In Reply: Thanks to Dr. Belur for his observation. He is correct in that the classic triad includes headaches, palpitations, and diaphoresis, although hypertension and hyperglycemia have been described in the literature as frequently occurring, and the clinical presentation can be extremely variable.

In Reply: Thanks to Dr. Belur for his observation. He is correct in that the classic triad includes headaches, palpitations, and diaphoresis, although hypertension and hyperglycemia have been described in the literature as frequently occurring, and the clinical presentation can be extremely variable.

In Reply: Thanks to Dr. Belur for his observation. He is correct in that the classic triad includes headaches, palpitations, and diaphoresis, although hypertension and hyperglycemia have been described in the literature as frequently occurring, and the clinical presentation can be extremely variable.

To the Editor: The article by Dr. Catherine Curley,¹ “Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist,” was very well written, but we would like to point out two facts regarding the diagnosis of pulmonary tuberculosis, especially in high-prevalence countries like India, that might make the article more informative.

First, it has been shown conclusively that good-quality microscopy of two consecutive sputum specimens identifies the majority (95%–98%) of smear-positive tuberculosis patients. The World Health Organization (WHO) therefore revised its policy on case detection by microscopy² in 2007 to recommend a reduction in the number of specimens examined, from three to two in settings with appropriate external quality assurance and documented good-quality microscopy. This approach greatly reduces the workload of laboratories, a considerable advantage in countries with a high proportion of smear-negative tuberculosis patients because of human immunodeficiency virus (HIV), extrapulmonary disease, or both.

Moreover, in 2011, the WHO recommended in a policy statement that countries that have implemented the current WHO policy for two-specimen case-finding consider switching to same-day diagnosis, especially in settings where patients are likely to default from the diagnostic pathway.³

Second, regarding the interferon-gamma-release assay, the 2011 WHO policy stated that there are not only insufficient data and low-quality evidence on the performance of this assay in low- and middle-income countries, typically those with a high tuberculosis and HIV burden, but also that the interferon-gamma-release assay and the tuberculin skin test cannot accurately predict the risk of infected individuals developing active tuberculosis. Moreover, neither the assay nor the skin test should be used for the diagnosis of active tuberculosis disease. The interferon-gamma-release assay is more costly and technically complex than the skin test. Given comparable performance but the increased cost, replacing the skin test with the interferon-gamma-release assay is not recommended as a public health intervention in resource-constrained settings.⁴ The majority of tuberculosis cases (on average 85.8%) were detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%.⁵

To the Editor: The article by Dr. Catherine Curley,¹ “Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist,” was very well written, but we would like to point out two facts regarding the diagnosis of pulmonary tuberculosis, especially in high-prevalence countries like India, that might make the article more informative.

First, it has been shown conclusively that good-quality microscopy of two consecutive sputum specimens identifies the majority (95%–98%) of smear-positive tuberculosis patients. The World Health Organization (WHO) therefore revised its policy on case detection by microscopy² in 2007 to recommend a reduction in the number of specimens examined, from three to two in settings with appropriate external quality assurance and documented good-quality microscopy. This approach greatly reduces the workload of laboratories, a considerable advantage in countries with a high proportion of smear-negative tuberculosis patients because of human immunodeficiency virus (HIV), extrapulmonary disease, or both.

Moreover, in 2011, the WHO recommended in a policy statement that countries that have implemented the current WHO policy for two-specimen case-finding consider switching to same-day diagnosis, especially in settings where patients are likely to default from the diagnostic pathway.³

Second, regarding the interferon-gamma-release assay, the 2011 WHO policy stated that there are not only insufficient data and low-quality evidence on the performance of this assay in low- and middle-income countries, typically those with a high tuberculosis and HIV burden, but also that the interferon-gamma-release assay and the tuberculin skin test cannot accurately predict the risk of infected individuals developing active tuberculosis. Moreover, neither the assay nor the skin test should be used for the diagnosis of active tuberculosis disease. The interferon-gamma-release assay is more costly and technically complex than the skin test. Given comparable performance but the increased cost, replacing the skin test with the interferon-gamma-release assay is not recommended as a public health intervention in resource-constrained settings.⁴ The majority of tuberculosis cases (on average 85.8%) were detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%.⁵

To the Editor: The article by Dr. Catherine Curley,¹ “Rule out pulmonary tuberculosis: clinical and radiographic clues for the internist,” was very well written, but we would like to point out two facts regarding the diagnosis of pulmonary tuberculosis, especially in high-prevalence countries like India, that might make the article more informative.

First, it has been shown conclusively that good-quality microscopy of two consecutive sputum specimens identifies the majority (95%–98%) of smear-positive tuberculosis patients. The World Health Organization (WHO) therefore revised its policy on case detection by microscopy² in 2007 to recommend a reduction in the number of specimens examined, from three to two in settings with appropriate external quality assurance and documented good-quality microscopy. This approach greatly reduces the workload of laboratories, a considerable advantage in countries with a high proportion of smear-negative tuberculosis patients because of human immunodeficiency virus (HIV), extrapulmonary disease, or both.

Moreover, in 2011, the WHO recommended in a policy statement that countries that have implemented the current WHO policy for two-specimen case-finding consider switching to same-day diagnosis, especially in settings where patients are likely to default from the diagnostic pathway.³

Second, regarding the interferon-gamma-release assay, the 2011 WHO policy stated that there are not only insufficient data and low-quality evidence on the performance of this assay in low- and middle-income countries, typically those with a high tuberculosis and HIV burden, but also that the interferon-gamma-release assay and the tuberculin skin test cannot accurately predict the risk of infected individuals developing active tuberculosis. Moreover, neither the assay nor the skin test should be used for the diagnosis of active tuberculosis disease. The interferon-gamma-release assay is more costly and technically complex than the skin test. Given comparable performance but the increased cost, replacing the skin test with the interferon-gamma-release assay is not recommended as a public health intervention in resource-constrained settings.⁴ The majority of tuberculosis cases (on average 85.8%) were detected with the first sputum specimen. With the second sputum specimen, the average incremental yield was 11.9%, while the incremental yield of the third specimen, when the first two specimens were negative, was 3.1%.⁵

In Reply: Thank you for your interesting and appropriate comments. The workup and testing of patients with suspected tuberculosis is clearly different in countries with a higher prevalence of tuberculosis than in countries with a lower prevalence. I appreciate that both the purified protein derivative and the interferon-gamma-release assay have very limited utility in the evaluation for active tuberculosis when there is a very high background prevalence of latent tuberculosis infection. In low-prevalence countries like the United States, tuberculosis is often considered in the differential diagnosis even when other infections or lung cancer is more likely. The tests for latent tuberculosis are considered quite important in the workup of active tuberculosis in this setting.

In Reply: Thank you for your interesting and appropriate comments. The workup and testing of patients with suspected tuberculosis is clearly different in countries with a higher prevalence of tuberculosis than in countries with a lower prevalence. I appreciate that both the purified protein derivative and the interferon-gamma-release assay have very limited utility in the evaluation for active tuberculosis when there is a very high background prevalence of latent tuberculosis infection. In low-prevalence countries like the United States, tuberculosis is often considered in the differential diagnosis even when other infections or lung cancer is more likely. The tests for latent tuberculosis are considered quite important in the workup of active tuberculosis in this setting.

In Reply: Thank you for your interesting and appropriate comments. The workup and testing of patients with suspected tuberculosis is clearly different in countries with a higher prevalence of tuberculosis than in countries with a lower prevalence. I appreciate that both the purified protein derivative and the interferon-gamma-release assay have very limited utility in the evaluation for active tuberculosis when there is a very high background prevalence of latent tuberculosis infection. In low-prevalence countries like the United States, tuberculosis is often considered in the differential diagnosis even when other infections or lung cancer is more likely. The tests for latent tuberculosis are considered quite important in the workup of active tuberculosis in this setting.

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

 

 

Woman sunbathing

 

Vitamin D deficiency may negatively impact outcomes in patients with follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.

The study showed that FL patients with vitamin D deficiency had inferior progression-free survival (PFS) and overall survival (OS) compared to patients with higher vitamin D levels.

According to researchers, this suggests serum vitamin D might be the first potentially modifiable factor to be associated with survival in FL.

However, additional research is needed to determine the effects of vitamin D supplementation in these patients.

Jonathan W. Friedberg, MD, of the Wilmot Cancer Institute at the University of Rochester in New York, and his colleagues conducted this research, analyzing data from 2 cohorts of FL patients.

One cohort consisted of patients derived from 3 SWOG trials (S9800, S9911, and S0016), and the other consisted of patients from a Lymphoma Study Association (LYSA) trial known as PRIMA.

SWOG patients had received CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab), and LYSA patients had received rituximab plus chemotherapy (and were randomized to rituximab maintenance or observation).

SWOG cohort

After a median follow-up of 5.4 years, patients with vitamin D deficiency (defined as <20 ng/mL) had significantly inferior PFS (hazard ratio [HR]=2.00; P=0.011) and OS (HR=3.57; P=0.003) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (IPI), body mass index, and latitude (≥ vs <35°N). For PFS, the adjusted HR was 1.97 (P=0.023). And for OS, the adjusted HR was 4.16 (P=0.002).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but neither result was significant.

LYSA cohort

After a median follow-up of 6.6 years, patients with vitamin D deficiency (defined as <10 ng/mL) had significantly inferior PFS (HR=1.66; P=0.013) but not OS (HR=1.84; P=0.14) compared to patients with higher vitamin D levels.

Results were similar when the researchers adjusted for other variables, such as prognostic index (FLIPI), body mass index, latitude (Europe vs Australia), and hemoglobin. For PFS, the adjusted HR was 1.50 (P=0.095). For OS, the adjusted HR was 1.92 (P=0.192).

