent randomized controlled trials in patients with AECOPD demonstrated the benefit of oral regimens compared with placebo with regard to FEV1, LOS, and risk of treatment failure.^6,7,8

Similarities in the bioavailability of oral and IV steroids have been known for a long time.⁹ Comparisons in efficacy initially were completed in the management of acute asthma exacerbations, with increasing evidence, including a meta-analysis, demonstrating no difference in improvement in pulmonary function and in preventing relapse of exacerbations for oral compared with IV steroids.¹⁰ However, only recently have oral and IV steroids been compared in the treatment of AECOPD. De Jong et al randomized more than 200 patients hospitalized for AECOPD to 60 mg of either IV or oral prednisolone for five days, followed by a week of an oral taper.¹¹ There were no significant differences in treatment failure between the IV and oral groups (62% vs. 56%, respectively, at 90 days; one-sided lower bound of the 95% confidence interval [CI], −5.8%).

click for large version

A large observational study by Lindenauer et al, including nearly 80,000 AECOPD patients admitted at more than 400 hospitals, added further support to the idea that oral and IV steroids were comparable in efficacy.¹² In this study, multivariate analysis found no difference in treatment failure between oral and IV groups (odds ratio [OR] 0.93; 95% CI, 0.84-1.02). The authors also found, however, that current clinical practice still overwhelmingly favors intravenous steroids, with 92% of study patients initially being administered IV steroids.¹²

Based on the evidence from de Jong and Lindenauer, it appears that there is no significant benefit to the use of IV over oral steroids. Additionally, there is evidence for oral administration being associated with beneficial effects on cost and hospital LOS.¹² Oral steroids, therefore, are the preferred route of administration to treat a hospitalized patient with AECOPD, unless the patient is unable to tolerate oral medications. Current guidelines support the practice of giving oral steroids as first-line treatment for AECOPD (see Table 2, above).

High dose vs. low dose. Another important clinical issue concerns the dosing of steroids. The randomized trials examining the use of corticosteroids in AECOPD vary widely in the dosages studied. Further, the majority of these trials have compared steroids to placebo, rather than comparing different dosage regimens. The agents studied have included prednisone, prednisolone, methylprednisolone, and hydrocortisone, or combinations thereof. In order to compare regimens of these different drugs, steroid doses often are converted into prednisone equivalents (see Table 3, below). Though no guidelines define “high dose” and “low dose,” some studies have designated doses of >80 mg prednisone equivalents daily as high-dose and prednisone equivalents of ≤80 mg daily as low-dose.^13,14

click for large version

Starting doses of systemic corticosteroids in the treatment of AECOPD in clinical studies range from prednisone equivalents of 30 mg daily to 625 mg on the first day of treatment.^5,8 No randomized studies of high- versus low-dose steroid regimens have been conducted. One retrospective chart review of 145 AECOPD admissions evaluated outcomes among patients who were given higher (mean daily dose >80 mg prednisone equivalent) and lower (mean daily dose of ≤80 mg prednisone) doses.¹⁴ The authors found that patients who received higher doses of steroids had significantly longer LOS compared with those who received lower doses, especially among the subset of patients who were admitted to the floor rather than the ICU, though this analysis did not adjust for severity of illness. In this study, the most striking finding noted by the authors was the wide variability in the steroid doses prescribed for the inpatient treatment of AECOPD.

More recently, the study by Lindenauer et al examined outcomes between patients treated with high-dose IV steroids (equivalent of 120 mg-800 mg of prednisone on the first or second day of treatment) compared to low-dose oral steroids (prednisone equivalents of 20 mg-80 mg per day).¹² The authors found no differences between the two groups regarding the rate of treatment failure, defined by initiation of mechanical ventilation after the second hospital day, in-hospital mortality, or readmission for COPD within 30 days of discharge. After multivariate adjustment, including the propensity for oral treatment, the low-dose oral therapy group was found to have lower risk of treatment failure, shorter LOS, and lower total hospital cost.

Despite the heterogeneity of the published data and the lack of randomized trials, the existing evidence suggests that low-dose prednisone (or equivalent) is similar in efficacy to higher doses and generally is associated with shorter hospital stays. Recognizing these benefits, guidelines do favor initiating treatment with low-dose steroids in patients admitted with AECOPD. The most recent publications from the American Thoracic Society/European Respiratory Society Task Force (ATS/ERS), the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the National Clinical Guidelines Centre in the United Kingdom, and the Canadian Thoracic Society all recommend equivalent dosing of prednisone in patients admitted with AECOPD who are able to tolerate oral intake (see Table 2).^1,2,15,16

Duration. As with the dosing of systemic corticosteroids in AECOPD, the optimal duration of treatment is not well-established. National and international consensus panels vary in their recommendations, as outlined in Table 2. This may be related to the variability in length of treatment found in the literature.

Treatment durations ranging from one day to eight weeks have been studied in inpatients with AECOPD. The landmark randomized controlled trial by Niewoehner and colleagues compared two-week and eight-week courses of systemic corticosteroids and found no difference in the rates of treatment failure, which included death, need for mechanical ventilation, readmission for COPD, and intensification of pharmacologic therapy.⁵ Based on these results, many experts have concluded that there is no benefit to steroid courses lasting beyond two weeks.

Although improvements in outcomes have been demonstrated with corticosteroid regimens as short as three days compared with placebo, most of the randomized controlled trials have included courses of seven to 14 days.⁴ Given the risks of adverse events (e.g. hyperglycemia) that are associated with systemic administration of steroids, the shortest effective duration should be considered.

click for large version

In both clinical practice and clinical studies, steroid regimens often include a taper. A study by Vondracek and Hemstreet found that 79% of hospital discharges for AECOPD included a tapered corticosteroid regimen.¹⁴ From a physiologic standpoint, durations of corticosteroid treatment approximately three weeks or less, regardless of dosage, should not lead to adrenal suppression.¹⁷ There also is no evidence to suggest that abrupt discontinuation of steroids leads to clinical worsening of disease, and complicated steroid tapers are a potential source of medication errors after hospital discharge.¹⁸ Furthermore, the clinical guidelines do not address the tapering of corticosteroids. Therefore, there is a lack of evidence advocating for or against the use of tapered steroid regimens in AECOPD.

Back to the Case

In addition to standard treatment modalities for AECOPD, our patient was administered oral prednisone 40 mg daily. She experienced steroid-induced hyperglycemia, which was corrected with adjustment of her insulin regimen. The patient’s pulmonary symptoms improved within 72 hours, and she was discharged home on hospital day four to complete a seven-day steroid course. At hospital discharge, she was administered influenza and pneumococcal vaccinations, and she was instructed to resume her usual insulin dosing once she finished her prednisone course.

Overview

In the management of AECOPD, there remains a lack of consensus in defining the ideal steroid regimen. Based on current literature, the use of low-dose oral corticosteroids, such as prednisone 40 mg daily, for a seven- to 14-day course is recommended. TH

Dr. Cunningham is an assistant professor of internal medicine and academic hospitalist in the section of hospital medicine at Vanderbilt University School of Medicine in Nashville, Tenn. Dr. LaBrin is an assistant professor of internal medicine and pediatrics and academic hospitalist at Vanderbilt University School of Medicine.

