To the Editor: In their article “The clinical picture: bilateral adrenal masses” in the December 2012 issue,¹ Drs. Saberi and Esfandiari provide excellent points about adrenal hemorrhage as a differential diagnosis for adrenal masses. However, there are two points worth emphasizing when mentioning this diagnosis, especially in the case they presented.

Drs. Saberi and Esfandiari cryptically mention this patient’s coagulopathy (with thrombocytopenia and a rise in creatinine) and anticoagulation as the probable causes of adrenal hemorrhage. We wonder if a diagnosis of antiphospholipid syndrome (APS) was overlooked. Even though overt Addison disease is reported in only 0.4% of patients with APS² and APS is diagnosed in fewer than 0.5% of all patients with Addison disease,³ we think that in this case, since the patient initially presented with an arterial thrombus in the abdominal aorta, screening for APS would have been warranted.

Second, though it is rare, bilateral adrenal hemorrhage with normal imaging on initial presentation has been described,^2,4 which raises this additional question: Should screening for adrenal insufficiency in a patient with possible APS or other coagulopathy be done early while waiting for repeat computed tomography to reveal hemorrhage? Occasionally, intraparenchymal microhemorrhages may not be recognized by sectional imaging but can nonetheless compromise adrenal function.⁴

To the Editor: In their article “The clinical picture: bilateral adrenal masses” in the December 2012 issue,¹ Drs. Saberi and Esfandiari provide excellent points about adrenal hemorrhage as a differential diagnosis for adrenal masses. However, there are two points worth emphasizing when mentioning this diagnosis, especially in the case they presented.

Drs. Saberi and Esfandiari cryptically mention this patient’s coagulopathy (with thrombocytopenia and a rise in creatinine) and anticoagulation as the probable causes of adrenal hemorrhage. We wonder if a diagnosis of antiphospholipid syndrome (APS) was overlooked. Even though overt Addison disease is reported in only 0.4% of patients with APS² and APS is diagnosed in fewer than 0.5% of all patients with Addison disease,³ we think that in this case, since the patient initially presented with an arterial thrombus in the abdominal aorta, screening for APS would have been warranted.

Second, though it is rare, bilateral adrenal hemorrhage with normal imaging on initial presentation has been described,^2,4 which raises this additional question: Should screening for adrenal insufficiency in a patient with possible APS or other coagulopathy be done early while waiting for repeat computed tomography to reveal hemorrhage? Occasionally, intraparenchymal microhemorrhages may not be recognized by sectional imaging but can nonetheless compromise adrenal function.⁴

To the Editor: In their article “The clinical picture: bilateral adrenal masses” in the December 2012 issue,¹ Drs. Saberi and Esfandiari provide excellent points about adrenal hemorrhage as a differential diagnosis for adrenal masses. However, there are two points worth emphasizing when mentioning this diagnosis, especially in the case they presented.

Drs. Saberi and Esfandiari cryptically mention this patient’s coagulopathy (with thrombocytopenia and a rise in creatinine) and anticoagulation as the probable causes of adrenal hemorrhage. We wonder if a diagnosis of antiphospholipid syndrome (APS) was overlooked. Even though overt Addison disease is reported in only 0.4% of patients with APS² and APS is diagnosed in fewer than 0.5% of all patients with Addison disease,³ we think that in this case, since the patient initially presented with an arterial thrombus in the abdominal aorta, screening for APS would have been warranted.

Second, though it is rare, bilateral adrenal hemorrhage with normal imaging on initial presentation has been described,^2,4 which raises this additional question: Should screening for adrenal insufficiency in a patient with possible APS or other coagulopathy be done early while waiting for repeat computed tomography to reveal hemorrhage? Occasionally, intraparenchymal microhemorrhages may not be recognized by sectional imaging but can nonetheless compromise adrenal function.⁴

To the Editor: The review article “Statins and diabetes: fact, fiction, and clinical implications” ¹ left out one major fact: there are sex-based differences in the statin research results, particularly a higher risk for diabetes in postmenopausal women on statins, with an adjusted hazard ratio of 1.48.² The article promulgated the fiction that statins should be used for primary prevention in women. The first study the author reviewed when discussing the risk of diabetes in “patients” was WOSCOPS—which was an all male study.³

While statin therapy is an effective intervention for secondary prevention of cardiovascular disease in both sexes, it is important to note there is no benefit in rates of all-cause mortality or stroke in women.⁴ The use of statins for primary prevention in women rightly remains controversial.

Any review article on statins or any condition or drug used in both sexes should include some discussion about sex-based differences. While it might be advanced that the increased risk for diabetes, depression, cognitive impairment, and musculoskeletal pain can be justified in secondary prevention in both sexes, that argument is much, much weaker for primary prevention in women, especially since we have evidence showing a reduction in all-cause mortality and primary cardiovascular reduction in women given early postmenopausal hormone therapy.⁵

To the Editor: The review article “Statins and diabetes: fact, fiction, and clinical implications” ¹ left out one major fact: there are sex-based differences in the statin research results, particularly a higher risk for diabetes in postmenopausal women on statins, with an adjusted hazard ratio of 1.48.² The article promulgated the fiction that statins should be used for primary prevention in women. The first study the author reviewed when discussing the risk of diabetes in “patients” was WOSCOPS—which was an all male study.³

While statin therapy is an effective intervention for secondary prevention of cardiovascular disease in both sexes, it is important to note there is no benefit in rates of all-cause mortality or stroke in women.⁴ The use of statins for primary prevention in women rightly remains controversial.