Multivariable analysis of vitamin D by tertile confirmed that the lowest tertile of vitamin D was associated with a greater increase in the risk of either progression or death, but only the association with OS reached statistical significance (HR=5.32; P=0.037).

Dr Friedberg said that, taken together, these results suggest vitamin D levels may be a modifiable factor associated with prognosis in patients with FL.

“Our data, replicated internationally, supports other published observations linking vitamin D deficiency with inferior cancer outcomes,” he said. “However, the mechanisms of this link are likely complex and require further study.”

The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).

Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.

The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.

Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.

Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.

Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).

Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.

The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.

Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.

Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.

Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.

The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).

Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.

Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.

The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.

Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.

Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.

Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Maria E. Figueroa, MD

Photo courtesy of

University of Michigan

Newly identified molecular signatures may allow us to predict which patients with chronic myelomonocytic leukemia (CMML) will respond to treatment, according to a study published in The Journal of Clinical Investigation.

Finding effective biomarkers is particularly crucial for CMML, the investigators said, because current treatment is slow-acting. Patients must often undergo as much as 6 months of treatment before there are signs of response.

“The slow kinetics is what gets us,” said study author Maria E. Figueroa, MD, of the University of Michigan Medical School in Ann Arbor.

“It’s not just one week or one dose to see signs of response. A good biomarker test could potentially prevent patients who are unlikely to respond from receiving prolonged, unwarranted treatments.”

With this in mind, Dr Figueroa and her colleagues used next-generation sequencing techniques to analyze 40 CMML samples from patients treated with the DNA methyltransferase inhibitor decitabine.

The researchers found 167 differentially methylated regions of DNA at baseline that distinguished patients who responded to decitabine from those who did not. There was a methylation difference of 25% or more between responders and nonresponders.

The investigators speculated that the baseline differences in DNA methylation could be used to predict treatment response at diagnosis.

So they used the percentage of cytosine methylation at each genomic location among the 40 patients as potential predictors and applied a machine-learning approach to build an epigenetic classifier.

The investigators tested the classifier in 28 additional CMML samples and found it was 87% accurate in predicting a patient’s response to decitabine.

The researchers also investigated why nonresponders were resistant to decitabine and found that 2 proteins, CXCL4 and CXCL7, were overexpressed in nonresponders. In cells exposed to high levels of these chemokines, the effects of decitabine were blocked.

“We are pursuing this to understand why these proteins block the effect of the drug and whether we can develop a new compound that could be used along with decitabine to turn nonresponders into responders,” Dr Figueroa said.

The researchers are also working to refine and translate their findings into a viable biomarker test that could be used in the clinic.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Carbon Monoxide Poisoning

A 72-year-old man was brought to the ED by paramedics with inability to move his left leg and difficulty speaking. The patient had been heating his home with a generator placed inside the house during an ice storm, and paramedics reported a strong smell of gas inside the house.

The patient was unable to describe the time of onset of his symptoms. He complained of headache, slurred speech, and inability to move his left leg. He also said he felt the urge to urinate, but was unable to do so. He denied chest pain or shortness of breath. His medical history was significant only for hypertension, which was controlled with hydrochlorothiazide and lisinopril. He admitted to smoking a few cigarettes daily, but denied any alcohol use.

On physical examination, the patient’s vital signs were: blood pressure (BP) 162/98 mm Hg; heart rate (HR), 110 beats/minute; respiratory rate (RR), 20 breaths/minute; and temperature (T), 98.6˚F. The patient had 100% oxygen (O₂) saturation on 4L O₂ via nasal cannula. The head, eyes, ears, nose, and throat examination was normal. There was no facial droop; his speech was slurred, but he was easily understandable. The cardiopulmonary examination revealed tachycardia without murmurs, rubs, or gallop; the lungs were clear to auscultation bilaterally. The neurological examination revealed 5/5 motor strength in the upper extremities and symmetrical; there was no pronator drift. The left leg had 2/5 motor strength compared to 5/5 in the right lower extremity. There was also fullness and tenderness over his suprapubic region. 

The emergency physician (EP) ordered a complete blood count, basic metabolic profile, carboxyhemoglobin (COHb) test, electrocardiogram (ECG), portable chest X-ray (CXR), and a noncontrast computed tomography (CT) scan of the head. Since the history and physical examination suggested urinary retention, a Foley catheter was placed; a total of 1,200 cc of clear urine was obtained, after which the patient expressed a feeling of relief.

The patient’s COHb level was 8.5%. The portable CXR and CT scan of the head were both reported as normal by the radiologist. Likewise, the results of the rest of the laboratory evaluation were normal. The ECG revealed sinus tachycardia without evidence of strain or injury.

The EP diagnosed an acute cerebrovascular accident (CVA) and admitted the patient to the hospital. He did not feel that carbon monoxide (CO) contributed to the event given the low level in a cigarette smoker. After an uneventful hospital stay, the patient was transferred to a physical rehabilitation unit. He was ultimately discharged with a neurogenic bladder and weak left leg.

The patient sued the EP for negligence in the failure to diagnose CO poisoning and prompt initiation of 100% O₂ therapy. The EP argued that CO poisoning had been properly ruled out and that the diagnosis of CVA was correct. The defense also claimed that even if the patient had suffered CO poisoning, the length of the exposure would have led to the same outcome. A defense verdict was returned.

Discussion

Carbon monoxide poisoning is one of the leading causes of poisoning morbidity and mortality in the United States. This is in part due to the fact that CO is a colorless, odorless, and tasteless gas. The peak incidence for CO poisoning is in the fall and winter, when people are more likely to use space heaters, wood burning stoves, or portable generators inside without adequate ventilation. 

The clinical presentation of CO poisoning can range from mild (eg, headache, flu-like symptoms) to devastating (eg, coma, death). The central nervous system is the organ system that is most sensitive to CO poisoning. Symptoms can range from a dull frontal headache, dizziness, and ataxia, to syncope, seizures, focal neurological deficit, and coma. In fact, the most serious complication of CO poisoning may be persistent or delayed neurological or neurocognitive sequelae, which can occur in up to 50% of patients with symptomatic acute poisoning.¹  Unfortunately, COHb levels and symptoms do not always correlate well. In fact, particular COHb levels are not predictive of symptoms or outcome.¹

The treatment for CO poisoning consists of administering 100% O₂ as soon as the diagnosis is considered. If 100% O₂ is administered, the half-life of COHb can be reduced from 5 hours (room air) to approximately 1 hour.¹ While some argue that treatment with hyperbaric O₂ (HBO) therapy should be considered standard of care, it has not yet been determined which patient population benefits from HBO therapy; moreover, there is currently no established optimum timing of therapy. Regardless, the jury came to the correct decision in this case as it is impossible to determine, with any degree of medical certainty, if the patient’s neurological deficits were due to the natural course of an ischemic stroke, or if CO contributed to or was the sole cause of the CVA.

Death in the Emergency Department

A 43-year-old man presented to the ED with the chief complaint of a lower lip laceration. The patient stated he had gotten into an altercation with his girlfriend just prior to arrival. She had punched the patient in the face with her fist, resulting in the lip laceration. The patient denied any loss of consciousness or other pain. He did, however, smell of alcohol and was emotionally labile, crying one moment and yelling the next.

The patient was instructed to remove all of his clothes, change into a hospital gown and give all of his belongings to hospital security. He removed his clothes, but refused to turn them over to security. This prompted a physical altercation between the patient and hospital security. Three hospital security guards wrestled the patient to the ground and placed him face down; one guard placed the patient in a choke hold while the other two guards sat on top of him. Within a few moments, the patient became unresponsive. He was placed immediately on a stretcher and intubated by the EP. After successful intubation and bagging with 100% O₂, the patient regained a palpable pulse, but remained unresponsive.

The patient was admitted to the intensive care unit, but never regained consciousness and died 5 days later. The cause of death was thought to be anoxic brain injury due to asphyxiation. The family of the patient sued the hospital and the EP for causing asphyxiation and death in this patient seeking medical care. The hospital denied responsibility for the death because the patient both instigated the altercation and had a preexisting heart condition. According to published reports, a $2.5 million settlement was reached.

Discussion

This unfortunate case did not involve the EP; all of the important events transpired prior to the EP’s initial interaction with the patient. There are not enough details to explain how this situation escalated so rapidly, or why hospital security felt this was the best way to subdue the patient.

Unfortunately, EPs are no strangers to agitated patients. Behavioral emergencies account for approximately 5% of all ED visits, and these usually involve some form of violence or agitation.¹  Every physician and nurse working in the ED must be prepared to deal with patients who have the potential to become violent. Clearly, training of all patient-care personnel to handle such patients in the ED is important to ensuring both staff and patient safety. Having the patient undress and change into a hospital gown is the correct first step. This allows for removal of real or potential weapons, and makes it much less likely for the patient to leave before his or her evaluation and management is complete. Doing this properly, however, is key. Providing the patient with a warm blanket or food, or just talking to him or her in a calm and reassuring voice, can often prevent escalation. Simply arguing with the patient rarely works, and often has the opposite desired effect.

If the situation continues to escalate, and it appears either physical or chemical restraint will be necessary, a “show of force” should be made. A restraint team consisting of at least five trained members should be assembled, with the EP acting as the team leader. The team should all enter the room at the same time, explain what will happen, and then move quickly.¹ The leader should move to the head of the bed and direct the team, while the remaining four members each take a limb. To preserve the physician-patient relationship, it is best if the EP is not actively involved in placing the physical restraints.

The choke hold should only be considered as a method of last resort. Many police departments in the country prohibit use of the choke hold because of complications such as those observed in this case. The use of choke holds became a topic of intense debate this summer with the death of Eric Garner in Staten Island, New York; it was thought that his pre-existing conditions of obesity, asthma, and heart disease were all aggravated by the choke hold. Although obese patients are often at a higher risk for complications due to pre-existing issues with adequate oxygenation, it is unclear whether the patient in this case was obese.