References

1. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2010. Global Initiative for Chronic Obstructive Lung Disease website. Available at: www.goldcopd.org/GuidelineItem.asp?intId=989. Accessed Feb. 21, 2011.
2. Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946.
3. Morbidity and mortality: 2009 chart book on cardiovascular, lung, and blood diseases. National Institutes of Health’s National Heart, Lung, and Blood Institute website. Available at: www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf. Accessed Feb. 24, 2011.
4. Albert RK, Martin TR, Lewis SW. Controlled trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med. 1980;92(6):753-758.
5. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340(25):1941-1947.
6. Thompson WH, Nielson C, Carvalho P, Charan NB, Crowley JJ. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med. 1996;154:407-412.
7. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161:1608-1613.
8. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet. 1999;354(9177):456-460.
9. Al-Habet S, Rogers HJ. Pharmacokinetics of intravenous and oral prednisolone. Br J Clin Pharmacol. 1980;10(5):503-508.
10. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbations of asthma: a meta-analysis. Am J Emerg Med. 1992;10:301-310.
11. De Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: A randomized, controlled, double-blind study. Chest. 2007;132(6):1741-1747.
12. Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB. Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303(23):2359-2367.
13. Manser R, Reid D, Abramsom MJ. Corticosteroids for acute severe asthma in hospitalized patients. Cochrane Database Syst Rev. 2000;(2):CD001740.
14. Vondracek SF, Hemstreet BA. Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations of chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2006;63:645-652.
15. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. National Institute for Health and Clinical Excellence website. Available at: guidance.nice.org.uk/CG101/Guidance/pdf/English. Accessed Feb. 21, 2011.
16. O’Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2007 update. Can Respir J. 2007;14 Suppl B:5B-32B.
17. Webb J, Clark TJ. Recovery of plasma corticotrophin and cortisol levels after three-week course of prednisolone. Thorax. 1981;36:22-24.
18. O’Driscoll BR, Kalra S, Wilson M, Pickering CA, Carroll KB, Woodcock AA. Double-blind trial of steroid tapering in acute asthma. Lancet. 1993; 341:324-7.

Case

A 58-year-old woman with diabetes mellitus and hypertension presents with dysarthria and weakness on the right side of her body starting six hours prior to presentation. She is afebrile and has a blood pressure of 162/84 mmHg. Exam reveals the absence of a heart murmur and no lower-extremity swelling or calf tenderness. There is weakness of the right side of the body on exam with diminished proprioception. A noncontrast head CT shows no intracranial hemorrhage. She is admitted to the hospital with the diagnosis of acute ischemic stroke. What anticlotting or antiplatelet medications should she receive?

Overview

Stroke remains a significant cause of morbidity and mortality in the U.S. and around the world. The majority of strokes are ischemic in etiology. Although thrombolytic therapy is the most effective way to salvage ischemic brain tissue that has not yet infarcted, there is a narrow window for the use of thrombolytics in the treatment of acute ischemic stroke. As a result, many patients will not be eligible for thrombolysis. Outside of 4.5 hours from symptom onset, evidence suggests that the risk outweighs the benefit of using the thrombolytic alteplase. For patients ineligible for thrombolytic therapy, antiplatelet therapy remains the best choice for treatment.

Medications that prevent blood from coagulating or clotting are used to treat and prevent a recurring or second stroke. Typically, an antiplatelet agent (most often aspirin) is initiated within 48 hours of an ischemic stroke and continued in low doses as maintenance. Multiple studies suggest that antiplatelet therapy can reduce the risk for a second stroke by 25%. Specific anticlotting agents might be warranted in some patients with high-risk conditions for a stroke.

Review of Data

Early initiation of aspirin has shown benefit in the treatment of an acute ischemic stroke. Two major trials—the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST)— evaluated the role of aspirin (see Table 1, p. 15).^1,2 The IST and CAST trials showed that roughly nine nonfatal strokes were avoided per every 1,000 early treatments. Taking the endpoint of death, as well as focal deficits, the two trials confirmed a rate of reduction of 13 per 1,000 patients.

Overall, the consensus was that initiating aspirin within 48 hours of a presumed ischemic cerebrovascular accident posed no major risk of hemorrhagic complication and improved the long-term outcomes.

Along with aspirin, other antiplatelet agents have been studied, most commonly dipyridamole and clopidrogel. The EARLY trial demonstrated no significant differences in the aspirin and dipyridamole groups at 90 days.³

Another large trial, which focused on clopidrogel and aspirin, looked at aspirin plus clopidrogel or aspirin alone. The FASTER trial enrolled mostly patients with mild cerebrovasular accidents (CVA) or transient ischemic attacks (TIA), and there was no difference in outcome measures between the groups.⁴ However, the MATCH trial found that aspirin and clopidrogel did not provide improved stroke preventions versus clopidogrel alone but had a larger risk of hemorrhagic/bleeding complications.⁵

Aspirin dosage is somewhat controversial. Fewer side effects occur with lower doses. Combining the trials, consensus treatment includes early aspirin dosing (325 mg initially, then 150 mg-325 mg daily) given to patients with ischemic stroke. Early aspirin should be avoided in those patients who qualify for and are receiving alteplase, heparin, or oral warfarin therapy.

There are other antiplatelet agents for long-term management of ischemic stroke. Whereas aspirin alone is used in the early management of acute ischemic stroke in those ineligible for thrombolytic therapy, many patients are transitioned to other antiplatelet strategies for secondary prevention long-term. The number needed to treat for aspirin to reduce one future stroke, myocardial infarction (MI), or vascular death when compared to placebo is quite high at 33. However, the combination of aspirin and dipyradimole does not prevent MI, vascular death, or the combined endpoint of either stroke or death.

click for large version

Clopidogrel is more effective than aspirin in preventing a combined endpoint of ischemic stroke, MI, or vascular death, but it is not superior to aspirin in preventing recurrent stroke in TIA or stroke patients. The effects of clopidrogel are greater in patients with peripheral arterial disease, previous coronary artery bypass grafting, insulin-dependent diabetes, or recurrent vascular events.

There is a substantially high cost of treatment and long-term disability associated with stroke. Costs can vary from 3% to 5% of the annual healthcare budget. The newer antiplatelet agents are more expensive than aspirin, and overall cost-effectiveness is difficult to estimate. Yet, from an economic standpoint, the combination of aspirin and dipyradimole can be recommended as an alternative for secondary stroke prevention in patients without major comorbidities. In those patients with higher risk factors and/or comorbidities, clopidogrel might be more cost-effective than aspirin alone. Furthermore, in patients with aspirin intolerance, clopidogrel is a useful, but expensive, alternative.

Thrombolytic therapy. Restora-tion of blood flow with thrombolytic therapy is the most effective way of salvaging ischemic brain tissue that has not already infarcted. The window for use of the thrombolytic alteplase is narrow; studies suggest that its benefit diminishes with increasing time to treatment. Indeed, after 4.5 hours from the onset of symptoms, evidence suggests that the harm might outweigh the benefit, so the determination of who is eligible for its use has to be made quickly.

Guidelines published by the American Heart Association/American Stoke Association stroke council outline strict inclusion and exclusion criteria for the use of alteplase in the management of acute ischemic stroke.⁶ Obtaining informed consent and emergent neuroimaging are vital in preventing delays in alteplase administration.

Two major trials that illustrate the benefit of alteplase in the treatment of acute ischemic stroke are the NINDS trial and the ECASS 3 trial. NINDS showed that when intravenous alteplase was used within three hours of symptom onset, patients had improved functional outcome at three months.⁷ The ECASS 3 trial showed that intravenous alteplase has benefit when given up to 4.5 hours after symptom onset.⁸ Treatment with intravenous alteplase from three-4.5 hours in the ECASS 3 trial showed a modest improvement in patient outcomes at three months, with a number needed to treat of 14 for a favorable outcome.

click for large version

A 2010 meta-analysis looked specifically at outcomes in stroke based on time to treat with alteplase using pooled data from the NINDS, ATLANTIS, ECASS (1, 2, and 3), and EPITHET trials.⁹ It showed that the number needed to treat for a favorable outcome at three months increased steadily when time to treatment was delayed. It also showed that the risk of death after alteplase administration increased significantly after 4.5 hours. Thus, after 4.5 hours, it suggests that harm might exceed the benefits of treatment.

Anticoagulant use in ischemic stroke. Clinical trials have not been effective in demonstrating the use of heparin and low-molecular-weight heparins (LMWHs). A 2008 systematic review of 24 trials (approximately 24,000 patients) demonstrated:

• Anticoagulant therapy did not reduce odds of death;
• Therapy was associated with nine fewer recurrent ischemic strokes per 1,000 patients, but also showed a similar increase in symptomatic intracranial hemorrhages; and
• Overall, researchers could not specify a particular anticoagulant mode or regimen that had an overall net patient benefit.