Any review article on statins or any condition or drug used in both sexes should include some discussion about sex-based differences. While it might be advanced that the increased risk for diabetes, depression, cognitive impairment, and musculoskeletal pain can be justified in secondary prevention in both sexes, that argument is much, much weaker for primary prevention in women, especially since we have evidence showing a reduction in all-cause mortality and primary cardiovascular reduction in women given early postmenopausal hormone therapy.⁵

To the Editor: The review article “Statins and diabetes: fact, fiction, and clinical implications” ¹ left out one major fact: there are sex-based differences in the statin research results, particularly a higher risk for diabetes in postmenopausal women on statins, with an adjusted hazard ratio of 1.48.² The article promulgated the fiction that statins should be used for primary prevention in women. The first study the author reviewed when discussing the risk of diabetes in “patients” was WOSCOPS—which was an all male study.³

While statin therapy is an effective intervention for secondary prevention of cardiovascular disease in both sexes, it is important to note there is no benefit in rates of all-cause mortality or stroke in women.⁴ The use of statins for primary prevention in women rightly remains controversial.

Any review article on statins or any condition or drug used in both sexes should include some discussion about sex-based differences. While it might be advanced that the increased risk for diabetes, depression, cognitive impairment, and musculoskeletal pain can be justified in secondary prevention in both sexes, that argument is much, much weaker for primary prevention in women, especially since we have evidence showing a reduction in all-cause mortality and primary cardiovascular reduction in women given early postmenopausal hormone therapy.⁵

In Reply: As Dr. Thacker notes, women are underrepresented in statin clinical trials. This, in addition to the fact that the metaanalyses reviewed did not generally stratify results by sex, makes a detailed discussion of sex-based differences on diabetes incidence and comparative outcomes difficult.

In terms of outcomes, some metaanalyses have found similar reductions of cardiovascular events with statin treatment in men and women, particularly in secondary-prevention populations.^1–3 Even though the cited report from Gutierrez et al⁴ may not have been as inclusive as some other studies, it also demonstrated similar reductions in myocardial infarction, need for intervention, and coronary mortality rates compared with men. The lack of significant reduction in rates of cerebrovascular accidents and all-cause mortality in this study may be a function of the low percentage of women in the analysis (20.6%), the low number of events, and the lack of power. However, the results did trend in a positive direction.

It is true that outcome benefits are harder to demonstrate in primary-prevention populations. However, a meta-analysis by Brugts et al⁵ in 2009 examined 10 placebocontrolled statin trials, including at least 80% of individuals without cardiovascular disease or whose data were reported from a sole primary prevention group. Thirty-four percent of the participants were women. Overall, there was a 12% reduction in mortality, 30% reduction in coronary events, and 19% reduction in cerebrovascular events. Although sex-specific analysis did not show significant reductions in women alone, the directional trends were similar to those in men, and subgroup analysis revealed no heterogeneity in treatment effect by sex, age, or diabetes status.

The meta-analysis from the Cholesterol Treatment Trialists cited in this review included 27 controlled trials and stratified patients by estimated 5-year major vascular event risk⁶; 29% of the patients were women. As expected, annual event rates increased with increasing estimate of risk. Rates of major vascular and major coronary events were reduced by 21% and 30%, respectively. Similar significant proportional reductions were noted in all risk groups, including the lowest two risk groups (< 5% and 5 to < 10%). Although analysis was not stratified by sex, there was a proportionately higher percentage of women (54%) represented in the lowest-risk group, which had a similar relative risk reduction. In the primary-prevention trial JUPITER⁷ in patients with elevated C-reactive protein and low low-density lipoprotein cholesterol levels, rosuvastatin significantly reduced the primary composite end point in women (38% of the study group) by 46%, which was similar to that in the men.^7,8 In the same paper, an additional meta-analysis of exclusively primary prevention trials reported a significant 37% reduction in cardiovascular events.

As for comparable diabetes incidence on statins, it is not accurate to imply that women have a higher risk of developing diabetes than men based only on the Women’s Health Initiative observational analysis—an all-female study with no male comparison arm, without randomization to statins, and in which only 7% of participants at entry were taking the drug in question.

The use of statins in low-risk individuals and in women in particular does remain controversial, partially because of the lack of controlled data and sufficiently powered studies with women. It was not my intent to “promulgate a fiction” that statins should be used in primary prevention in all women, but rather to recommend the use of statins appropriately in at-risk patients after weighing the treatment risks. All therapies, including statin therapy, should be directed toward those who would have the best benefit-risk ratio. To lump together all primary-prevention women, however, is overly simplistic and may result in denying therapy to a patient who may benefit from the intervention. In women as in men, the available data (although imperfect) support statin use with an acceptable risk profile in those at moderate to high risk of subsequent cardiovascular events. Some of these patients would be in the primary prevention classification. Every decision to treat needs to factor in the patient’s overall cardiovascular risk, the likelihood of adverse effects including diabetes, and the patient’s sex.

In Reply: As Dr. Thacker notes, women are underrepresented in statin clinical trials. This, in addition to the fact that the metaanalyses reviewed did not generally stratify results by sex, makes a detailed discussion of sex-based differences on diabetes incidence and comparative outcomes difficult.