An alternative strategy in handling an agitated patient would be the use of a taser by trained security personnel. In one study, 99.75% of tasered patients had no significant injury as a result of the device.² In 2009, the American Medical Association found that tasers, “when used appropriately, can save lives during interventions that would have otherwise involved the use of deadly force.” While the safety of patients and the ED staff (nurses, physicians, and technicians) is paramount, the clinician should always adhere to the principle of “primum non nocere”—“first, do no harm.”

Carbon Monoxide Poisoning

A 72-year-old man was brought to the ED by paramedics with inability to move his left leg and difficulty speaking. The patient had been heating his home with a generator placed inside the house during an ice storm, and paramedics reported a strong smell of gas inside the house.

The patient was unable to describe the time of onset of his symptoms. He complained of headache, slurred speech, and inability to move his left leg. He also said he felt the urge to urinate, but was unable to do so. He denied chest pain or shortness of breath. His medical history was significant only for hypertension, which was controlled with hydrochlorothiazide and lisinopril. He admitted to smoking a few cigarettes daily, but denied any alcohol use.

On physical examination, the patient’s vital signs were: blood pressure (BP) 162/98 mm Hg; heart rate (HR), 110 beats/minute; respiratory rate (RR), 20 breaths/minute; and temperature (T), 98.6˚F. The patient had 100% oxygen (O₂) saturation on 4L O₂ via nasal cannula. The head, eyes, ears, nose, and throat examination was normal. There was no facial droop; his speech was slurred, but he was easily understandable. The cardiopulmonary examination revealed tachycardia without murmurs, rubs, or gallop; the lungs were clear to auscultation bilaterally. The neurological examination revealed 5/5 motor strength in the upper extremities and symmetrical; there was no pronator drift. The left leg had 2/5 motor strength compared to 5/5 in the right lower extremity. There was also fullness and tenderness over his suprapubic region. 

The emergency physician (EP) ordered a complete blood count, basic metabolic profile, carboxyhemoglobin (COHb) test, electrocardiogram (ECG), portable chest X-ray (CXR), and a noncontrast computed tomography (CT) scan of the head. Since the history and physical examination suggested urinary retention, a Foley catheter was placed; a total of 1,200 cc of clear urine was obtained, after which the patient expressed a feeling of relief.

The patient’s COHb level was 8.5%. The portable CXR and CT scan of the head were both reported as normal by the radiologist. Likewise, the results of the rest of the laboratory evaluation were normal. The ECG revealed sinus tachycardia without evidence of strain or injury.

The EP diagnosed an acute cerebrovascular accident (CVA) and admitted the patient to the hospital. He did not feel that carbon monoxide (CO) contributed to the event given the low level in a cigarette smoker. After an uneventful hospital stay, the patient was transferred to a physical rehabilitation unit. He was ultimately discharged with a neurogenic bladder and weak left leg.

The patient sued the EP for negligence in the failure to diagnose CO poisoning and prompt initiation of 100% O₂ therapy. The EP argued that CO poisoning had been properly ruled out and that the diagnosis of CVA was correct. The defense also claimed that even if the patient had suffered CO poisoning, the length of the exposure would have led to the same outcome. A defense verdict was returned.

Discussion

Carbon monoxide poisoning is one of the leading causes of poisoning morbidity and mortality in the United States. This is in part due to the fact that CO is a colorless, odorless, and tasteless gas. The peak incidence for CO poisoning is in the fall and winter, when people are more likely to use space heaters, wood burning stoves, or portable generators inside without adequate ventilation. 

The clinical presentation of CO poisoning can range from mild (eg, headache, flu-like symptoms) to devastating (eg, coma, death). The central nervous system is the organ system that is most sensitive to CO poisoning. Symptoms can range from a dull frontal headache, dizziness, and ataxia, to syncope, seizures, focal neurological deficit, and coma. In fact, the most serious complication of CO poisoning may be persistent or delayed neurological or neurocognitive sequelae, which can occur in up to 50% of patients with symptomatic acute poisoning.¹  Unfortunately, COHb levels and symptoms do not always correlate well. In fact, particular COHb levels are not predictive of symptoms or outcome.¹

The treatment for CO poisoning consists of administering 100% O₂ as soon as the diagnosis is considered. If 100% O₂ is administered, the half-life of COHb can be reduced from 5 hours (room air) to approximately 1 hour.¹ While some argue that treatment with hyperbaric O₂ (HBO) therapy should be considered standard of care, it has not yet been determined which patient population benefits from HBO therapy; moreover, there is currently no established optimum timing of therapy. Regardless, the jury came to the correct decision in this case as it is impossible to determine, with any degree of medical certainty, if the patient’s neurological deficits were due to the natural course of an ischemic stroke, or if CO contributed to or was the sole cause of the CVA.

Death in the Emergency Department

A 43-year-old man presented to the ED with the chief complaint of a lower lip laceration. The patient stated he had gotten into an altercation with his girlfriend just prior to arrival. She had punched the patient in the face with her fist, resulting in the lip laceration. The patient denied any loss of consciousness or other pain. He did, however, smell of alcohol and was emotionally labile, crying one moment and yelling the next.

The patient was instructed to remove all of his clothes, change into a hospital gown and give all of his belongings to hospital security. He removed his clothes, but refused to turn them over to security. This prompted a physical altercation between the patient and hospital security. Three hospital security guards wrestled the patient to the ground and placed him face down; one guard placed the patient in a choke hold while the other two guards sat on top of him. Within a few moments, the patient became unresponsive. He was placed immediately on a stretcher and intubated by the EP. After successful intubation and bagging with 100% O₂, the patient regained a palpable pulse, but remained unresponsive.

The patient was admitted to the intensive care unit, but never regained consciousness and died 5 days later. The cause of death was thought to be anoxic brain injury due to asphyxiation. The family of the patient sued the hospital and the EP for causing asphyxiation and death in this patient seeking medical care. The hospital denied responsibility for the death because the patient both instigated the altercation and had a preexisting heart condition. According to published reports, a $2.5 million settlement was reached.

Discussion

This unfortunate case did not involve the EP; all of the important events transpired prior to the EP’s initial interaction with the patient. There are not enough details to explain how this situation escalated so rapidly, or why hospital security felt this was the best way to subdue the patient.

Unfortunately, EPs are no strangers to agitated patients. Behavioral emergencies account for approximately 5% of all ED visits, and these usually involve some form of violence or agitation.¹  Every physician and nurse working in the ED must be prepared to deal with patients who have the potential to become violent. Clearly, training of all patient-care personnel to handle such patients in the ED is important to ensuring both staff and patient safety. Having the patient undress and change into a hospital gown is the correct first step. This allows for removal of real or potential weapons, and makes it much less likely for the patient to leave before his or her evaluation and management is complete. Doing this properly, however, is key. Providing the patient with a warm blanket or food, or just talking to him or her in a calm and reassuring voice, can often prevent escalation. Simply arguing with the patient rarely works, and often has the opposite desired effect.

If the situation continues to escalate, and it appears either physical or chemical restraint will be necessary, a “show of force” should be made. A restraint team consisting of at least five trained members should be assembled, with the EP acting as the team leader. The team should all enter the room at the same time, explain what will happen, and then move quickly.¹ The leader should move to the head of the bed and direct the team, while the remaining four members each take a limb. To preserve the physician-patient relationship, it is best if the EP is not actively involved in placing the physical restraints.

The choke hold should only be considered as a method of last resort. Many police departments in the country prohibit use of the choke hold because of complications such as those observed in this case. The use of choke holds became a topic of intense debate this summer with the death of Eric Garner in Staten Island, New York; it was thought that his pre-existing conditions of obesity, asthma, and heart disease were all aggravated by the choke hold. Although obese patients are often at a higher risk for complications due to pre-existing issues with adequate oxygenation, it is unclear whether the patient in this case was obese.

An alternative strategy in handling an agitated patient would be the use of a taser by trained security personnel. In one study, 99.75% of tasered patients had no significant injury as a result of the device.² In 2009, the American Medical Association found that tasers, “when used appropriately, can save lives during interventions that would have otherwise involved the use of deadly force.” While the safety of patients and the ED staff (nurses, physicians, and technicians) is paramount, the clinician should always adhere to the principle of “primum non nocere”—“first, do no harm.”

Carbon Monoxide Poisoning

A 72-year-old man was brought to the ED by paramedics with inability to move his left leg and difficulty speaking. The patient had been heating his home with a generator placed inside the house during an ice storm, and paramedics reported a strong smell of gas inside the house.

The patient was unable to describe the time of onset of his symptoms. He complained of headache, slurred speech, and inability to move his left leg. He also said he felt the urge to urinate, but was unable to do so. He denied chest pain or shortness of breath. His medical history was significant only for hypertension, which was controlled with hydrochlorothiazide and lisinopril. He admitted to smoking a few cigarettes daily, but denied any alcohol use.

On physical examination, the patient’s vital signs were: blood pressure (BP) 162/98 mm Hg; heart rate (HR), 110 beats/minute; respiratory rate (RR), 20 breaths/minute; and temperature (T), 98.6˚F. The patient had 100% oxygen (O₂) saturation on 4L O₂ via nasal cannula. The head, eyes, ears, nose, and throat examination was normal. There was no facial droop; his speech was slurred, but he was easily understandable. The cardiopulmonary examination revealed tachycardia without murmurs, rubs, or gallop; the lungs were clear to auscultation bilaterally. The neurological examination revealed 5/5 motor strength in the upper extremities and symmetrical; there was no pronator drift. The left leg had 2/5 motor strength compared to 5/5 in the right lower extremity. There was also fullness and tenderness over his suprapubic region. 