The use of heparin in atrial fibrillation and stroke has generated controversy in recent years. Review of the data, however, indicates that early treatment with heparin might cause more harm than benefit. A 2007 meta-analysis did not support the use of early anticoagulant therapy. Seven trials (4,200 patients) compared heparin or LMWH started within 48 hours to other treatments (aspirin, placebo). The study authors found:

• Nonsignificant reduction in recurrent ischemic stroke within seven to 14 days;
• Statistically significant increase in symptomatic intracranial hemorrhages; and
• Similar rates of death/disability at final follow-up of studies.

click for large version

For those patients who continue to demonstrate neurological deterioration, heparin and LMWH use did not appear to improve outcomes. Therefore, based on a consensus of national guidelines, the use of full-dose anticoagulation with heparin or LMWH is not recommended.

The data suggest that in patients with stroke secondary to:

• Dissection of cervical or intracranial arteries;
• Intracardiac thrombus and valvular disease; and
• Mechanical heart valves, full-dose anticoagulation can be initiated. However, the benefit is unproven.

Back to the Case

Our patient with acute ischemic stroke with right-sided weakness on exam presented outside of the window within which alteplase could be administered safely. She was started on aspirin 325 mg daily. There was no indication for full anticoagulation with intravenous heparin or warfarin. Her weakness showed slight improvement on exam during the hospitalization. As an insulin-dependent diabetic, she was thought to be at high risk for recurrent stroke. As such, she was transitioned to a combination of aspirin and clopidogrel prior to her discharge to an acute inpatient rehabilitation hospital.

Bottom Line

Early aspirin therapy (within 48 hours) is recommended (initial dose 325 mg, then 150 mg-325 mg daily) for patients with ischemic stroke who are not candidates for alteplase, IV heparin, or oral anticoagulants.¹⁰ Aspirin is the only antiplatelet agent that has been shown to be effective for the early treatment of acute ischemic stroke. In patients without contraindications, aspirin, the combination of aspirin-dipyradimole, or clopidogrel is appropriate for secondary prevention.

The subset of patients at high risk of recurrent stroke should be transitioned to clopidogrel or aspirin/clopidogrel, unless otherwise contraindicated. TH

Dr. Chaturvedi is an instructor in the Division of Hospital Medicine at Northwestern University’s Feinberg School of Medicine in Chicago, and medical director of HM at Northwestern Lake Forest Hospital. Dr. Abraham is an instructor in the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine.

References

1. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-1581.
2. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997;349:1641-1649.
3. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9:159-166.
4. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6:961-969.
5. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.
6. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655-1711.
7. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695-1703.
8. Hacke W, Kaste M, Bluhmki E, et al. Thombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329.
9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.
10. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:630S-669S.

Case

A 58-year-old woman with diabetes mellitus and hypertension presents with dysarthria and weakness on the right side of her body starting six hours prior to presentation. She is afebrile and has a blood pressure of 162/84 mmHg. Exam reveals the absence of a heart murmur and no lower-extremity swelling or calf tenderness. There is weakness of the right side of the body on exam with diminished proprioception. A noncontrast head CT shows no intracranial hemorrhage. She is admitted to the hospital with the diagnosis of acute ischemic stroke. What anticlotting or antiplatelet medications should she receive?

Overview

Stroke remains a significant cause of morbidity and mortality in the U.S. and around the world. The majority of strokes are ischemic in etiology. Although thrombolytic therapy is the most effective way to salvage ischemic brain tissue that has not yet infarcted, there is a narrow window for the use of thrombolytics in the treatment of acute ischemic stroke. As a result, many patients will not be eligible for thrombolysis. Outside of 4.5 hours from symptom onset, evidence suggests that the risk outweighs the benefit of using the thrombolytic alteplase. For patients ineligible for thrombolytic therapy, antiplatelet therapy remains the best choice for treatment.

Medications that prevent blood from coagulating or clotting are used to treat and prevent a recurring or second stroke. Typically, an antiplatelet agent (most often aspirin) is initiated within 48 hours of an ischemic stroke and continued in low doses as maintenance. Multiple studies suggest that antiplatelet therapy can reduce the risk for a second stroke by 25%. Specific anticlotting agents might be warranted in some patients with high-risk conditions for a stroke.

Review of Data

Early initiation of aspirin has shown benefit in the treatment of an acute ischemic stroke. Two major trials—the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST)— evaluated the role of aspirin (see Table 1, p. 15).^1,2 The IST and CAST trials showed that roughly nine nonfatal strokes were avoided per every 1,000 early treatments. Taking the endpoint of death, as well as focal deficits, the two trials confirmed a rate of reduction of 13 per 1,000 patients.

Overall, the consensus was that initiating aspirin within 48 hours of a presumed ischemic cerebrovascular accident posed no major risk of hemorrhagic complication and improved the long-term outcomes.

Along with aspirin, other antiplatelet agents have been studied, most commonly dipyridamole and clopidrogel. The EARLY trial demonstrated no significant differences in the aspirin and dipyridamole groups at 90 days.³

Another large trial, which focused on clopidrogel and aspirin, looked at aspirin plus clopidrogel or aspirin alone. The FASTER trial enrolled mostly patients with mild cerebrovasular accidents (CVA) or transient ischemic attacks (TIA), and there was no difference in outcome measures between the groups.⁴ However, the MATCH trial found that aspirin and clopidrogel did not provide improved stroke preventions versus clopidogrel alone but had a larger risk of hemorrhagic/bleeding complications.⁵

Aspirin dosage is somewhat controversial. Fewer side effects occur with lower doses. Combining the trials, consensus treatment includes early aspirin dosing (325 mg initially, then 150 mg-325 mg daily) given to patients with ischemic stroke. Early aspirin should be avoided in those patients who qualify for and are receiving alteplase, heparin, or oral warfarin therapy.

There are other antiplatelet agents for long-term management of ischemic stroke. Whereas aspirin alone is used in the early management of acute ischemic stroke in those ineligible for thrombolytic therapy, many patients are transitioned to other antiplatelet strategies for secondary prevention long-term. The number needed to treat for aspirin to reduce one future stroke, myocardial infarction (MI), or vascular death when compared to placebo is quite high at 33. However, the combination of aspirin and dipyradimole does not prevent MI, vascular death, or the combined endpoint of either stroke or death.

click for large version

Clopidogrel is more effective than aspirin in preventing a combined endpoint of ischemic stroke, MI, or vascular death, but it is not superior to aspirin in preventing recurrent stroke in TIA or stroke patients. The effects of clopidrogel are greater in patients with peripheral arterial disease, previous coronary artery bypass grafting, insulin-dependent diabetes, or recurrent vascular events.

There is a substantially high cost of treatment and long-term disability associated with stroke. Costs can vary from 3% to 5% of the annual healthcare budget. The newer antiplatelet agents are more expensive than aspirin, and overall cost-effectiveness is difficult to estimate. Yet, from an economic standpoint, the combination of aspirin and dipyradimole can be recommended as an alternative for secondary stroke prevention in patients without major comorbidities. In those patients with higher risk factors and/or comorbidities, clopidogrel might be more cost-effective than aspirin alone. Furthermore, in patients with aspirin intolerance, clopidogrel is a useful, but expensive, alternative.

Thrombolytic therapy. Restora-tion of blood flow with thrombolytic therapy is the most effective way of salvaging ischemic brain tissue that has not already infarcted. The window for use of the thrombolytic alteplase is narrow; studies suggest that its benefit diminishes with increasing time to treatment. Indeed, after 4.5 hours from the onset of symptoms, evidence suggests that the harm might outweigh the benefit, so the determination of who is eligible for its use has to be made quickly.

Guidelines published by the American Heart Association/American Stoke Association stroke council outline strict inclusion and exclusion criteria for the use of alteplase in the management of acute ischemic stroke.⁶ Obtaining informed consent and emergent neuroimaging are vital in preventing delays in alteplase administration.