In terms of outcomes, some metaanalyses have found similar reductions of cardiovascular events with statin treatment in men and women, particularly in secondary-prevention populations.^1–3 Even though the cited report from Gutierrez et al⁴ may not have been as inclusive as some other studies, it also demonstrated similar reductions in myocardial infarction, need for intervention, and coronary mortality rates compared with men. The lack of significant reduction in rates of cerebrovascular accidents and all-cause mortality in this study may be a function of the low percentage of women in the analysis (20.6%), the low number of events, and the lack of power. However, the results did trend in a positive direction.

It is true that outcome benefits are harder to demonstrate in primary-prevention populations. However, a meta-analysis by Brugts et al⁵ in 2009 examined 10 placebocontrolled statin trials, including at least 80% of individuals without cardiovascular disease or whose data were reported from a sole primary prevention group. Thirty-four percent of the participants were women. Overall, there was a 12% reduction in mortality, 30% reduction in coronary events, and 19% reduction in cerebrovascular events. Although sex-specific analysis did not show significant reductions in women alone, the directional trends were similar to those in men, and subgroup analysis revealed no heterogeneity in treatment effect by sex, age, or diabetes status.

The meta-analysis from the Cholesterol Treatment Trialists cited in this review included 27 controlled trials and stratified patients by estimated 5-year major vascular event risk⁶; 29% of the patients were women. As expected, annual event rates increased with increasing estimate of risk. Rates of major vascular and major coronary events were reduced by 21% and 30%, respectively. Similar significant proportional reductions were noted in all risk groups, including the lowest two risk groups (< 5% and 5 to < 10%). Although analysis was not stratified by sex, there was a proportionately higher percentage of women (54%) represented in the lowest-risk group, which had a similar relative risk reduction. In the primary-prevention trial JUPITER⁷ in patients with elevated C-reactive protein and low low-density lipoprotein cholesterol levels, rosuvastatin significantly reduced the primary composite end point in women (38% of the study group) by 46%, which was similar to that in the men.^7,8 In the same paper, an additional meta-analysis of exclusively primary prevention trials reported a significant 37% reduction in cardiovascular events.

As for comparable diabetes incidence on statins, it is not accurate to imply that women have a higher risk of developing diabetes than men based only on the Women’s Health Initiative observational analysis—an all-female study with no male comparison arm, without randomization to statins, and in which only 7% of participants at entry were taking the drug in question.

The use of statins in low-risk individuals and in women in particular does remain controversial, partially because of the lack of controlled data and sufficiently powered studies with women. It was not my intent to “promulgate a fiction” that statins should be used in primary prevention in all women, but rather to recommend the use of statins appropriately in at-risk patients after weighing the treatment risks. All therapies, including statin therapy, should be directed toward those who would have the best benefit-risk ratio. To lump together all primary-prevention women, however, is overly simplistic and may result in denying therapy to a patient who may benefit from the intervention. In women as in men, the available data (although imperfect) support statin use with an acceptable risk profile in those at moderate to high risk of subsequent cardiovascular events. Some of these patients would be in the primary prevention classification. Every decision to treat needs to factor in the patient’s overall cardiovascular risk, the likelihood of adverse effects including diabetes, and the patient’s sex.

In Reply: As Dr. Thacker notes, women are underrepresented in statin clinical trials. This, in addition to the fact that the metaanalyses reviewed did not generally stratify results by sex, makes a detailed discussion of sex-based differences on diabetes incidence and comparative outcomes difficult.

In terms of outcomes, some metaanalyses have found similar reductions of cardiovascular events with statin treatment in men and women, particularly in secondary-prevention populations.^1–3 Even though the cited report from Gutierrez et al⁴ may not have been as inclusive as some other studies, it also demonstrated similar reductions in myocardial infarction, need for intervention, and coronary mortality rates compared with men. The lack of significant reduction in rates of cerebrovascular accidents and all-cause mortality in this study may be a function of the low percentage of women in the analysis (20.6%), the low number of events, and the lack of power. However, the results did trend in a positive direction.

It is true that outcome benefits are harder to demonstrate in primary-prevention populations. However, a meta-analysis by Brugts et al⁵ in 2009 examined 10 placebocontrolled statin trials, including at least 80% of individuals without cardiovascular disease or whose data were reported from a sole primary prevention group. Thirty-four percent of the participants were women. Overall, there was a 12% reduction in mortality, 30% reduction in coronary events, and 19% reduction in cerebrovascular events. Although sex-specific analysis did not show significant reductions in women alone, the directional trends were similar to those in men, and subgroup analysis revealed no heterogeneity in treatment effect by sex, age, or diabetes status.

The meta-analysis from the Cholesterol Treatment Trialists cited in this review included 27 controlled trials and stratified patients by estimated 5-year major vascular event risk⁶; 29% of the patients were women. As expected, annual event rates increased with increasing estimate of risk. Rates of major vascular and major coronary events were reduced by 21% and 30%, respectively. Similar significant proportional reductions were noted in all risk groups, including the lowest two risk groups (< 5% and 5 to < 10%). Although analysis was not stratified by sex, there was a proportionately higher percentage of women (54%) represented in the lowest-risk group, which had a similar relative risk reduction. In the primary-prevention trial JUPITER⁷ in patients with elevated C-reactive protein and low low-density lipoprotein cholesterol levels, rosuvastatin significantly reduced the primary composite end point in women (38% of the study group) by 46%, which was similar to that in the men.^7,8 In the same paper, an additional meta-analysis of exclusively primary prevention trials reported a significant 37% reduction in cardiovascular events.