The emergency physician (EP) ordered a complete blood count, basic metabolic profile, carboxyhemoglobin (COHb) test, electrocardiogram (ECG), portable chest X-ray (CXR), and a noncontrast computed tomography (CT) scan of the head. Since the history and physical examination suggested urinary retention, a Foley catheter was placed; a total of 1,200 cc of clear urine was obtained, after which the patient expressed a feeling of relief.

The patient’s COHb level was 8.5%. The portable CXR and CT scan of the head were both reported as normal by the radiologist. Likewise, the results of the rest of the laboratory evaluation were normal. The ECG revealed sinus tachycardia without evidence of strain or injury.

The EP diagnosed an acute cerebrovascular accident (CVA) and admitted the patient to the hospital. He did not feel that carbon monoxide (CO) contributed to the event given the low level in a cigarette smoker. After an uneventful hospital stay, the patient was transferred to a physical rehabilitation unit. He was ultimately discharged with a neurogenic bladder and weak left leg.

The patient sued the EP for negligence in the failure to diagnose CO poisoning and prompt initiation of 100% O₂ therapy. The EP argued that CO poisoning had been properly ruled out and that the diagnosis of CVA was correct. The defense also claimed that even if the patient had suffered CO poisoning, the length of the exposure would have led to the same outcome. A defense verdict was returned.

Discussion

Carbon monoxide poisoning is one of the leading causes of poisoning morbidity and mortality in the United States. This is in part due to the fact that CO is a colorless, odorless, and tasteless gas. The peak incidence for CO poisoning is in the fall and winter, when people are more likely to use space heaters, wood burning stoves, or portable generators inside without adequate ventilation. 

The clinical presentation of CO poisoning can range from mild (eg, headache, flu-like symptoms) to devastating (eg, coma, death). The central nervous system is the organ system that is most sensitive to CO poisoning. Symptoms can range from a dull frontal headache, dizziness, and ataxia, to syncope, seizures, focal neurological deficit, and coma. In fact, the most serious complication of CO poisoning may be persistent or delayed neurological or neurocognitive sequelae, which can occur in up to 50% of patients with symptomatic acute poisoning.¹  Unfortunately, COHb levels and symptoms do not always correlate well. In fact, particular COHb levels are not predictive of symptoms or outcome.¹

The treatment for CO poisoning consists of administering 100% O₂ as soon as the diagnosis is considered. If 100% O₂ is administered, the half-life of COHb can be reduced from 5 hours (room air) to approximately 1 hour.¹ While some argue that treatment with hyperbaric O₂ (HBO) therapy should be considered standard of care, it has not yet been determined which patient population benefits from HBO therapy; moreover, there is currently no established optimum timing of therapy. Regardless, the jury came to the correct decision in this case as it is impossible to determine, with any degree of medical certainty, if the patient’s neurological deficits were due to the natural course of an ischemic stroke, or if CO contributed to or was the sole cause of the CVA.

Death in the Emergency Department

A 43-year-old man presented to the ED with the chief complaint of a lower lip laceration. The patient stated he had gotten into an altercation with his girlfriend just prior to arrival. She had punched the patient in the face with her fist, resulting in the lip laceration. The patient denied any loss of consciousness or other pain. He did, however, smell of alcohol and was emotionally labile, crying one moment and yelling the next.

The patient was instructed to remove all of his clothes, change into a hospital gown and give all of his belongings to hospital security. He removed his clothes, but refused to turn them over to security. This prompted a physical altercation between the patient and hospital security. Three hospital security guards wrestled the patient to the ground and placed him face down; one guard placed the patient in a choke hold while the other two guards sat on top of him. Within a few moments, the patient became unresponsive. He was placed immediately on a stretcher and intubated by the EP. After successful intubation and bagging with 100% O₂, the patient regained a palpable pulse, but remained unresponsive.

The patient was admitted to the intensive care unit, but never regained consciousness and died 5 days later. The cause of death was thought to be anoxic brain injury due to asphyxiation. The family of the patient sued the hospital and the EP for causing asphyxiation and death in this patient seeking medical care. The hospital denied responsibility for the death because the patient both instigated the altercation and had a preexisting heart condition. According to published reports, a $2.5 million settlement was reached.

Discussion

This unfortunate case did not involve the EP; all of the important events transpired prior to the EP’s initial interaction with the patient. There are not enough details to explain how this situation escalated so rapidly, or why hospital security felt this was the best way to subdue the patient.

Unfortunately, EPs are no strangers to agitated patients. Behavioral emergencies account for approximately 5% of all ED visits, and these usually involve some form of violence or agitation.¹  Every physician and nurse working in the ED must be prepared to deal with patients who have the potential to become violent. Clearly, training of all patient-care personnel to handle such patients in the ED is important to ensuring both staff and patient safety. Having the patient undress and change into a hospital gown is the correct first step. This allows for removal of real or potential weapons, and makes it much less likely for the patient to leave before his or her evaluation and management is complete. Doing this properly, however, is key. Providing the patient with a warm blanket or food, or just talking to him or her in a calm and reassuring voice, can often prevent escalation. Simply arguing with the patient rarely works, and often has the opposite desired effect.

If the situation continues to escalate, and it appears either physical or chemical restraint will be necessary, a “show of force” should be made. A restraint team consisting of at least five trained members should be assembled, with the EP acting as the team leader. The team should all enter the room at the same time, explain what will happen, and then move quickly.¹ The leader should move to the head of the bed and direct the team, while the remaining four members each take a limb. To preserve the physician-patient relationship, it is best if the EP is not actively involved in placing the physical restraints.

The choke hold should only be considered as a method of last resort. Many police departments in the country prohibit use of the choke hold because of complications such as those observed in this case. The use of choke holds became a topic of intense debate this summer with the death of Eric Garner in Staten Island, New York; it was thought that his pre-existing conditions of obesity, asthma, and heart disease were all aggravated by the choke hold. Although obese patients are often at a higher risk for complications due to pre-existing issues with adequate oxygenation, it is unclear whether the patient in this case was obese.

An alternative strategy in handling an agitated patient would be the use of a taser by trained security personnel. In one study, 99.75% of tasered patients had no significant injury as a result of the device.² In 2009, the American Medical Association found that tasers, “when used appropriately, can save lives during interventions that would have otherwise involved the use of deadly force.” While the safety of patients and the ED staff (nurses, physicians, and technicians) is paramount, the clinician should always adhere to the principle of “primum non nocere”—“first, do no harm.”

Sepsis is familiar to most physicians in clinical practice, but guidance from the medical literature on how best to manage it has traditionally been confusing.

Starting in 2002, the Surviving Sepsis Campaign has worked to reduce worldwide mortality from severe sepsis and septic shock by developing and publicizing guidelines of best practices based on evidence from the literature. The campaign published its first management guidelines in 2004.

In this article, I review the most recent guidelines^1,2 (published in 2013) and discuss the campaign’s ongoing performance-improvement program.

DEFINING SEPSIS

Sepsis is a known or suspected infection plus systemic manifestations of infection. This includes the sepsis inflammatory response syndrome. Criteria include:

• Tachycardia (heart rate > 90 beats per minute)
• Tachypnea (> 20 breaths/minute or Paco₂ < 32 mm Hg)
• Fever (temperature > 38.3°C [100.9°F]) or hypothermia (core temperature < 36°C [96.8°F])
• High or low white blood cell count (> 12.0 × 10⁹/L or < 4.0 × 10⁹/L), or a normal count with more than 10% immature cells.

The definition of sepsis was broadened in 2002 to include other systemic manifestations of infection, such as changes in blood glucose level and organ dysfunction.

Severe sepsis is defined as sepsis plus either acute organ dysfunction or tissue hypoperfusion due to infection, with tissue hypoperfusion defined as:

• Hypotension (systolic blood pressure < 90 mm Hg, or a drop in systolic blood pressure of > 40 mm Hg)
• Elevated lactate
• Low urine output
• Altered mental status.

In severe sepsis, organ dysfunction is caused by blood-borne toxins and involves acute lung and kidney injury, coagulopathy (thrombocytopenia and increased international normalized ratio), and liver dysfunction.

Septic shock is present when a patient requires vasopressors after adequate intravascular volume repletion.

SEPSIS IS DEADLY AND COSTLY

Severe sepsis is the leading cause of hospital death. Patients admitted with severe sepsis are eight times more likely to die than those admitted with other conditions.³ The economic burden is enormous: it is the most expensive condition treated in US hospitals, costing an estimated $20.3 billion in 2011, of which $12.7 billion came from Medicare.

THE SURVIVING SEPSIS CAMPAIGN

The Surviving Sepsis Campaign is a global effort to reduce the rate of death from severe sepsis. The campaign’s methods include:

Patients with severe sepsis are eight times more likely to die than those with other conditions

• Educating physicians, the public, the media, and government about the high rates of morbidity and death in severe sepsis
• Creating evidence-based guidelines for managing sepsis and establishing global best-practice standards
• Facilitating the transfer of knowledge by developing performance-improvement programs to change bedside practice.

The campaign is funded with a grant from the Gordon and Betty Moore Foundation. The campaign’s guidelines are not associated with any direct or indirect industry support. The 2013 guidelines were backed by 30 international organizations.^1,2

All recommendations are ranked with numerical and letter scores, according to the GRADE system: 1 indicates a strong recommendation and 2 a weak one. The letters A through D reflect the quality of evidence, ranging from high (A) to very low (D).

GIVING ANTIBIOTICS EARLY IMPROVES OUTCOMES

A number of studies have suggested that starting appropriate antibiotics early improves outcomes in severe sepsis and septic shock. The death rate increases with each hour of delay.⁴

Recommendation. Intravenous antibiotic therapy should be started as soon as possible, and within the first hour after recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C).