Two major trials that illustrate the benefit of alteplase in the treatment of acute ischemic stroke are the NINDS trial and the ECASS 3 trial. NINDS showed that when intravenous alteplase was used within three hours of symptom onset, patients had improved functional outcome at three months.⁷ The ECASS 3 trial showed that intravenous alteplase has benefit when given up to 4.5 hours after symptom onset.⁸ Treatment with intravenous alteplase from three-4.5 hours in the ECASS 3 trial showed a modest improvement in patient outcomes at three months, with a number needed to treat of 14 for a favorable outcome.

click for large version

A 2010 meta-analysis looked specifically at outcomes in stroke based on time to treat with alteplase using pooled data from the NINDS, ATLANTIS, ECASS (1, 2, and 3), and EPITHET trials.⁹ It showed that the number needed to treat for a favorable outcome at three months increased steadily when time to treatment was delayed. It also showed that the risk of death after alteplase administration increased significantly after 4.5 hours. Thus, after 4.5 hours, it suggests that harm might exceed the benefits of treatment.

Anticoagulant use in ischemic stroke. Clinical trials have not been effective in demonstrating the use of heparin and low-molecular-weight heparins (LMWHs). A 2008 systematic review of 24 trials (approximately 24,000 patients) demonstrated:

• Anticoagulant therapy did not reduce odds of death;
• Therapy was associated with nine fewer recurrent ischemic strokes per 1,000 patients, but also showed a similar increase in symptomatic intracranial hemorrhages; and
• Overall, researchers could not specify a particular anticoagulant mode or regimen that had an overall net patient benefit.

The use of heparin in atrial fibrillation and stroke has generated controversy in recent years. Review of the data, however, indicates that early treatment with heparin might cause more harm than benefit. A 2007 meta-analysis did not support the use of early anticoagulant therapy. Seven trials (4,200 patients) compared heparin or LMWH started within 48 hours to other treatments (aspirin, placebo). The study authors found:

• Nonsignificant reduction in recurrent ischemic stroke within seven to 14 days;
• Statistically significant increase in symptomatic intracranial hemorrhages; and
• Similar rates of death/disability at final follow-up of studies.

click for large version

For those patients who continue to demonstrate neurological deterioration, heparin and LMWH use did not appear to improve outcomes. Therefore, based on a consensus of national guidelines, the use of full-dose anticoagulation with heparin or LMWH is not recommended.

The data suggest that in patients with stroke secondary to:

• Dissection of cervical or intracranial arteries;
• Intracardiac thrombus and valvular disease; and
• Mechanical heart valves, full-dose anticoagulation can be initiated. However, the benefit is unproven.

Back to the Case

Our patient with acute ischemic stroke with right-sided weakness on exam presented outside of the window within which alteplase could be administered safely. She was started on aspirin 325 mg daily. There was no indication for full anticoagulation with intravenous heparin or warfarin. Her weakness showed slight improvement on exam during the hospitalization. As an insulin-dependent diabetic, she was thought to be at high risk for recurrent stroke. As such, she was transitioned to a combination of aspirin and clopidogrel prior to her discharge to an acute inpatient rehabilitation hospital.

Bottom Line

Early aspirin therapy (within 48 hours) is recommended (initial dose 325 mg, then 150 mg-325 mg daily) for patients with ischemic stroke who are not candidates for alteplase, IV heparin, or oral anticoagulants.¹⁰ Aspirin is the only antiplatelet agent that has been shown to be effective for the early treatment of acute ischemic stroke. In patients without contraindications, aspirin, the combination of aspirin-dipyradimole, or clopidogrel is appropriate for secondary prevention.

The subset of patients at high risk of recurrent stroke should be transitioned to clopidogrel or aspirin/clopidogrel, unless otherwise contraindicated. TH

Dr. Chaturvedi is an instructor in the Division of Hospital Medicine at Northwestern University’s Feinberg School of Medicine in Chicago, and medical director of HM at Northwestern Lake Forest Hospital. Dr. Abraham is an instructor in the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine.

References

1. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-1581.
2. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997;349:1641-1649.
3. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9:159-166.
4. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6:961-969.
5. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.
6. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655-1711.
7. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695-1703.
8. Hacke W, Kaste M, Bluhmki E, et al. Thombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329.
9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.
10. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:630S-669S.

Case

A 58-year-old woman with diabetes mellitus and hypertension presents with dysarthria and weakness on the right side of her body starting six hours prior to presentation. She is afebrile and has a blood pressure of 162/84 mmHg. Exam reveals the absence of a heart murmur and no lower-extremity swelling or calf tenderness. There is weakness of the right side of the body on exam with diminished proprioception. A noncontrast head CT shows no intracranial hemorrhage. She is admitted to the hospital with the diagnosis of acute ischemic stroke. What anticlotting or antiplatelet medications should she receive?

Overview

Stroke remains a significant cause of morbidity and mortality in the U.S. and around the world. The majority of strokes are ischemic in etiology. Although thrombolytic therapy is the most effective way to salvage ischemic brain tissue that has not yet infarcted, there is a narrow window for the use of thrombolytics in the treatment of acute ischemic stroke. As a result, many patients will not be eligible for thrombolysis. Outside of 4.5 hours from symptom onset, evidence suggests that the risk outweighs the benefit of using the thrombolytic alteplase. For patients ineligible for thrombolytic therapy, antiplatelet therapy remains the best choice for treatment.

Medications that prevent blood from coagulating or clotting are used to treat and prevent a recurring or second stroke. Typically, an antiplatelet agent (most often aspirin) is initiated within 48 hours of an ischemic stroke and continued in low doses as maintenance. Multiple studies suggest that antiplatelet therapy can reduce the risk for a second stroke by 25%. Specific anticlotting agents might be warranted in some patients with high-risk conditions for a stroke.

Review of Data

Early initiation of aspirin has shown benefit in the treatment of an acute ischemic stroke. Two major trials—the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST)— evaluated the role of aspirin (see Table 1, p. 15).^1,2 The IST and CAST trials showed that roughly nine nonfatal strokes were avoided per every 1,000 early treatments. Taking the endpoint of death, as well as focal deficits, the two trials confirmed a rate of reduction of 13 per 1,000 patients.

Overall, the consensus was that initiating aspirin within 48 hours of a presumed ischemic cerebrovascular accident posed no major risk of hemorrhagic complication and improved the long-term outcomes.

Along with aspirin, other antiplatelet agents have been studied, most commonly dipyridamole and clopidrogel. The EARLY trial demonstrated no significant differences in the aspirin and dipyridamole groups at 90 days.³

Another large trial, which focused on clopidrogel and aspirin, looked at aspirin plus clopidrogel or aspirin alone. The FASTER trial enrolled mostly patients with mild cerebrovasular accidents (CVA) or transient ischemic attacks (TIA), and there was no difference in outcome measures between the groups.⁴ However, the MATCH trial found that aspirin and clopidrogel did not provide improved stroke preventions versus clopidogrel alone but had a larger risk of hemorrhagic/bleeding complications.⁵

Aspirin dosage is somewhat controversial. Fewer side effects occur with lower doses. Combining the trials, consensus treatment includes early aspirin dosing (325 mg initially, then 150 mg-325 mg daily) given to patients with ischemic stroke. Early aspirin should be avoided in those patients who qualify for and are receiving alteplase, heparin, or oral warfarin therapy.

There are other antiplatelet agents for long-term management of ischemic stroke. Whereas aspirin alone is used in the early management of acute ischemic stroke in those ineligible for thrombolytic therapy, many patients are transitioned to other antiplatelet strategies for secondary prevention long-term. The number needed to treat for aspirin to reduce one future stroke, myocardial infarction (MI), or vascular death when compared to placebo is quite high at 33. However, the combination of aspirin and dipyradimole does not prevent MI, vascular death, or the combined endpoint of either stroke or death.