As for comparable diabetes incidence on statins, it is not accurate to imply that women have a higher risk of developing diabetes than men based only on the Women’s Health Initiative observational analysis—an all-female study with no male comparison arm, without randomization to statins, and in which only 7% of participants at entry were taking the drug in question.

The use of statins in low-risk individuals and in women in particular does remain controversial, partially because of the lack of controlled data and sufficiently powered studies with women. It was not my intent to “promulgate a fiction” that statins should be used in primary prevention in all women, but rather to recommend the use of statins appropriately in at-risk patients after weighing the treatment risks. All therapies, including statin therapy, should be directed toward those who would have the best benefit-risk ratio. To lump together all primary-prevention women, however, is overly simplistic and may result in denying therapy to a patient who may benefit from the intervention. In women as in men, the available data (although imperfect) support statin use with an acceptable risk profile in those at moderate to high risk of subsequent cardiovascular events. Some of these patients would be in the primary prevention classification. Every decision to treat needs to factor in the patient’s overall cardiovascular risk, the likelihood of adverse effects including diabetes, and the patient’s sex.

Glenn J. Lesser, MD, Doug Case, PhD, Nancy Stark, RN, PhD, et al

Background Coenzyme Q₁₀ (CoQ₁₀) is a common antioxidant supplement with known cardioprotective effects and potential anticancer benefits.

Objectives We performed a randomized, double-blind, placebo-controlled study of oral CoQ₁₀ in female breast cancer patients with the primary objective of determining CoQ₁₀ ’s effects on self-reported fatigue, depression, and quality of life (QOL).

Methods Eligible women with newly diagnosed breast cancer and planned adjuvant chemotherapy were randomized to oralsupplements of 300 mg CoQ₁₀ or placebo, each combined with 300 IU vitamin E, divided into 3 daily doses. Treatment wascontinued for 24 weeks. Blood tests, QOL measures, and levels of plasma CoQ₁₀ and vitamin E were obtained at baseline and at 8,16, and 24 weeks. Mixed-effects models were used to assess treatment differences in outcomes over time.

Results Between September 2004 and March 2009, 236 women were enrolled. Treatment arms were well balanced with respect to age(range, 28-85 years), pathologic stage (stage 0, 91%; stage I, 8%; stage II, 1%), ethnicity (white, 87%; black, 11%; Hispanic, 2%), and planned therapy. Baseline CoQ₁₀ levels in the CoQ₁₀ and placebo arms were 0.70 and 0.73 g/mL, respectively; the 24-week CoQ₁₀ levels were 1.83 and 0.79g/mL, respectively. There were no significant differences between the CoQ₁₀ and placebo arms at 24 weeks for scores on the Profile of Mood States–Fatigue questionnaire (least squares means, 7.08 vs 8.24, P = .257), the Functional Assessment of Chronic Illness Therapy–Fatigue tool (37.6 vs 37.6, P = .965), the Functional Assessment of Cancer Therapy–Breast Cancer instrument (111.9 vs 110.4, P = .577), or the Center for Epidemiologic Studies–Depression scale (11.6 vs 12.3, P = .632).

Conclusions Supplementation with conventional doses of CoQ₁₀ led to sustained increases in plasma CoQ₁₀ levels but did not result in improved self-reported fatigue or QOL after 24 weeks of treatment.

*For a PDF of the full article, click on the link to the left of this introduction.

Glenn J. Lesser, MD, Doug Case, PhD, Nancy Stark, RN, PhD, et al

Background Coenzyme Q₁₀ (CoQ₁₀) is a common antioxidant supplement with known cardioprotective effects and potential anticancer benefits.

Objectives We performed a randomized, double-blind, placebo-controlled study of oral CoQ₁₀ in female breast cancer patients with the primary objective of determining CoQ₁₀ ’s effects on self-reported fatigue, depression, and quality of life (QOL).

Methods Eligible women with newly diagnosed breast cancer and planned adjuvant chemotherapy were randomized to oralsupplements of 300 mg CoQ₁₀ or placebo, each combined with 300 IU vitamin E, divided into 3 daily doses. Treatment wascontinued for 24 weeks. Blood tests, QOL measures, and levels of plasma CoQ₁₀ and vitamin E were obtained at baseline and at 8,16, and 24 weeks. Mixed-effects models were used to assess treatment differences in outcomes over time.

Results Between September 2004 and March 2009, 236 women were enrolled. Treatment arms were well balanced with respect to age(range, 28-85 years), pathologic stage (stage 0, 91%; stage I, 8%; stage II, 1%), ethnicity (white, 87%; black, 11%; Hispanic, 2%), and planned therapy. Baseline CoQ₁₀ levels in the CoQ₁₀ and placebo arms were 0.70 and 0.73 g/mL, respectively; the 24-week CoQ₁₀ levels were 1.83 and 0.79g/mL, respectively. There were no significant differences between the CoQ₁₀ and placebo arms at 24 weeks for scores on the Profile of Mood States–Fatigue questionnaire (least squares means, 7.08 vs 8.24, P = .257), the Functional Assessment of Chronic Illness Therapy–Fatigue tool (37.6 vs 37.6, P = .965), the Functional Assessment of Cancer Therapy–Breast Cancer instrument (111.9 vs 110.4, P = .577), or the Center for Epidemiologic Studies–Depression scale (11.6 vs 12.3, P = .632).

Conclusions Supplementation with conventional doses of CoQ₁₀ led to sustained increases in plasma CoQ₁₀ levels but did not result in improved self-reported fatigue or QOL after 24 weeks of treatment.