The feasibility of achieving this goal has not been scientifically validated, and the recommendation should not be misinterpreted as the current standard of care. Even hospitals that participate in performance-improvement programs often struggle to start antibiotics, even within 6 hours of recognition. Nevertheless, the goal is a good one.

Some have questioned the early antibiotic recommendation because of concerns about antibiotic overuse and resistance. For a patient with some manifestation of systemic inflammation, such as organ dysfunction or hypotension with no clear cause, the campaign’s position is to provide empiric antibiotics early and then, if a noninfectious cause is found, to stop the antibiotics. Moreover, as soon as a causative pathogen has been identified, the regimen should be switched to the most appropriate antimicrobial that covers the pathogen and is safe and cost-effective. Collaboration with an antimicrobial stewardship program, if available, is encouraged.

FIND THE INFECTION SOURCE PROMPTLY: SOURCE CONTROL MAY BE REQUIRED

Recommendation. A specific anatomic diagnosis of infection (eg, necrotizing soft-tissue infection, peritonitis complicated by intra-abdominal infection, cholangitis, intestinal infarction) requiring consideration of emergency source control should be confirmed or excluded as soon as possible. If needed, surgical drainage should be undertaken for source control within the first 12 hours after a diagnosis is made (grade 1C).

FLUID THERAPY: CRYSTALLOIDS FIRST

Recommendation. In fluid resuscitation of severe sepsis, use crystalloids first (grade 1B).

Mortality risk increases with each hour of delay in starting antibiotics

No head-to-head trial has shown albumin to be superior to crystalloids, and crystalloids are less expensive. However, normal saline has a higher chloride content than plasma, which leads to non-anion-gap metabolic acidosis. It is called an unbalanced crystalloid, having a high chloride content and no buffer. There is concern that this reduces renal blood flow and the glomerular filtration rate, creating the potential for acute kidney injury. Although no high-level evidence supports this concern, some animal studies and historical control studies suggest that a balanced crystalloid such as Ringer’s lactate, Ringer’s acetate, or PlasmaLyte (having a chloride content close to that of plasma and the buffers acetate or lactate) may be associated with better outcome in resuscitation of severe sepsis.

Use albumin solution if necessary

Recommendation. Albumin should be used in the fluid resuscitation of severe sepsis and septic shock for patients who require substantial amounts of crystalloids (grade 2C).

Finfer et al⁵ compared the effect of fluid resuscitation with either an albumin or saline solution in nearly 7,000 patients in intensive care and found that death rates over 28 days were nearly identical between the two groups. Although this study was not designed to measure an effect in subsets of patients, the subgroup with severe sepsis had a lower mortality rate with albumin (relative risk 0.87, 95% confidence interval 0.74–1.02). In a meta-analysis of 17 studies of albumin vs crystalloids or albumin vs saline, Delaney et al⁶ found a significant survival advantage with an albumin solution in patients with sepsis and severe septic shock.

Sometimes, in patients admitted to intensive care with septic shock and receiving two or three vasopressors and large amounts of a crystalloid solution, vasopressors can be reduced when fluid is being given, but as soon as the fluid infusion rate is decreased, the need for increasing vasopressors returns. This scenario is an indication for changing to an albumin solution.

Recommendation. Initial fluid challenge in sepsis-induced tissue hypoperfusion (as evidenced by hypotension or elevated lactate) with suspicion of hypovolemia should be a minimum of 30 mL/kg of crystalloids, a portion of which can be an albumin equivalent. Some patients require more rapid administration and greater amounts of fluid (grade 1B).

Other fluid resuscitation considerations

Recommendation. Hydroxyethyl starch (hetastarch) should not be used for fluid resuscitation of severe sepsis and septic shock (grade 1B).

Five large clinical trials^7–11 compared hetastarch with crystalloids in the resuscitation of severe sepsis or septic shock. None found an advantage to using hetastarch, and three found it to be associated with higher rates of acute kidney injury and renal-replacement therapy.

Blood is not considered a resuscitation fluid.

Full fluid replacement is still needed in heart or kidney disease

Often, doctors hesitate to administer full fluid resuscitation to patients with septic shock or sepsis-induced hypotension who have baseline cardiomyopathy with a low ejection fraction or who have end-stage renal disease and are anuric. However, these patients’ baseline intravascular volume status has changed because of venodilation and capillary leak leading to reduced blood return to the heart. They require the same amount of fluids as other patients to return to their baseline state.

To avoid fluid overload in these patients, however, we recommend providing fluid in smaller boluses. For a young, previously healthy patient, 2 L of crystalloid should be provided as quickly as possible. Patients with heart or kidney disease should receive smaller (250- or 500-mL) boluses, with oxygen saturation checked after each dose, as hypoxemia is one of only two potential downsides of aggressive fluid resuscitation (the other being the further raising of intra-abdominal pressure in the intra-abdominal compartment syndrome).

WHAT DRIVES HYPOTENSION IN SEPTIC SHOCK?

In septic shock, mechanisms that can lower the blood pressure include capillary leakage (loss of intravascular volume), decreased arteriolar resistance, decreased cardiac contractility, increased ventricular compliance, and increased venous capacitance (loss of intra-arterial volume).

Capillary leakage ranges from moderate to severe, and it is difficult to know the severity early on during resuscitation. The extent of capillary leakage is often apparent only after 24 hours of fluid resuscitation, when the large amount of fluid needed to maintain intravascular volume produces significant tissue edema. Within the first 24 hours of resuscitation of a patient with septic shock or in the presence of ongoing inflammation, one cannot use intake and output to judge the adequacy of fluid resuscitation.

Reduced arteriolar resistance may be an advantage in the nonhypotensive severely septic patient, compensating for the decreased ejection fraction, but it becomes problematic in the presence of hypotension. In addition, venodilation increases venous capacitance, producing a “sink” for blood and inadequate return of blood volume to the heart.

Decreased contractility of the left and right ventricles leads to compensatory sinus tachycardia.¹² Reduced heart contractility can be seen by radionuclide angiography: little difference in chamber size is apparent in systole (immediately before contraction) vs diastole (immediately after contraction) (Figure 1).

Images courtesy of Joseph E. Parrillo, MD.

NOREPINEPHRINE IS THE FIRST-CHOICE VASOPRESSOR

If a patient remains hypotensive after replacement of intravascular volume, the hypotension is due to a combination of vasodilation and reduced contractility, and a combined inotrope-vasopressor is an appropriate drug to raise blood pressure. Therefore, the drug of first choice for raising blood pressure should be a combined inotrope-vasopressor.

There are three combined inotrope-vasopressors: dopamine, norepinephrine, and epinephrine. Head-to-head comparisons of norepinephrine and dopamine have supported a survival advantage with norepinephrine in patients with shock, including septic shock.¹³ A meta-analysis of six randomized trials totaling 2,768 patients also supports norepinephrine over dopamine in septic shock. Dopamine has been associated with a higher incidence of tachyarrhythmic events.¹⁴

Recommendations. Norepinephrine is the first choice for vasopressor therapy (grade 1B). If an additional agent is needed to maintain blood pressure, epinephrine should be added to norepinephrine (grade 2B). Alternatively, vasopressin (0.03 U/minute) can be added to norepinephrine to raise mean arterial pressure to target or to decrease the norepinephrine dose (ungraded recommendation).

Dopamine is not recommended as empiric or additive therapy for septic shock. It may be considered, however, in the presence of septic shock with sinus bradycardia.

Phenylephrine for special cases

Phenylephrine is a pure vasopressor: it decreases stroke volume and is particularly disadvantageous in patients with low cardiac output.

Recommendation. Phenylephrine is not recommended as empiric or additive therapy in the treatment of septic shock, with these exceptions (grade 1C):

• In unusual cases in which norepinephrine is associated with serious tachyarrhythmia, phenylephrine would be the least likely vasopressor to exacerbate arrhythmia
• If cardiac output is known to be high and blood pressure is persistently low
• If it is used as salvage therapy when combined inotrope-vasopressor drugs and low-dose vasopressin have failed to achieve the mean arterial pressure target.

RESUSCITATION OF SEPSIS-INDUCED TISSUE HYPOPERFUSION

A more severe form of sepsis-induced tissue hypoperfusion occurs in patients with severe sepsis, who require vasopressors after fluid challenge or have a lactate level of at least 4 mmol/L (36 mg/dL). Initial resuscitation is of utmost importance in these patients and often is done in the emergency department or regular hospital unit. These patients are targeted for “quantitative resuscitation,” ie, a protocol of fluid therapy and vasoactive agent support to achieve predefined end points.

Rivers et al¹⁵ published a landmark study of “early goal-directed therapy” targeting the early management of sepsis-induced tissue hypoperfusion (vasopressor requirement after fluid resuscitation or lactate > 4 mmol/L) and reported significant improvement in the survival rate when resuscitation was targeted to a superior vena cava oxygen saturation of 70%. Both control-group and active-treatment-group patients had central venous pressure targets of 8 mm Hg or greater. The Surviving Sepsis Campaign adopted these targets as recommendations in the original 2004 guidelines and continued through the 2013 guidelines, although the campaign’s sepsis management “bundles” that had originally included specific targets for central venous pressure and central venous oxygen saturation as above were changed in the 2013 guidelines to only measuring these variables (see discussion below).

Jones et al¹⁶ analyzed studies that involved early (within 24 hours of presentation) vs late (after 24 hours or unknown) quantitative resuscitation for sepsis-induced tissue hypoperfusion and found a significant reduction in the rate of death with early resuscitation but no difference with late resuscitation compared with standard therapy.