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Clopidogrel is more effective than aspirin in preventing a combined endpoint of ischemic stroke, MI, or vascular death, but it is not superior to aspirin in preventing recurrent stroke in TIA or stroke patients. The effects of clopidrogel are greater in patients with peripheral arterial disease, previous coronary artery bypass grafting, insulin-dependent diabetes, or recurrent vascular events.

There is a substantially high cost of treatment and long-term disability associated with stroke. Costs can vary from 3% to 5% of the annual healthcare budget. The newer antiplatelet agents are more expensive than aspirin, and overall cost-effectiveness is difficult to estimate. Yet, from an economic standpoint, the combination of aspirin and dipyradimole can be recommended as an alternative for secondary stroke prevention in patients without major comorbidities. In those patients with higher risk factors and/or comorbidities, clopidogrel might be more cost-effective than aspirin alone. Furthermore, in patients with aspirin intolerance, clopidogrel is a useful, but expensive, alternative.

Thrombolytic therapy. Restora-tion of blood flow with thrombolytic therapy is the most effective way of salvaging ischemic brain tissue that has not already infarcted. The window for use of the thrombolytic alteplase is narrow; studies suggest that its benefit diminishes with increasing time to treatment. Indeed, after 4.5 hours from the onset of symptoms, evidence suggests that the harm might outweigh the benefit, so the determination of who is eligible for its use has to be made quickly.

Guidelines published by the American Heart Association/American Stoke Association stroke council outline strict inclusion and exclusion criteria for the use of alteplase in the management of acute ischemic stroke.⁶ Obtaining informed consent and emergent neuroimaging are vital in preventing delays in alteplase administration.

Two major trials that illustrate the benefit of alteplase in the treatment of acute ischemic stroke are the NINDS trial and the ECASS 3 trial. NINDS showed that when intravenous alteplase was used within three hours of symptom onset, patients had improved functional outcome at three months.⁷ The ECASS 3 trial showed that intravenous alteplase has benefit when given up to 4.5 hours after symptom onset.⁸ Treatment with intravenous alteplase from three-4.5 hours in the ECASS 3 trial showed a modest improvement in patient outcomes at three months, with a number needed to treat of 14 for a favorable outcome.

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A 2010 meta-analysis looked specifically at outcomes in stroke based on time to treat with alteplase using pooled data from the NINDS, ATLANTIS, ECASS (1, 2, and 3), and EPITHET trials.⁹ It showed that the number needed to treat for a favorable outcome at three months increased steadily when time to treatment was delayed. It also showed that the risk of death after alteplase administration increased significantly after 4.5 hours. Thus, after 4.5 hours, it suggests that harm might exceed the benefits of treatment.

Anticoagulant use in ischemic stroke. Clinical trials have not been effective in demonstrating the use of heparin and low-molecular-weight heparins (LMWHs). A 2008 systematic review of 24 trials (approximately 24,000 patients) demonstrated:

• Anticoagulant therapy did not reduce odds of death;
• Therapy was associated with nine fewer recurrent ischemic strokes per 1,000 patients, but also showed a similar increase in symptomatic intracranial hemorrhages; and
• Overall, researchers could not specify a particular anticoagulant mode or regimen that had an overall net patient benefit.

The use of heparin in atrial fibrillation and stroke has generated controversy in recent years. Review of the data, however, indicates that early treatment with heparin might cause more harm than benefit. A 2007 meta-analysis did not support the use of early anticoagulant therapy. Seven trials (4,200 patients) compared heparin or LMWH started within 48 hours to other treatments (aspirin, placebo). The study authors found:

• Nonsignificant reduction in recurrent ischemic stroke within seven to 14 days;
• Statistically significant increase in symptomatic intracranial hemorrhages; and
• Similar rates of death/disability at final follow-up of studies.

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For those patients who continue to demonstrate neurological deterioration, heparin and LMWH use did not appear to improve outcomes. Therefore, based on a consensus of national guidelines, the use of full-dose anticoagulation with heparin or LMWH is not recommended.

The data suggest that in patients with stroke secondary to:

• Dissection of cervical or intracranial arteries;
• Intracardiac thrombus and valvular disease; and
• Mechanical heart valves, full-dose anticoagulation can be initiated. However, the benefit is unproven.

Back to the Case

Our patient with acute ischemic stroke with right-sided weakness on exam presented outside of the window within which alteplase could be administered safely. She was started on aspirin 325 mg daily. There was no indication for full anticoagulation with intravenous heparin or warfarin. Her weakness showed slight improvement on exam during the hospitalization. As an insulin-dependent diabetic, she was thought to be at high risk for recurrent stroke. As such, she was transitioned to a combination of aspirin and clopidogrel prior to her discharge to an acute inpatient rehabilitation hospital.

Bottom Line

Early aspirin therapy (within 48 hours) is recommended (initial dose 325 mg, then 150 mg-325 mg daily) for patients with ischemic stroke who are not candidates for alteplase, IV heparin, or oral anticoagulants.¹⁰ Aspirin is the only antiplatelet agent that has been shown to be effective for the early treatment of acute ischemic stroke. In patients without contraindications, aspirin, the combination of aspirin-dipyradimole, or clopidogrel is appropriate for secondary prevention.

The subset of patients at high risk of recurrent stroke should be transitioned to clopidogrel or aspirin/clopidogrel, unless otherwise contraindicated. TH

Dr. Chaturvedi is an instructor in the Division of Hospital Medicine at Northwestern University’s Feinberg School of Medicine in Chicago, and medical director of HM at Northwestern Lake Forest Hospital. Dr. Abraham is an instructor in the Division of Hospital Medicine at Northwestern University Feinberg School of Medicine.

References

1. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997;349:1569-1581.
2. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet. 1997;349:1641-1649.
3. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9:159-166.
4. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6:961-969.
5. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.
6. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655-1711.
7. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695-1703.
8. Hacke W, Kaste M, Bluhmki E, et al. Thombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329.
9. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.
10. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:630S-669S.

Case

A 54-year-old man with end-stage liver disease (ESLD) and no prior history of spontaneous bacterial peritonitis (SBP) presents with increasing shortness of breath and abdominal distention. He is admitted for worsening volume overload. The patient reveals that he has not been compliant with his diuretics. On the day of admission, a large-volume paracentesis is performed. Results are significant for a white blood cell count of 150 cells/mm3 and a total protein of 0.9 g/ul. The patient is started on furosemide and spironolactone, and his symptoms significantly improve throughout his hospitalization. His medications are reconciled on the day of discharge. He is not on any antibiotics for SBP prophylaxis; should he be? In general, which patients with ascites should receive SBP prophylaxis?

Overview

Spontaneous bacterial peritonitis is an infection of ascitic fluid that occurs in the absence of an indentified intra-abdominal source of infection or inflammation, i.e., perforation or abscess.¹ It is diagnosed when the polymorphonuclear cell (PMN) count in the ascitic fluid is equal to or greater than 250 cells/mm3, with or without positive cultures.

SBP is a significant cause of morbidity and mortality in patients with cirrhosis, with the mortality rate approaching 20% to 40%.2 Of the 32% to 34% of cirrhotic patients who present with, or develop, a bacterial infection during their hospitalization, 25% are due to SBP.¹ Changes in gut motility, mucosal defense, and microflora allow for translocation of bacteria into enteric lymph nodes and the bloodstream, resulting in seeding of the peritoneal fluid and SBP.¹ Alterations in both systemic and localized immune defenses, both of which are reduced in patients with liver disease, also play a role in SBP pathogenesis (see Table 1, p. 41).