*For a PDF of the full article, click on the link to the left of this introduction.

Glenn J. Lesser, MD, Doug Case, PhD, Nancy Stark, RN, PhD, et al

Background Coenzyme Q₁₀ (CoQ₁₀) is a common antioxidant supplement with known cardioprotective effects and potential anticancer benefits.

Objectives We performed a randomized, double-blind, placebo-controlled study of oral CoQ₁₀ in female breast cancer patients with the primary objective of determining CoQ₁₀ ’s effects on self-reported fatigue, depression, and quality of life (QOL).

Methods Eligible women with newly diagnosed breast cancer and planned adjuvant chemotherapy were randomized to oralsupplements of 300 mg CoQ₁₀ or placebo, each combined with 300 IU vitamin E, divided into 3 daily doses. Treatment wascontinued for 24 weeks. Blood tests, QOL measures, and levels of plasma CoQ₁₀ and vitamin E were obtained at baseline and at 8,16, and 24 weeks. Mixed-effects models were used to assess treatment differences in outcomes over time.

Results Between September 2004 and March 2009, 236 women were enrolled. Treatment arms were well balanced with respect to age(range, 28-85 years), pathologic stage (stage 0, 91%; stage I, 8%; stage II, 1%), ethnicity (white, 87%; black, 11%; Hispanic, 2%), and planned therapy. Baseline CoQ₁₀ levels in the CoQ₁₀ and placebo arms were 0.70 and 0.73 g/mL, respectively; the 24-week CoQ₁₀ levels were 1.83 and 0.79g/mL, respectively. There were no significant differences between the CoQ₁₀ and placebo arms at 24 weeks for scores on the Profile of Mood States–Fatigue questionnaire (least squares means, 7.08 vs 8.24, P = .257), the Functional Assessment of Chronic Illness Therapy–Fatigue tool (37.6 vs 37.6, P = .965), the Functional Assessment of Cancer Therapy–Breast Cancer instrument (111.9 vs 110.4, P = .577), or the Center for Epidemiologic Studies–Depression scale (11.6 vs 12.3, P = .632).

Conclusions Supplementation with conventional doses of CoQ₁₀ led to sustained increases in plasma CoQ₁₀ levels but did not result in improved self-reported fatigue or QOL after 24 weeks of treatment.

*For a PDF of the full article, click on the link to the left of this introduction.

Background The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioningand health-related quality of life (HRQoL) has not been well-studied.

Objective To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper  extremity function, activities, and HRQoL.

Methods The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparingsentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and armvolume were measured objectively.  PROs included symptoms; arm function; limitations in social, recreational, occupational,and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariablelinear regression models.

Results In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM.

Limitations Arm mobility and edema were measured simultaneously only once during the follow-up (6 months).

Conclusion Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.

Click on the PDF icon at the top of this introduction to read the full article.

Background The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioningand health-related quality of life (HRQoL) has not been well-studied.

Objective To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper  extremity function, activities, and HRQoL.

Methods The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparingsentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and armvolume were measured objectively.  PROs included symptoms; arm function; limitations in social, recreational, occupational,and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariablelinear regression models.

Results In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM.

Limitations Arm mobility and edema were measured simultaneously only once during the follow-up (6 months).

Conclusion Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.

Click on the PDF icon at the top of this introduction to read the full article.

Background The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioningand health-related quality of life (HRQoL) has not been well-studied.

Objective To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper  extremity function, activities, and HRQoL.

Methods The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparingsentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and armvolume were measured objectively.  PROs included symptoms; arm function; limitations in social, recreational, occupational,and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariablelinear regression models.

Results In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM.

Limitations Arm mobility and edema were measured simultaneously only once during the follow-up (6 months).

Conclusion Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.

Click on the PDF icon at the top of this introduction to read the full article.

George Dranitsaris, BPharm, PhD, Nathaniel Bouganim, MD, Carolyn Milano, Lisa Vandermeer, MSc, Susan Dent, MD, Paul Wheatley-Price, MD, Jenny Laporte, RN, Karen-Ann Oxborough, RN, and Mark Clemons, MD

Background Even with modern antiemetic regimens, up to 20% of cancer patients suffer from moderate to severechemotherapy-induced nausea and vomiting (CINV) (grade 2). We previously developed chemotherapy cycle–based risk predictive models forgrade 2 acute and delayed CINV. In this study, the prospective validation of the prediction models andassociated scoring systems is described.

Objective Our objective was to prospectively validate prediction models designed to identify patients at high risk for moderate tosevere CINV.

Methods Patients receiving chemotherapy were provided with CINV symptom diaries. Prior to each cycle of chemotherapy, the acute and delayed CINV scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression was used tocompare the occurrence of grade 2 CINV between patients considered by the model to be at high vs low risk. The external validity of each system was assessed via an area under the receiver operating characteristic (AUROC) curve analysis.

Results Outcome data were collected from 97 patients following 401 cycles of chemotherapy. The incidence of grade 2 acute and delayed CINV was 13.5% and 21.4%, respectively. There was a significant correlation between the risk score and the probability of developing acute and delayed CINV following chemotherapy. Both the acute and delayed scoring systems had good predictive accuracy when applied to the validation sample (acute, AUROC = 0.70, 95% CI, 0.62– 0.77; delayed, AUROC = 0.75, 95% CI, 0.69 – 0.80). Patients who were identified as high risk were 3.1 (P = .006) and 4.2 (P < .001) times more likely to develop grade 2 acute and delayed CINV than were those identified as low risk.