ALTERNATIVES TO MEASURING PRESSURE TO PREDICT RESPONSE TO FLUID

The campaign recognizes the limitation of pressure measurements to predict the response to fluid resuscitation. Some clinicians have objected to the guidelines, arguing that new bedside technology provides better information than central venous pressure or superior vena cava oxygen saturation.

It is useful to recall the Starling principle, which is based on the behavior of isolated myocardial fibrils that are put under the strain of graduated weights and then are stimulated to contract, modeling the contractility of the heart. The more the fibril is stretched, the more intense the contraction. Increased contractility explains why fluid resuscitation increases cardiac output; it is not simply a matter of increasing fluid volume in the veins. Increased volume in the left ventricle increases stretch, causing more intense contractility and higher stroke-volume cardiac output.

Crystalloids should be used for initial fluid resuscitation

The guidelines are based on pressure measurements, but volume is the important measure that drives contractility. For this reason, the 2013 guidelines encourage the use of alternative measures if a hospital has the capability to assess and use them. These alternative measures include changes in pulse pressure, systolic pressure, and stroke volume during the respiratory cycle or with fluid bolus. The greater the variation in these measures, the more likely the patient will respond to additional fluid therapy.¹⁷ Normal values:

• Pulse pressure variation: < 13%
• Systolic pressure variation: < 10 mm Hg
• Stroke volume variation: < 10%.

The problem with the more sophisticated technologies is that they tend to be available only in academic centers and not at hospitals doing the critical early resuscitation of septic shock.

The serum lactate level

Measuring serum lactate levels is an alternative method for monitoring resuscitation of early septic shock. This method is widely available even with point-of-care testing. If the lactate level is elevated, quantitative resuscitation, fluids, inotropes, and oxygen delivery can be targeted to lactate clearance.

Recommendation. In patients in whom elevated lactate levels are used as a marker of tissue hypoperfusion, resuscitation should be targeted to normalize lactate as rapidly as possible (grade 2C).

STEROID THERAPY IS CONTROVERSIAL

Corticosteroid therapy for septic shock remains controversial. Although it has been deemphasized, it likely has a role in select patients.

Recommendation. Intravenous corticosteroids should not be used in adults with septic shock if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability (grade 2C). However, a patient on high doses of multiple vasopressors after adequate fluid resuscitation would likely benefit.

Recommendation. If corticosteroid therapy is used, hydrocortisone 200 mg should be given over 24 hours, preferentially by continuous intravenous infusion but alternatively 50 mg every 6 hours (grade 2D). This regimen can be continued for up to 7 days or tapered when shock resolves.

SURVIVING SEPSIS CAMPAIGN PERFORMANCE-IMPROVEMENT PROGRAM

By themselves, guidelines change bedside care very slowly. To effect change, protocols must be put in place and quality indicators must be measured. Beginning in 2005, the Surviving Sepsis Campaign converted its guidelines to selected sets of quality indicators, ie, severe sepsis bundles. The campaign published tools that hospitals could use to initiate performance improvement programs for diagnosis and management of severe sepsis and septic shock. The information was disseminated worldwide with a free software program. The program allowed data collection at the bedside to record performance with quality indicators.

In addition, the campaign requested user data so that performance could be tracked over time. In 2010, data on more than 10,000 patients in participating hospitals showed improved ability to achieve quality indicators. The longer a hospital continued the program, the better its compliance with management bundles; in addition, there was a concomitant reduction in hospital mortality rates.¹⁸

Among participants, mortality rates decreased from 37% in the first quarter to 26% in the 16th

At this time, the database holds records for more than 30,000 patients. Mortality rates among campaign participants decreased from 37% in the first quarter to 26% in the 16th quarter worldwide, with a reduced relative risk of mortality of 28%.¹⁹ To assess whether background factors unrelated to campaign participation were contributing to the reduced rates, mortality rates of long-term participants were compared with those of new program participants; the finding supported the association with program participation.

Bundles revised

The campaign published updated performance bundles in the 2013 guidelines.

The 3-hour bundle remains the same. Within the first 3 hours of presentation with sepsis:

• Measure the serum lactate level.
• Obtain blood cultures before starting antibiotics.
• Start broad-spectrum antibiotics.
• Give a crystalloid (30 mL/kg) for hypotension or for lactate ≥ 4 mmol/L.

The 6-hour bundle has changed somewhat. Within 6 hours of presentation:

• If hypotension does not respond to initial fluid resuscitation, apply vasopressors to maintain mean arterial pressure ≥ 65 mm Hg.
• In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L, measure central venous pressure and central venous oxygen saturation.
• Remeasure lactate if the initial lactate level was elevated.

In light of the campaign’s recognition of alternatives to central venous pressure and central venous oxygen saturation for quantitative resuscitation targets, specific targets for these measures were not defined, allowing institutions the flexibility to base decisions on other technologies, such as inferior vena cava ultrasonography, systolic pressure variation, and changes in flow measures or estimates with fluid boluses if they have the capability.

Moreover, the second point in the 6-hour bundle is being further revised. The Protocolized Care for Early Septic Shock (ProCESS) trial²⁰ and the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial,²¹ both published in 2013, demonstrated that measuring central venous pressure and central venous oxygen saturation, although safe, is not necessary for successful resuscitation of patients with septic shock. Therefore, newer versions of the 6-hour bundle propose that physicians reassess intravascular volume status and tissue perfusion, after initial 30 mL/kg crystalloid administration, in the event of persistent hypotension (mean arterial pressure < 65 mm Hg, ie, vasopressor requirement) or an initial lactate level of 4 mmol/L or higher, and then document the findings. To meet the requirements, one must document either a repeat focused examination by a licensed independent practitioner (to include vital signs, cardiopulmonary, capillary refill, pulse, and skin findings) or two alternative items from the following options: central venous pressure, central venous oxygen saturation, bedside cardiovascular ultrasonography,  and dynamic assessment of fluid responsiveness with passive leg-raising or fluid challenge.

Of interest, the ProCESS²⁰ and ARISE²¹ trials supported early identification of septic shock, early use of antibiotics, and early aggressive fluid resuscitation as the likely reasons for the reduced mortality rates across all treatment groups in these studies.

REDUCING HOSPITAL MORTALITY RATES

Phase 3 of the campaign involves data from 30,000 patients with severe sepsis or septic shock in emergency departments (52%), medical and surgical units (35%), and critical care units (13%).

Hospital mortality rates were 28% for those who presented to the emergency department with sepsis vs 47% for those who developed it in the hospital.²² The reason for the substantial difference is unclear; possibly, diagnosis takes longer in medical and surgical units because of a lower nurse-to-patient ratio, leading to delay in diagnosis and treatment.

Phase 4 of the campaign: Improve recognition of sepsis in the hospital

The finding of the greater risk of dying from sepsis in those who develop severe sepsis on medical and surgical floors has led to initiation of phase 4 of the campaign, conducted in four US-based collaborative groups in California, Illinois, New Jersey, and Florida, with 12 to 20 sites per collaborative. The collaborative is funded by the Moore Foundation and sponsored by the Society of Critical Care Medicine and the Society of Hospital Medicine. The purpose is to improve early recognition of severe sepsis through nurse screening of every patient during every shift of every day of hospitalization. The program empowers nurses to recognize and report sepsis, severe sepsis, and septic shock. The response differs depending on the hospital: some employ a rapid response or “sepsis alert,” others have a designated hospitalist on each shift who is informed, and hospitals that use private doctors may have a call-in system.

MUCH REMAINS TO BE DONE

The Surviving Sepsis Campaign has come far since the initial guidelines published in 2004. Thirty international organizations now sponsor and support the evidence-based guidelines. The sepsis performance improvement program deployed internationally has been associated with significant improvement in outcome in patients with severe sepsis.

How much of this is related to the campaign as opposed to other changes in health care cannot be clearly ascertained. In addition, how much of the Surviving Sepsis Campaign’s performance-improvement program effect is from attention to this patient group or from precise indicators is difficult to deduce. However, most experts in the field believe the Surviving Sepsis Campaign has significantly improved outcomes since its inception in 2002. Much still needs to be done as new evidence evolves.

Sepsis is familiar to most physicians in clinical practice, but guidance from the medical literature on how best to manage it has traditionally been confusing.

Starting in 2002, the Surviving Sepsis Campaign has worked to reduce worldwide mortality from severe sepsis and septic shock by developing and publicizing guidelines of best practices based on evidence from the literature. The campaign published its first management guidelines in 2004.

In this article, I review the most recent guidelines^1,2 (published in 2013) and discuss the campaign’s ongoing performance-improvement program.

DEFINING SEPSIS

Sepsis is a known or suspected infection plus systemic manifestations of infection. This includes the sepsis inflammatory response syndrome. Criteria include:

• Tachycardia (heart rate > 90 beats per minute)
• Tachypnea (> 20 breaths/minute or Paco₂ < 32 mm Hg)
• Fever (temperature > 38.3°C [100.9°F]) or hypothermia (core temperature < 36°C [96.8°F])
• High or low white blood cell count (> 12.0 × 10⁹/L or < 4.0 × 10⁹/L), or a normal count with more than 10% immature cells.

The definition of sepsis was broadened in 2002 to include other systemic manifestations of infection, such as changes in blood glucose level and organ dysfunction.

Severe sepsis is defined as sepsis plus either acute organ dysfunction or tissue hypoperfusion due to infection, with tissue hypoperfusion defined as:

• Hypotension (systolic blood pressure < 90 mm Hg, or a drop in systolic blood pressure of > 40 mm Hg)
• Elevated lactate
• Low urine output
• Altered mental status.

In severe sepsis, organ dysfunction is caused by blood-borne toxins and involves acute lung and kidney injury, coagulopathy (thrombocytopenia and increased international normalized ratio), and liver dysfunction.

Septic shock is present when a patient requires vasopressors after adequate intravascular volume repletion.