Current evidence supports the use of a third-generation cephalosporin or amoxicillin/clavulanate for initial treatment of SBP, as most infections are caused by gram-negative bacilli, in particular E. coli (see Table 2 on p. 41 and Table 3 on p. 42).1 Alternatively, an oral or intravenous fluoroquinolone could be used if the prevalence of fluoroquinolone-resistant organisms is low.¹

Due to the frequency and morbidity associated with SBP, there is great interest in preventing it. However, the use of prophylactic antibiotics needs to be restricted to patients who are at highest risk of developing SBP. According to numerous studies, patients at high risk for SBP include:

1. Patients with a prior SBP history;
2. Patients admitted with a gastrointestinal bleed; and
3. Patients with low total protein content in their ascitic fluid (defined as <1.5 g/ul).¹

SBP History

Spontaneous bacterial peritonitis portends bad outcomes. The one-year mortality rate after an episode of SBP is 30% to 50%.1 Furthermore, patients who have recovered from a previous episode of SBP have a 70% chance of developing another episode of SBP in that year.^1,2 In one study, norfloxacin was shown to decrease the one-year risk of SBP to 20% from 68% in patients with a history of SBP.³ Additionally, the likelihood of developing SBP from gram-negative bacilli was reduced to 3% from 60%. In order to be efficacious, norfloxacin must be given daily. When fluoroquinolones are prescribed less than once daily, there is a higher rate of fluoroquinolone resistant organisms in the stool.¹

Though once-daily dosing of norfloxacin is recommended to decrease the promotion of resistant organisms in prophylaxis against SBP, ciprofloxacin once weekly is acceptable. In a group of patients with low ascitic protein content, with or without a history of SBP, weekly ciprofloxacin has been shown to decrease SBP incidence to 4% from 22% at six months.⁴ In regard to length of treatment, recommendations are to continue prophylactic antibiotics until resolution of ascites, the patient receives a transplant, or the patient passes away.¹

Saab et al studied the impact of oral antibiotic prophylaxis in patients with advanced liver disease on morbidity and mortality.5 The authors examined prospective, randomized, controlled trials that compared high-risk cirrhotic patients receiving oral antibiotic prophylaxis for SBP with groups receiving placebo or no intervention. Eight studies totaling 647 patients were included in the analysis.

The overall mortality rate for patients treated with SBP prophylaxis was 16%, compared with 25% for the control group. Groups treated with prophylactic antibiotics also had a lower incidence of all infections (6.2% vs. 22.2% in the control groups). Additionally, a survival benefit was seen at three months in the group that received prophylactic antibiotics.

The absolute risk reduction with prophylactic antibiotics for primary prevention of SBP was 8% with a number needed to treat of 13. The incidence of gastrointestinal (GI) bleeding, renal failure, and hepatic failure did not significantly differ between treatment and control groups. Thus, survival benefit is thought to be related to the reduced incidence of infections in the group receiving prophylactic antibiotics.⁵

History of GI Bleeding

The incidence of developing SBP in cirrhotics with an active GI bleed is anywhere from 20% to 45%.^1,2 For those with ascites of any etiology and a GI bleed, the incidence can be as high as 60%.⁵ In general, bacterial infections are frequently diagnosed in patients with cirrhosis and GI bleeding, and have been documented in 22% of these patients within the first 48 hours after admission. According to several studies, that percentage can reach as high as 35% to 66% within seven to 14 days of admission.⁶ A seven-day course of antibiotics, or antibiotics until discharge, is generally acceptable for SBP prophylaxis in the setting of ascites and GI bleeding (see Table 2, right).¹

Bernard et al performed a meta-analysis of five trials to assess the efficacy of antibiotic prophylaxis in the prevention of infections and effect on survival in patients with cirrhosis and GI bleeding. Out of 534 patients, 264 were treated with antibiotics between four and 10 days, and 270 did not receive any antibiotics.

The endpoints of the study were infection, bacteremia and/or SBP; incidence of SBP; and death. Antibiotic prophylaxis not only increased the mean survival rate by 9.1%, but also increased the mean percentage of patients free of infection (32% improvement); bacteremia and/or SBP (19% improvement); and SBP (7% improvement).⁷

Low Ascitic Fluid Protein

Of the three major risk factors for SBP, ascitic fluid protein content is the most debated. Guarner et al studied the risk of first community-acquired SBP in cirrhotics with low ascitic fluid protein.² Patients were seen immediately after discharge from the hospital and at two- to three-month intervals. Of the 109 hospitalized patients, 23 (21%) developed SBP, nine of which developed SBP during their hospitalization. The one-year cumulative probability of SBP in these patients with low ascitic fluid protein levels was 35%.

During this study, the authors also looked at 20 different patient variables on admission and found that two parameters—high bilirubin (>3.2mg/dL) and low platelet count (<98,000 cells/ul)—were associated with an increased risk of SBP. This is consistent with studies showing that patients with higher Model for End-Stage Liver Disease (MELD) or Child-Pugh scores, indicating more severe liver disease, are at increased risk for SBP. This likely is the reason SBP prophylaxis is recommended for patients with an elevated bilirubin, and higher Child-Pugh scores, by the American Association for the Study of Liver Disease (see Table 2, p. 41).

Runyon et al showed that 15% of patients with low ascitic fluid protein developed SBP during their hospitalization, as compared with 2% of patients with ascitic fluid levels greater than 1 g/dl.⁸ A randomized, non-placebo-controlled trial by Navasa et al evaluating 70 cirrhotic patients with low ascitic ascitic protein levels showed a lower probability of developing SBP in the group placed on SBP prophylaxis with norfloxacin (5% vs. 31%).⁹ Six-month mortality rate was also lower (19% vs. 36%).

In contrast to the previous studies, Grothe et al found that the presence of SBP was not related to ascitic protein content.¹⁰ Given conflicting studies, controversy still remains on whether patients with low ascitic protein should receive long-term prophylactic antibiotics.

Antibiotic Drawbacks

The consensus in the literature is that patients with ascites who are admitted with a GI bleed, or those with a history of SBP, should be placed on SBP prophylaxis. However, patients placed on long-term antibiotics are at risk for developing bacterial resistance. Bacterial resistance in cultures taken from cirrhotic patients with SBP has increased over the last decade, particularly in gram-negative bacteria.⁵ Patients who receive antibiotics in the pre-transplant setting also are at risk for post-transplant fungal infections.

Additionally, the antibiotic of choice for SBP prophylaxis is typically a fluoroquinolone, which can be expensive. However, numerous studies have shown that the cost of initiating prophylactic therapy for SBP in patients with a prior episode of SBP can be cheaper than treating SBP after diagnosis.²

Back to the Case

Our patient’s paracentesis was negative for SBP. Additionally, he does not have a history of SBP, nor does he have an active GI bleed. His only possible indication for SBP prophylaxis is low ascitic protein concentration. His electrolytes were all within normal limits. Additionally, total bilirubin was only slightly elevated at 2.3 mg/dL.

Based on the American Association for the Study of Liver Diseases guidelines, the patient was not started on SBP prophylaxis. Additionally, given his history of medication noncompliance, there is concern that he might not take the antibiotics as prescribed, thus leading to the development of bacterial resistance and more serious infections in the future.

Bottom Line

Patients with ascites and a prior episode of SBP, and those admitted to the hospital for GI bleeding, should be placed on SBP prophylaxis. SBP prophylaxis for low protein ascitic fluid remains controversial but is recommended by the American Association for the Study of Liver Diseases. TH

Dr. del Pino Jones is a hospitalist at the University of Colorado Denver.

References

1. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infections in patients with cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):77-93.
2. Guarner C, Solà R, Soriono G, et al. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology. 1999;117(2):414-419.
3. Ginés P, Rimola A, Planas R, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology. 1990;12(4 Pt 1):716-724.
4. Rolachon A, Cordier L, Bacq Y, et al. Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial. Hepatology. 1995;22(4 Pt 1):1171-1174.
5. Saab S, Hernandez J, Chi AC, Tong MJ. Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short-term survival in cirrhosis: a meta-analysis. Am J Gastroenterol. 2009;104(4):993-1001.
6. Deschênes M, Villeneuve J. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol. 1999;94(8):2193-2197.
7. Bernard B, Grangé J, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology. 1999;29(6):1655-1661.
8. Runyon B. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology. 1986;91(6):1343-1346.
9. Navasa M, Fernandez J, Montoliu S, et al. Randomized, double-blind, placebo-controlled trial evaluating norfloxacin in the primary prophylaxis of spontaneous bacterial peritonitis in cirrhotics with renal impairment, hyponatremia or severe liver failure. J Hepatol. 2006;44(Supp2):S51.
10. Grothe W, Lottere E, Fleig W. Factors predictive for spontaneous bacterial peritonitis (SBP) under routine inpatient conditions in patients with cirrhosis: a prospective multicenter trial. J Hepatol. 1990;34(4):547.