Conclusion This study demonstrates that the scoring systems are able to accurately identify patients at high risk for acute and delayed CINV.

*For a PDF of the full article, click on the link to the left of this introduction.

George Dranitsaris, BPharm, PhD, Nathaniel Bouganim, MD, Carolyn Milano, Lisa Vandermeer, MSc, Susan Dent, MD, Paul Wheatley-Price, MD, Jenny Laporte, RN, Karen-Ann Oxborough, RN, and Mark Clemons, MD

Background Even with modern antiemetic regimens, up to 20% of cancer patients suffer from moderate to severechemotherapy-induced nausea and vomiting (CINV) (grade 2). We previously developed chemotherapy cycle–based risk predictive models forgrade 2 acute and delayed CINV. In this study, the prospective validation of the prediction models andassociated scoring systems is described.

Objective Our objective was to prospectively validate prediction models designed to identify patients at high risk for moderate tosevere CINV.

Methods Patients receiving chemotherapy were provided with CINV symptom diaries. Prior to each cycle of chemotherapy, the acute and delayed CINV scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression was used tocompare the occurrence of grade 2 CINV between patients considered by the model to be at high vs low risk. The external validity of each system was assessed via an area under the receiver operating characteristic (AUROC) curve analysis.

Results Outcome data were collected from 97 patients following 401 cycles of chemotherapy. The incidence of grade 2 acute and delayed CINV was 13.5% and 21.4%, respectively. There was a significant correlation between the risk score and the probability of developing acute and delayed CINV following chemotherapy. Both the acute and delayed scoring systems had good predictive accuracy when applied to the validation sample (acute, AUROC = 0.70, 95% CI, 0.62– 0.77; delayed, AUROC = 0.75, 95% CI, 0.69 – 0.80). Patients who were identified as high risk were 3.1 (P = .006) and 4.2 (P < .001) times more likely to develop grade 2 acute and delayed CINV than were those identified as low risk.

Conclusion This study demonstrates that the scoring systems are able to accurately identify patients at high risk for acute and delayed CINV.

*For a PDF of the full article, click on the link to the left of this introduction.

George Dranitsaris, BPharm, PhD, Nathaniel Bouganim, MD, Carolyn Milano, Lisa Vandermeer, MSc, Susan Dent, MD, Paul Wheatley-Price, MD, Jenny Laporte, RN, Karen-Ann Oxborough, RN, and Mark Clemons, MD

Background Even with modern antiemetic regimens, up to 20% of cancer patients suffer from moderate to severechemotherapy-induced nausea and vomiting (CINV) (grade 2). We previously developed chemotherapy cycle–based risk predictive models forgrade 2 acute and delayed CINV. In this study, the prospective validation of the prediction models andassociated scoring systems is described.

Objective Our objective was to prospectively validate prediction models designed to identify patients at high risk for moderate tosevere CINV.

Methods Patients receiving chemotherapy were provided with CINV symptom diaries. Prior to each cycle of chemotherapy, the acute and delayed CINV scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression was used tocompare the occurrence of grade 2 CINV between patients considered by the model to be at high vs low risk. The external validity of each system was assessed via an area under the receiver operating characteristic (AUROC) curve analysis.

Results Outcome data were collected from 97 patients following 401 cycles of chemotherapy. The incidence of grade 2 acute and delayed CINV was 13.5% and 21.4%, respectively. There was a significant correlation between the risk score and the probability of developing acute and delayed CINV following chemotherapy. Both the acute and delayed scoring systems had good predictive accuracy when applied to the validation sample (acute, AUROC = 0.70, 95% CI, 0.62– 0.77; delayed, AUROC = 0.75, 95% CI, 0.69 – 0.80). Patients who were identified as high risk were 3.1 (P = .006) and 4.2 (P < .001) times more likely to develop grade 2 acute and delayed CINV than were those identified as low risk.

Conclusion This study demonstrates that the scoring systems are able to accurately identify patients at high risk for acute and delayed CINV.

*For a PDF of the full article, click on the link to the left of this introduction.

Nausea and vomiting are common and distressing symptoms in advanced cancer. Both are multifactorial and cause significant morbidity, nutritional failure, and reduced quality of life. Assessment includes a detailed history, physical examination and investigations for reversible causes. Assessment and management will be influenced by performance status, prognosis, and goals of care. Several drug classes are effective with some having the added benefit of multiple routes of administration. It is our institution’s practice to recommend metoclopramide as the first drug with haloperidol as an alternative antiemetic.

Click on the PDF icon at the top of this introduction to read the full article.

Nausea and vomiting are common and distressing symptoms in advanced cancer. Both are multifactorial and cause significant morbidity, nutritional failure, and reduced quality of life. Assessment includes a detailed history, physical examination and investigations for reversible causes. Assessment and management will be influenced by performance status, prognosis, and goals of care. Several drug classes are effective with some having the added benefit of multiple routes of administration. It is our institution’s practice to recommend metoclopramide as the first drug with haloperidol as an alternative antiemetic.

Click on the PDF icon at the top of this introduction to read the full article.

Nausea and vomiting are common and distressing symptoms in advanced cancer. Both are multifactorial and cause significant morbidity, nutritional failure, and reduced quality of life. Assessment includes a detailed history, physical examination and investigations for reversible causes. Assessment and management will be influenced by performance status, prognosis, and goals of care. Several drug classes are effective with some having the added benefit of multiple routes of administration. It is our institution’s practice to recommend metoclopramide as the first drug with haloperidol as an alternative antiemetic.