SEPSIS IS DEADLY AND COSTLY

Severe sepsis is the leading cause of hospital death. Patients admitted with severe sepsis are eight times more likely to die than those admitted with other conditions.³ The economic burden is enormous: it is the most expensive condition treated in US hospitals, costing an estimated $20.3 billion in 2011, of which $12.7 billion came from Medicare.

THE SURVIVING SEPSIS CAMPAIGN

The Surviving Sepsis Campaign is a global effort to reduce the rate of death from severe sepsis. The campaign’s methods include:

Patients with severe sepsis are eight times more likely to die than those with other conditions

• Educating physicians, the public, the media, and government about the high rates of morbidity and death in severe sepsis
• Creating evidence-based guidelines for managing sepsis and establishing global best-practice standards
• Facilitating the transfer of knowledge by developing performance-improvement programs to change bedside practice.

The campaign is funded with a grant from the Gordon and Betty Moore Foundation. The campaign’s guidelines are not associated with any direct or indirect industry support. The 2013 guidelines were backed by 30 international organizations.^1,2

All recommendations are ranked with numerical and letter scores, according to the GRADE system: 1 indicates a strong recommendation and 2 a weak one. The letters A through D reflect the quality of evidence, ranging from high (A) to very low (D).

GIVING ANTIBIOTICS EARLY IMPROVES OUTCOMES

A number of studies have suggested that starting appropriate antibiotics early improves outcomes in severe sepsis and septic shock. The death rate increases with each hour of delay.⁴

Recommendation. Intravenous antibiotic therapy should be started as soon as possible, and within the first hour after recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C).

The feasibility of achieving this goal has not been scientifically validated, and the recommendation should not be misinterpreted as the current standard of care. Even hospitals that participate in performance-improvement programs often struggle to start antibiotics, even within 6 hours of recognition. Nevertheless, the goal is a good one.

Some have questioned the early antibiotic recommendation because of concerns about antibiotic overuse and resistance. For a patient with some manifestation of systemic inflammation, such as organ dysfunction or hypotension with no clear cause, the campaign’s position is to provide empiric antibiotics early and then, if a noninfectious cause is found, to stop the antibiotics. Moreover, as soon as a causative pathogen has been identified, the regimen should be switched to the most appropriate antimicrobial that covers the pathogen and is safe and cost-effective. Collaboration with an antimicrobial stewardship program, if available, is encouraged.

FIND THE INFECTION SOURCE PROMPTLY: SOURCE CONTROL MAY BE REQUIRED

Recommendation. A specific anatomic diagnosis of infection (eg, necrotizing soft-tissue infection, peritonitis complicated by intra-abdominal infection, cholangitis, intestinal infarction) requiring consideration of emergency source control should be confirmed or excluded as soon as possible. If needed, surgical drainage should be undertaken for source control within the first 12 hours after a diagnosis is made (grade 1C).

FLUID THERAPY: CRYSTALLOIDS FIRST

Recommendation. In fluid resuscitation of severe sepsis, use crystalloids first (grade 1B).

Mortality risk increases with each hour of delay in starting antibiotics

No head-to-head trial has shown albumin to be superior to crystalloids, and crystalloids are less expensive. However, normal saline has a higher chloride content than plasma, which leads to non-anion-gap metabolic acidosis. It is called an unbalanced crystalloid, having a high chloride content and no buffer. There is concern that this reduces renal blood flow and the glomerular filtration rate, creating the potential for acute kidney injury. Although no high-level evidence supports this concern, some animal studies and historical control studies suggest that a balanced crystalloid such as Ringer’s lactate, Ringer’s acetate, or PlasmaLyte (having a chloride content close to that of plasma and the buffers acetate or lactate) may be associated with better outcome in resuscitation of severe sepsis.

Use albumin solution if necessary

Recommendation. Albumin should be used in the fluid resuscitation of severe sepsis and septic shock for patients who require substantial amounts of crystalloids (grade 2C).

Finfer et al⁵ compared the effect of fluid resuscitation with either an albumin or saline solution in nearly 7,000 patients in intensive care and found that death rates over 28 days were nearly identical between the two groups. Although this study was not designed to measure an effect in subsets of patients, the subgroup with severe sepsis had a lower mortality rate with albumin (relative risk 0.87, 95% confidence interval 0.74–1.02). In a meta-analysis of 17 studies of albumin vs crystalloids or albumin vs saline, Delaney et al⁶ found a significant survival advantage with an albumin solution in patients with sepsis and severe septic shock.

Sometimes, in patients admitted to intensive care with septic shock and receiving two or three vasopressors and large amounts of a crystalloid solution, vasopressors can be reduced when fluid is being given, but as soon as the fluid infusion rate is decreased, the need for increasing vasopressors returns. This scenario is an indication for changing to an albumin solution.

Recommendation. Initial fluid challenge in sepsis-induced tissue hypoperfusion (as evidenced by hypotension or elevated lactate) with suspicion of hypovolemia should be a minimum of 30 mL/kg of crystalloids, a portion of which can be an albumin equivalent. Some patients require more rapid administration and greater amounts of fluid (grade 1B).

Other fluid resuscitation considerations

Recommendation. Hydroxyethyl starch (hetastarch) should not be used for fluid resuscitation of severe sepsis and septic shock (grade 1B).

Five large clinical trials^7–11 compared hetastarch with crystalloids in the resuscitation of severe sepsis or septic shock. None found an advantage to using hetastarch, and three found it to be associated with higher rates of acute kidney injury and renal-replacement therapy.

Blood is not considered a resuscitation fluid.

Full fluid replacement is still needed in heart or kidney disease

Often, doctors hesitate to administer full fluid resuscitation to patients with septic shock or sepsis-induced hypotension who have baseline cardiomyopathy with a low ejection fraction or who have end-stage renal disease and are anuric. However, these patients’ baseline intravascular volume status has changed because of venodilation and capillary leak leading to reduced blood return to the heart. They require the same amount of fluids as other patients to return to their baseline state.

To avoid fluid overload in these patients, however, we recommend providing fluid in smaller boluses. For a young, previously healthy patient, 2 L of crystalloid should be provided as quickly as possible. Patients with heart or kidney disease should receive smaller (250- or 500-mL) boluses, with oxygen saturation checked after each dose, as hypoxemia is one of only two potential downsides of aggressive fluid resuscitation (the other being the further raising of intra-abdominal pressure in the intra-abdominal compartment syndrome).

WHAT DRIVES HYPOTENSION IN SEPTIC SHOCK?

In septic shock, mechanisms that can lower the blood pressure include capillary leakage (loss of intravascular volume), decreased arteriolar resistance, decreased cardiac contractility, increased ventricular compliance, and increased venous capacitance (loss of intra-arterial volume).

Capillary leakage ranges from moderate to severe, and it is difficult to know the severity early on during resuscitation. The extent of capillary leakage is often apparent only after 24 hours of fluid resuscitation, when the large amount of fluid needed to maintain intravascular volume produces significant tissue edema. Within the first 24 hours of resuscitation of a patient with septic shock or in the presence of ongoing inflammation, one cannot use intake and output to judge the adequacy of fluid resuscitation.

Reduced arteriolar resistance may be an advantage in the nonhypotensive severely septic patient, compensating for the decreased ejection fraction, but it becomes problematic in the presence of hypotension. In addition, venodilation increases venous capacitance, producing a “sink” for blood and inadequate return of blood volume to the heart.

Decreased contractility of the left and right ventricles leads to compensatory sinus tachycardia.¹² Reduced heart contractility can be seen by radionuclide angiography: little difference in chamber size is apparent in systole (immediately before contraction) vs diastole (immediately after contraction) (Figure 1).

Images courtesy of Joseph E. Parrillo, MD.

NOREPINEPHRINE IS THE FIRST-CHOICE VASOPRESSOR

If a patient remains hypotensive after replacement of intravascular volume, the hypotension is due to a combination of vasodilation and reduced contractility, and a combined inotrope-vasopressor is an appropriate drug to raise blood pressure. Therefore, the drug of first choice for raising blood pressure should be a combined inotrope-vasopressor.

There are three combined inotrope-vasopressors: dopamine, norepinephrine, and epinephrine. Head-to-head comparisons of norepinephrine and dopamine have supported a survival advantage with norepinephrine in patients with shock, including septic shock.¹³ A meta-analysis of six randomized trials totaling 2,768 patients also supports norepinephrine over dopamine in septic shock. Dopamine has been associated with a higher incidence of tachyarrhythmic events.¹⁴

Recommendations. Norepinephrine is the first choice for vasopressor therapy (grade 1B). If an additional agent is needed to maintain blood pressure, epinephrine should be added to norepinephrine (grade 2B). Alternatively, vasopressin (0.03 U/minute) can be added to norepinephrine to raise mean arterial pressure to target or to decrease the norepinephrine dose (ungraded recommendation).

Dopamine is not recommended as empiric or additive therapy for septic shock. It may be considered, however, in the presence of septic shock with sinus bradycardia.

Phenylephrine for special cases

Phenylephrine is a pure vasopressor: it decreases stroke volume and is particularly disadvantageous in patients with low cardiac output.

Recommendation. Phenylephrine is not recommended as empiric or additive therapy in the treatment of septic shock, with these exceptions (grade 1C):

• In unusual cases in which norepinephrine is associated with serious tachyarrhythmia, phenylephrine would be the least likely vasopressor to exacerbate arrhythmia
• If cardiac output is known to be high and blood pressure is persistently low
• If it is used as salvage therapy when combined inotrope-vasopressor drugs and low-dose vasopressin have failed to achieve the mean arterial pressure target.