Case

A 54-year-old man with end-stage liver disease (ESLD) and no prior history of spontaneous bacterial peritonitis (SBP) presents with increasing shortness of breath and abdominal distention. He is admitted for worsening volume overload. The patient reveals that he has not been compliant with his diuretics. On the day of admission, a large-volume paracentesis is performed. Results are significant for a white blood cell count of 150 cells/mm3 and a total protein of 0.9 g/ul. The patient is started on furosemide and spironolactone, and his symptoms significantly improve throughout his hospitalization. His medications are reconciled on the day of discharge. He is not on any antibiotics for SBP prophylaxis; should he be? In general, which patients with ascites should receive SBP prophylaxis?

Overview

Spontaneous bacterial peritonitis is an infection of ascitic fluid that occurs in the absence of an indentified intra-abdominal source of infection or inflammation, i.e., perforation or abscess.¹ It is diagnosed when the polymorphonuclear cell (PMN) count in the ascitic fluid is equal to or greater than 250 cells/mm3, with or without positive cultures.

SBP is a significant cause of morbidity and mortality in patients with cirrhosis, with the mortality rate approaching 20% to 40%.2 Of the 32% to 34% of cirrhotic patients who present with, or develop, a bacterial infection during their hospitalization, 25% are due to SBP.¹ Changes in gut motility, mucosal defense, and microflora allow for translocation of bacteria into enteric lymph nodes and the bloodstream, resulting in seeding of the peritoneal fluid and SBP.¹ Alterations in both systemic and localized immune defenses, both of which are reduced in patients with liver disease, also play a role in SBP pathogenesis (see Table 1, p. 41).

Current evidence supports the use of a third-generation cephalosporin or amoxicillin/clavulanate for initial treatment of SBP, as most infections are caused by gram-negative bacilli, in particular E. coli (see Table 2 on p. 41 and Table 3 on p. 42).1 Alternatively, an oral or intravenous fluoroquinolone could be used if the prevalence of fluoroquinolone-resistant organisms is low.¹

Due to the frequency and morbidity associated with SBP, there is great interest in preventing it. However, the use of prophylactic antibiotics needs to be restricted to patients who are at highest risk of developing SBP. According to numerous studies, patients at high risk for SBP include:

1. Patients with a prior SBP history;
2. Patients admitted with a gastrointestinal bleed; and
3. Patients with low total protein content in their ascitic fluid (defined as <1.5 g/ul).¹

SBP History

Spontaneous bacterial peritonitis portends bad outcomes. The one-year mortality rate after an episode of SBP is 30% to 50%.1 Furthermore, patients who have recovered from a previous episode of SBP have a 70% chance of developing another episode of SBP in that year.^1,2 In one study, norfloxacin was shown to decrease the one-year risk of SBP to 20% from 68% in patients with a history of SBP.³ Additionally, the likelihood of developing SBP from gram-negative bacilli was reduced to 3% from 60%. In order to be efficacious, norfloxacin must be given daily. When fluoroquinolones are prescribed less than once daily, there is a higher rate of fluoroquinolone resistant organisms in the stool.¹

Though once-daily dosing of norfloxacin is recommended to decrease the promotion of resistant organisms in prophylaxis against SBP, ciprofloxacin once weekly is acceptable. In a group of patients with low ascitic protein content, with or without a history of SBP, weekly ciprofloxacin has been shown to decrease SBP incidence to 4% from 22% at six months.⁴ In regard to length of treatment, recommendations are to continue prophylactic antibiotics until resolution of ascites, the patient receives a transplant, or the patient passes away.¹

Saab et al studied the impact of oral antibiotic prophylaxis in patients with advanced liver disease on morbidity and mortality.5 The authors examined prospective, randomized, controlled trials that compared high-risk cirrhotic patients receiving oral antibiotic prophylaxis for SBP with groups receiving placebo or no intervention. Eight studies totaling 647 patients were included in the analysis.

The overall mortality rate for patients treated with SBP prophylaxis was 16%, compared with 25% for the control group. Groups treated with prophylactic antibiotics also had a lower incidence of all infections (6.2% vs. 22.2% in the control groups). Additionally, a survival benefit was seen at three months in the group that received prophylactic antibiotics.

The absolute risk reduction with prophylactic antibiotics for primary prevention of SBP was 8% with a number needed to treat of 13. The incidence of gastrointestinal (GI) bleeding, renal failure, and hepatic failure did not significantly differ between treatment and control groups. Thus, survival benefit is thought to be related to the reduced incidence of infections in the group receiving prophylactic antibiotics.⁵

History of GI Bleeding

The incidence of developing SBP in cirrhotics with an active GI bleed is anywhere from 20% to 45%.^1,2 For those with ascites of any etiology and a GI bleed, the incidence can be as high as 60%.⁵ In general, bacterial infections are frequently diagnosed in patients with cirrhosis and GI bleeding, and have been documented in 22% of these patients within the first 48 hours after admission. According to several studies, that percentage can reach as high as 35% to 66% within seven to 14 days of admission.⁶ A seven-day course of antibiotics, or antibiotics until discharge, is generally acceptable for SBP prophylaxis in the setting of ascites and GI bleeding (see Table 2, right).¹

Bernard et al performed a meta-analysis of five trials to assess the efficacy of antibiotic prophylaxis in the prevention of infections and effect on survival in patients with cirrhosis and GI bleeding. Out of 534 patients, 264 were treated with antibiotics between four and 10 days, and 270 did not receive any antibiotics.

The endpoints of the study were infection, bacteremia and/or SBP; incidence of SBP; and death. Antibiotic prophylaxis not only increased the mean survival rate by 9.1%, but also increased the mean percentage of patients free of infection (32% improvement); bacteremia and/or SBP (19% improvement); and SBP (7% improvement).⁷

Low Ascitic Fluid Protein

Of the three major risk factors for SBP, ascitic fluid protein content is the most debated. Guarner et al studied the risk of first community-acquired SBP in cirrhotics with low ascitic fluid protein.² Patients were seen immediately after discharge from the hospital and at two- to three-month intervals. Of the 109 hospitalized patients, 23 (21%) developed SBP, nine of which developed SBP during their hospitalization. The one-year cumulative probability of SBP in these patients with low ascitic fluid protein levels was 35%.

During this study, the authors also looked at 20 different patient variables on admission and found that two parameters—high bilirubin (>3.2mg/dL) and low platelet count (<98,000 cells/ul)—were associated with an increased risk of SBP. This is consistent with studies showing that patients with higher Model for End-Stage Liver Disease (MELD) or Child-Pugh scores, indicating more severe liver disease, are at increased risk for SBP. This likely is the reason SBP prophylaxis is recommended for patients with an elevated bilirubin, and higher Child-Pugh scores, by the American Association for the Study of Liver Disease (see Table 2, p. 41).

Runyon et al showed that 15% of patients with low ascitic fluid protein developed SBP during their hospitalization, as compared with 2% of patients with ascitic fluid levels greater than 1 g/dl.⁸ A randomized, non-placebo-controlled trial by Navasa et al evaluating 70 cirrhotic patients with low ascitic ascitic protein levels showed a lower probability of developing SBP in the group placed on SBP prophylaxis with norfloxacin (5% vs. 31%).⁹ Six-month mortality rate was also lower (19% vs. 36%).

In contrast to the previous studies, Grothe et al found that the presence of SBP was not related to ascitic protein content.¹⁰ Given conflicting studies, controversy still remains on whether patients with low ascitic protein should receive long-term prophylactic antibiotics.