Click on the PDF icon at the top of this introduction to read the full article.

What are the ethical responsibilities of the medical staff (doctors, nurses, social workers, and chaplains) regarding thepreservation of meaningful life for their patients who are approaching the end of life (EOL)? In particular, what is the staff’sethical responsibility to initiate a conversation with their patient regarding palliative care? By subjecting traditional Jewish teachings to an ethical analysis and then exploring the underlying universal principles, we will suggest a general ethical duty toinform patients of the different care options, especially in a manner that preserves hope. The principle that we can derive from Jewish bioethics teaches that the medical staff has a responsibility to help our patients live in a way that is consistent with how they understand their task or responsibility in life. For some patients, the best way to preserve a meaningful life in which they can fulfill their sense of purpose in the time that remains is to focus on palliation. For this reason, although palliative and supportive care are provided from the time of diagnosis, it is critical we make sure our patients realize that they have the opportunity to make a decision between either pursuing additional active treatments or choosing to focus primarily on palliative therapies to maximize quality of life. The Jewish tradition and our experience in spiritual care suggest the importance of helping patients preserve hope while, simultaneously, honestly acknowledging their situation. Staff members can play a vital role in helping patients make the most of this new period of their lives.

Click on the PDF icon at the top of this introduction to read the full article.

What are the ethical responsibilities of the medical staff (doctors, nurses, social workers, and chaplains) regarding thepreservation of meaningful life for their patients who are approaching the end of life (EOL)? In particular, what is the staff’sethical responsibility to initiate a conversation with their patient regarding palliative care? By subjecting traditional Jewish teachings to an ethical analysis and then exploring the underlying universal principles, we will suggest a general ethical duty toinform patients of the different care options, especially in a manner that preserves hope. The principle that we can derive from Jewish bioethics teaches that the medical staff has a responsibility to help our patients live in a way that is consistent with how they understand their task or responsibility in life. For some patients, the best way to preserve a meaningful life in which they can fulfill their sense of purpose in the time that remains is to focus on palliation. For this reason, although palliative and supportive care are provided from the time of diagnosis, it is critical we make sure our patients realize that they have the opportunity to make a decision between either pursuing additional active treatments or choosing to focus primarily on palliative therapies to maximize quality of life. The Jewish tradition and our experience in spiritual care suggest the importance of helping patients preserve hope while, simultaneously, honestly acknowledging their situation. Staff members can play a vital role in helping patients make the most of this new period of their lives.

Click on the PDF icon at the top of this introduction to read the full article.

What are the ethical responsibilities of the medical staff (doctors, nurses, social workers, and chaplains) regarding thepreservation of meaningful life for their patients who are approaching the end of life (EOL)? In particular, what is the staff’sethical responsibility to initiate a conversation with their patient regarding palliative care? By subjecting traditional Jewish teachings to an ethical analysis and then exploring the underlying universal principles, we will suggest a general ethical duty toinform patients of the different care options, especially in a manner that preserves hope. The principle that we can derive from Jewish bioethics teaches that the medical staff has a responsibility to help our patients live in a way that is consistent with how they understand their task or responsibility in life. For some patients, the best way to preserve a meaningful life in which they can fulfill their sense of purpose in the time that remains is to focus on palliation. For this reason, although palliative and supportive care are provided from the time of diagnosis, it is critical we make sure our patients realize that they have the opportunity to make a decision between either pursuing additional active treatments or choosing to focus primarily on palliative therapies to maximize quality of life. The Jewish tradition and our experience in spiritual care suggest the importance of helping patients preserve hope while, simultaneously, honestly acknowledging their situation. Staff members can play a vital role in helping patients make the most of this new period of their lives.

Click on the PDF icon at the top of this introduction to read the full article.

Kevin P. High, MD, MS; Doug Case, PhD;  MD, David Hurd, MD; Bayard Powell, MD; Glenn Lesser, MD; Ann R. Falsey, MD; Robert Siegel, MD; Joanna Metzner-Sadurski, MD; John C. Krauss, MD; Bernard Chinnasami, MD, George Sanders, MD, Steven Rousey, MD, Edward G. Shaw, MD

*For a PDF of the full article and accompanying commentary by Paul Sloan, click on the links to the left of this introduction.

Kevin P. High, MD, MS; Doug Case, PhD;  MD, David Hurd, MD; Bayard Powell, MD; Glenn Lesser, MD; Ann R. Falsey, MD; Robert Siegel, MD; Joanna Metzner-Sadurski, MD; John C. Krauss, MD; Bernard Chinnasami, MD, George Sanders, MD, Steven Rousey, MD, Edward G. Shaw, MD

*For a PDF of the full article and accompanying commentary by Paul Sloan, click on the links to the left of this introduction.

Kevin P. High, MD, MS; Doug Case, PhD;  MD, David Hurd, MD; Bayard Powell, MD; Glenn Lesser, MD; Ann R. Falsey, MD; Robert Siegel, MD; Joanna Metzner-Sadurski, MD; John C. Krauss, MD; Bernard Chinnasami, MD, George Sanders, MD, Steven Rousey, MD, Edward G. Shaw, MD

*For a PDF of the full article and accompanying commentary by Paul Sloan, click on the links to the left of this introduction.

Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.¹ The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,^2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.⁴ (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.

INFLAMMATION AND VASODILATION

Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.^5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).⁷ Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.

DEFINITIONS

• Sepsis—infection together with systemic manifestation of inflammatory response
• Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
• Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.

EARLY MANAGEMENT OF SEPTIC SHOCK

Early in the course of septic shock, the physician’s job is to:

• Recognize it promptly
• Begin empiric antibiotic therapy quickly
• Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
• Give fluid resuscitation, titrated to specific goals
• Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo₂), or both.⁸ In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,⁹ and they correlate with sepsis-related organ failure scores and outcomes.^10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.¹² Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,¹³ impaired pyruvate dehydrogenase activity,¹⁴ increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,¹⁵ and even impaired clearance.¹⁶

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.^17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.¹⁹ Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al²⁰ evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.

If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.³⁹

But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al²⁷ did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.

The Surviving Sepsis Campaign²² recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.

The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.²² Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.

Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.²²

This is a topic of debate, with recent clinical studies offering further insight.

De Backer et al⁴⁰ compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.

Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,⁴¹ in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.

Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.⁴²

While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.

CONTINUED MANAGEMENT OF SEPTIC SHOCK

How to manage septic shock after the initial stages is much less defined.

Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.^43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.

The clinical decisions necessary after the initial stages of resuscitation include:

• Whether further fluid resuscitation is needed
• Assessment for further and additional hemodynamic therapies
• Consideration of adjunctive therapies
• Reevaluation of antibiotic choices (Table 2).

Is more fluid needed? How can we tell?

There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study²⁷ was that it used central venous pressure as a marker of fluid responsiveness.

Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.⁴⁵ In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.⁴⁶

In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.³¹ These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,³¹ but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.

Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.⁴⁷

Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.⁴⁸ The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).⁴⁹ Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.⁵⁰

In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.

In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.

Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.¹ The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,^2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.⁴ (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.

INFLAMMATION AND VASODILATION

Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.^5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).⁷ Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.

DEFINITIONS

• Sepsis—infection together with systemic manifestation of inflammatory response
• Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
• Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.

EARLY MANAGEMENT OF SEPTIC SHOCK

Early in the course of septic shock, the physician’s job is to:

• Recognize it promptly
• Begin empiric antibiotic therapy quickly
• Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
• Give fluid resuscitation, titrated to specific goals
• Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo₂), or both.⁸ In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,⁹ and they correlate with sepsis-related organ failure scores and outcomes.^10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.¹² Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,¹³ impaired pyruvate dehydrogenase activity,¹⁴ increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,¹⁵ and even impaired clearance.¹⁶

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.^17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.¹⁹ Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al²⁰ evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.

If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.³⁹

But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al²⁷ did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.

The Surviving Sepsis Campaign²² recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.

The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.²² Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.

Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.²²

This is a topic of debate, with recent clinical studies offering further insight.

De Backer et al⁴⁰ compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.

Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,⁴¹ in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.

Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.⁴²

While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.

CONTINUED MANAGEMENT OF SEPTIC SHOCK

How to manage septic shock after the initial stages is much less defined.

Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.^43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.

The clinical decisions necessary after the initial stages of resuscitation include:

• Whether further fluid resuscitation is needed
• Assessment for further and additional hemodynamic therapies
• Consideration of adjunctive therapies
• Reevaluation of antibiotic choices (Table 2).

Is more fluid needed? How can we tell?

There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study²⁷ was that it used central venous pressure as a marker of fluid responsiveness.

Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.⁴⁵ In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.⁴⁶

In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.³¹ These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,³¹ but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.

Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.⁴⁷

Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.⁴⁸ The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).⁴⁹ Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.⁵⁰

In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.

In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.

Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.¹ The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,^2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.⁴ (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.

INFLAMMATION AND VASODILATION

Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.^5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).⁷ Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.

DEFINITIONS

• Sepsis—infection together with systemic manifestation of inflammatory response
• Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
• Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.

EARLY MANAGEMENT OF SEPTIC SHOCK

Early in the course of septic shock, the physician’s job is to:

• Recognize it promptly
• Begin empiric antibiotic therapy quickly
• Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
• Give fluid resuscitation, titrated to specific goals
• Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo₂), or both.⁸ In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,⁹ and they correlate with sepsis-related organ failure scores and outcomes.^10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.¹² Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,¹³ impaired pyruvate dehydrogenase activity,¹⁴ increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,¹⁵ and even impaired clearance.¹⁶

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.^17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.¹⁹ Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al²⁰ evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.

If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.³⁹

But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al²⁷ did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.

The Surviving Sepsis Campaign²² recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.

The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.²² Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.

Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.²²

This is a topic of debate, with recent clinical studies offering further insight.

De Backer et al⁴⁰ compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.

Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,⁴¹ in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.

Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.⁴²

While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.

CONTINUED MANAGEMENT OF SEPTIC SHOCK

How to manage septic shock after the initial stages is much less defined.

Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.^43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.

The clinical decisions necessary after the initial stages of resuscitation include:

• Whether further fluid resuscitation is needed
• Assessment for further and additional hemodynamic therapies
• Consideration of adjunctive therapies
• Reevaluation of antibiotic choices (Table 2).

Is more fluid needed? How can we tell?

There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study²⁷ was that it used central venous pressure as a marker of fluid responsiveness.

Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.⁴⁵ In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.⁴⁶

In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.³¹ These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,³¹ but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.

Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.⁴⁷

Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.⁴⁸ The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).⁴⁹ Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.⁵⁰

In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.

In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.