Antibiotic Drawbacks

The consensus in the literature is that patients with ascites who are admitted with a GI bleed, or those with a history of SBP, should be placed on SBP prophylaxis. However, patients placed on long-term antibiotics are at risk for developing bacterial resistance. Bacterial resistance in cultures taken from cirrhotic patients with SBP has increased over the last decade, particularly in gram-negative bacteria.⁵ Patients who receive antibiotics in the pre-transplant setting also are at risk for post-transplant fungal infections.

Additionally, the antibiotic of choice for SBP prophylaxis is typically a fluoroquinolone, which can be expensive. However, numerous studies have shown that the cost of initiating prophylactic therapy for SBP in patients with a prior episode of SBP can be cheaper than treating SBP after diagnosis.²

Back to the Case

Our patient’s paracentesis was negative for SBP. Additionally, he does not have a history of SBP, nor does he have an active GI bleed. His only possible indication for SBP prophylaxis is low ascitic protein concentration. His electrolytes were all within normal limits. Additionally, total bilirubin was only slightly elevated at 2.3 mg/dL.

Based on the American Association for the Study of Liver Diseases guidelines, the patient was not started on SBP prophylaxis. Additionally, given his history of medication noncompliance, there is concern that he might not take the antibiotics as prescribed, thus leading to the development of bacterial resistance and more serious infections in the future.

Bottom Line

Patients with ascites and a prior episode of SBP, and those admitted to the hospital for GI bleeding, should be placed on SBP prophylaxis. SBP prophylaxis for low protein ascitic fluid remains controversial but is recommended by the American Association for the Study of Liver Diseases. TH

Dr. del Pino Jones is a hospitalist at the University of Colorado Denver.

References

1. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infections in patients with cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):77-93.
2. Guarner C, Solà R, Soriono G, et al. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology. 1999;117(2):414-419.
3. Ginés P, Rimola A, Planas R, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology. 1990;12(4 Pt 1):716-724.
4. Rolachon A, Cordier L, Bacq Y, et al. Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial. Hepatology. 1995;22(4 Pt 1):1171-1174.
5. Saab S, Hernandez J, Chi AC, Tong MJ. Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short-term survival in cirrhosis: a meta-analysis. Am J Gastroenterol. 2009;104(4):993-1001.
6. Deschênes M, Villeneuve J. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol. 1999;94(8):2193-2197.
7. Bernard B, Grangé J, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology. 1999;29(6):1655-1661.
8. Runyon B. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology. 1986;91(6):1343-1346.
9. Navasa M, Fernandez J, Montoliu S, et al. Randomized, double-blind, placebo-controlled trial evaluating norfloxacin in the primary prophylaxis of spontaneous bacterial peritonitis in cirrhotics with renal impairment, hyponatremia or severe liver failure. J Hepatol. 2006;44(Supp2):S51.
10. Grothe W, Lottere E, Fleig W. Factors predictive for spontaneous bacterial peritonitis (SBP) under routine inpatient conditions in patients with cirrhosis: a prospective multicenter trial. J Hepatol. 1990;34(4):547.

Case

A 54-year-old man with end-stage liver disease (ESLD) and no prior history of spontaneous bacterial peritonitis (SBP) presents with increasing shortness of breath and abdominal distention. He is admitted for worsening volume overload. The patient reveals that he has not been compliant with his diuretics. On the day of admission, a large-volume paracentesis is performed. Results are significant for a white blood cell count of 150 cells/mm3 and a total protein of 0.9 g/ul. The patient is started on furosemide and spironolactone, and his symptoms significantly improve throughout his hospitalization. His medications are reconciled on the day of discharge. He is not on any antibiotics for SBP prophylaxis; should he be? In general, which patients with ascites should receive SBP prophylaxis?

Overview

Spontaneous bacterial peritonitis is an infection of ascitic fluid that occurs in the absence of an indentified intra-abdominal source of infection or inflammation, i.e., perforation or abscess.¹ It is diagnosed when the polymorphonuclear cell (PMN) count in the ascitic fluid is equal to or greater than 250 cells/mm3, with or without positive cultures.

SBP is a significant cause of morbidity and mortality in patients with cirrhosis, with the mortality rate approaching 20% to 40%.2 Of the 32% to 34% of cirrhotic patients who present with, or develop, a bacterial infection during their hospitalization, 25% are due to SBP.¹ Changes in gut motility, mucosal defense, and microflora allow for translocation of bacteria into enteric lymph nodes and the bloodstream, resulting in seeding of the peritoneal fluid and SBP.¹ Alterations in both systemic and localized immune defenses, both of which are reduced in patients with liver disease, also play a role in SBP pathogenesis (see Table 1, p. 41).

Current evidence supports the use of a third-generation cephalosporin or amoxicillin/clavulanate for initial treatment of SBP, as most infections are caused by gram-negative bacilli, in particular E. coli (see Table 2 on p. 41 and Table 3 on p. 42).1 Alternatively, an oral or intravenous fluoroquinolone could be used if the prevalence of fluoroquinolone-resistant organisms is low.¹

Due to the frequency and morbidity associated with SBP, there is great interest in preventing it. However, the use of prophylactic antibiotics needs to be restricted to patients who are at highest risk of developing SBP. According to numerous studies, patients at high risk for SBP include:

1. Patients with a prior SBP history;
2. Patients admitted with a gastrointestinal bleed; and
3. Patients with low total protein content in their ascitic fluid (defined as <1.5 g/ul).¹

SBP History

Spontaneous bacterial peritonitis portends bad outcomes. The one-year mortality rate after an episode of SBP is 30% to 50%.1 Furthermore, patients who have recovered from a previous episode of SBP have a 70% chance of developing another episode of SBP in that year.^1,2 In one study, norfloxacin was shown to decrease the one-year risk of SBP to 20% from 68% in patients with a history of SBP.³ Additionally, the likelihood of developing SBP from gram-negative bacilli was reduced to 3% from 60%. In order to be efficacious, norfloxacin must be given daily. When fluoroquinolones are prescribed less than once daily, there is a higher rate of fluoroquinolone resistant organisms in the stool.¹

Though once-daily dosing of norfloxacin is recommended to decrease the promotion of resistant organisms in prophylaxis against SBP, ciprofloxacin once weekly is acceptable. In a group of patients with low ascitic protein content, with or without a history of SBP, weekly ciprofloxacin has been shown to decrease SBP incidence to 4% from 22% at six months.⁴ In regard to length of treatment, recommendations are to continue prophylactic antibiotics until resolution of ascites, the patient receives a transplant, or the patient passes away.¹

Saab et al studied the impact of oral antibiotic prophylaxis in patients with advanced liver disease on morbidity and mortality.5 The authors examined prospective, randomized, controlled trials that compared high-risk cirrhotic patients receiving oral antibiotic prophylaxis for SBP with groups receiving placebo or no intervention. Eight studies totaling 647 patients were included in the analysis.

The overall mortality rate for patients treated with SBP prophylaxis was 16%, compared with 25% for the control group. Groups treated with prophylactic antibiotics also had a lower incidence of all infections (6.2% vs. 22.2% in the control groups). Additionally, a survival benefit was seen at three months in the group that received prophylactic antibiotics.

The absolute risk reduction with prophylactic antibiotics for primary prevention of SBP was 8% with a number needed to treat of 13. The incidence of gastrointestinal (GI) bleeding, renal failure, and hepatic failure did not significantly differ between treatment and control groups. Thus, survival benefit is thought to be related to the reduced incidence of infections in the group receiving prophylactic antibiotics.⁵

History of GI Bleeding

The incidence of developing SBP in cirrhotics with an active GI bleed is anywhere from 20% to 45%.^1,2 For those with ascites of any etiology and a GI bleed, the incidence can be as high as 60%.⁵ In general, bacterial infections are frequently diagnosed in patients with cirrhosis and GI bleeding, and have been documented in 22% of these patients within the first 48 hours after admission. According to several studies, that percentage can reach as high as 35% to 66% within seven to 14 days of admission.⁶ A seven-day course of antibiotics, or antibiotics until discharge, is generally acceptable for SBP prophylaxis in the setting of ascites and GI bleeding (see Table 2, right).¹