RESUSCITATION OF SEPSIS-INDUCED TISSUE HYPOPERFUSION

A more severe form of sepsis-induced tissue hypoperfusion occurs in patients with severe sepsis, who require vasopressors after fluid challenge or have a lactate level of at least 4 mmol/L (36 mg/dL). Initial resuscitation is of utmost importance in these patients and often is done in the emergency department or regular hospital unit. These patients are targeted for “quantitative resuscitation,” ie, a protocol of fluid therapy and vasoactive agent support to achieve predefined end points.

Rivers et al¹⁵ published a landmark study of “early goal-directed therapy” targeting the early management of sepsis-induced tissue hypoperfusion (vasopressor requirement after fluid resuscitation or lactate > 4 mmol/L) and reported significant improvement in the survival rate when resuscitation was targeted to a superior vena cava oxygen saturation of 70%. Both control-group and active-treatment-group patients had central venous pressure targets of 8 mm Hg or greater. The Surviving Sepsis Campaign adopted these targets as recommendations in the original 2004 guidelines and continued through the 2013 guidelines, although the campaign’s sepsis management “bundles” that had originally included specific targets for central venous pressure and central venous oxygen saturation as above were changed in the 2013 guidelines to only measuring these variables (see discussion below).

Jones et al¹⁶ analyzed studies that involved early (within 24 hours of presentation) vs late (after 24 hours or unknown) quantitative resuscitation for sepsis-induced tissue hypoperfusion and found a significant reduction in the rate of death with early resuscitation but no difference with late resuscitation compared with standard therapy.

ALTERNATIVES TO MEASURING PRESSURE TO PREDICT RESPONSE TO FLUID

The campaign recognizes the limitation of pressure measurements to predict the response to fluid resuscitation. Some clinicians have objected to the guidelines, arguing that new bedside technology provides better information than central venous pressure or superior vena cava oxygen saturation.

It is useful to recall the Starling principle, which is based on the behavior of isolated myocardial fibrils that are put under the strain of graduated weights and then are stimulated to contract, modeling the contractility of the heart. The more the fibril is stretched, the more intense the contraction. Increased contractility explains why fluid resuscitation increases cardiac output; it is not simply a matter of increasing fluid volume in the veins. Increased volume in the left ventricle increases stretch, causing more intense contractility and higher stroke-volume cardiac output.

Crystalloids should be used for initial fluid resuscitation

The guidelines are based on pressure measurements, but volume is the important measure that drives contractility. For this reason, the 2013 guidelines encourage the use of alternative measures if a hospital has the capability to assess and use them. These alternative measures include changes in pulse pressure, systolic pressure, and stroke volume during the respiratory cycle or with fluid bolus. The greater the variation in these measures, the more likely the patient will respond to additional fluid therapy.¹⁷ Normal values:

• Pulse pressure variation: < 13%
• Systolic pressure variation: < 10 mm Hg
• Stroke volume variation: < 10%.

The problem with the more sophisticated technologies is that they tend to be available only in academic centers and not at hospitals doing the critical early resuscitation of septic shock.

The serum lactate level

Measuring serum lactate levels is an alternative method for monitoring resuscitation of early septic shock. This method is widely available even with point-of-care testing. If the lactate level is elevated, quantitative resuscitation, fluids, inotropes, and oxygen delivery can be targeted to lactate clearance.

Recommendation. In patients in whom elevated lactate levels are used as a marker of tissue hypoperfusion, resuscitation should be targeted to normalize lactate as rapidly as possible (grade 2C).

STEROID THERAPY IS CONTROVERSIAL

Corticosteroid therapy for septic shock remains controversial. Although it has been deemphasized, it likely has a role in select patients.

Recommendation. Intravenous corticosteroids should not be used in adults with septic shock if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability (grade 2C). However, a patient on high doses of multiple vasopressors after adequate fluid resuscitation would likely benefit.

Recommendation. If corticosteroid therapy is used, hydrocortisone 200 mg should be given over 24 hours, preferentially by continuous intravenous infusion but alternatively 50 mg every 6 hours (grade 2D). This regimen can be continued for up to 7 days or tapered when shock resolves.

SURVIVING SEPSIS CAMPAIGN PERFORMANCE-IMPROVEMENT PROGRAM

By themselves, guidelines change bedside care very slowly. To effect change, protocols must be put in place and quality indicators must be measured. Beginning in 2005, the Surviving Sepsis Campaign converted its guidelines to selected sets of quality indicators, ie, severe sepsis bundles. The campaign published tools that hospitals could use to initiate performance improvement programs for diagnosis and management of severe sepsis and septic shock. The information was disseminated worldwide with a free software program. The program allowed data collection at the bedside to record performance with quality indicators.

In addition, the campaign requested user data so that performance could be tracked over time. In 2010, data on more than 10,000 patients in participating hospitals showed improved ability to achieve quality indicators. The longer a hospital continued the program, the better its compliance with management bundles; in addition, there was a concomitant reduction in hospital mortality rates.¹⁸

Among participants, mortality rates decreased from 37% in the first quarter to 26% in the 16th

At this time, the database holds records for more than 30,000 patients. Mortality rates among campaign participants decreased from 37% in the first quarter to 26% in the 16th quarter worldwide, with a reduced relative risk of mortality of 28%.¹⁹ To assess whether background factors unrelated to campaign participation were contributing to the reduced rates, mortality rates of long-term participants were compared with those of new program participants; the finding supported the association with program participation.

Bundles revised

The campaign published updated performance bundles in the 2013 guidelines.

The 3-hour bundle remains the same. Within the first 3 hours of presentation with sepsis:

• Measure the serum lactate level.
• Obtain blood cultures before starting antibiotics.
• Start broad-spectrum antibiotics.
• Give a crystalloid (30 mL/kg) for hypotension or for lactate ≥ 4 mmol/L.

The 6-hour bundle has changed somewhat. Within 6 hours of presentation:

• If hypotension does not respond to initial fluid resuscitation, apply vasopressors to maintain mean arterial pressure ≥ 65 mm Hg.
• In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L, measure central venous pressure and central venous oxygen saturation.
• Remeasure lactate if the initial lactate level was elevated.

In light of the campaign’s recognition of alternatives to central venous pressure and central venous oxygen saturation for quantitative resuscitation targets, specific targets for these measures were not defined, allowing institutions the flexibility to base decisions on other technologies, such as inferior vena cava ultrasonography, systolic pressure variation, and changes in flow measures or estimates with fluid boluses if they have the capability.

Moreover, the second point in the 6-hour bundle is being further revised. The Protocolized Care for Early Septic Shock (ProCESS) trial²⁰ and the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial,²¹ both published in 2013, demonstrated that measuring central venous pressure and central venous oxygen saturation, although safe, is not necessary for successful resuscitation of patients with septic shock. Therefore, newer versions of the 6-hour bundle propose that physicians reassess intravascular volume status and tissue perfusion, after initial 30 mL/kg crystalloid administration, in the event of persistent hypotension (mean arterial pressure < 65 mm Hg, ie, vasopressor requirement) or an initial lactate level of 4 mmol/L or higher, and then document the findings. To meet the requirements, one must document either a repeat focused examination by a licensed independent practitioner (to include vital signs, cardiopulmonary, capillary refill, pulse, and skin findings) or two alternative items from the following options: central venous pressure, central venous oxygen saturation, bedside cardiovascular ultrasonography,  and dynamic assessment of fluid responsiveness with passive leg-raising or fluid challenge.

Of interest, the ProCESS²⁰ and ARISE²¹ trials supported early identification of septic shock, early use of antibiotics, and early aggressive fluid resuscitation as the likely reasons for the reduced mortality rates across all treatment groups in these studies.

REDUCING HOSPITAL MORTALITY RATES

Phase 3 of the campaign involves data from 30,000 patients with severe sepsis or septic shock in emergency departments (52%), medical and surgical units (35%), and critical care units (13%).

Hospital mortality rates were 28% for those who presented to the emergency department with sepsis vs 47% for those who developed it in the hospital.²² The reason for the substantial difference is unclear; possibly, diagnosis takes longer in medical and surgical units because of a lower nurse-to-patient ratio, leading to delay in diagnosis and treatment.

Phase 4 of the campaign: Improve recognition of sepsis in the hospital

The finding of the greater risk of dying from sepsis in those who develop severe sepsis on medical and surgical floors has led to initiation of phase 4 of the campaign, conducted in four US-based collaborative groups in California, Illinois, New Jersey, and Florida, with 12 to 20 sites per collaborative. The collaborative is funded by the Moore Foundation and sponsored by the Society of Critical Care Medicine and the Society of Hospital Medicine. The purpose is to improve early recognition of severe sepsis through nurse screening of every patient during every shift of every day of hospitalization. The program empowers nurses to recognize and report sepsis, severe sepsis, and septic shock. The response differs depending on the hospital: some employ a rapid response or “sepsis alert,” others have a designated hospitalist on each shift who is informed, and hospitals that use private doctors may have a call-in system.

MUCH REMAINS TO BE DONE

The Surviving Sepsis Campaign has come far since the initial guidelines published in 2004. Thirty international organizations now sponsor and support the evidence-based guidelines. The sepsis performance improvement program deployed internationally has been associated with significant improvement in outcome in patients with severe sepsis.

How much of this is related to the campaign as opposed to other changes in health care cannot be clearly ascertained. In addition, how much of the Surviving Sepsis Campaign’s performance-improvement program effect is from attention to this patient group or from precise indicators is difficult to deduce. However, most experts in the field believe the Surviving Sepsis Campaign has significantly improved outcomes since its inception in 2002. Much still needs to be done as new evidence evolves.

Sepsis is familiar to most physicians in clinical practice, but guidance from the medical literature on how best to manage it has traditionally been confusing.

Starting in 2002, the Surviving Sepsis Campaign has worked to reduce worldwide mortality from severe sepsis and septic shock by developing and publicizing guidelines of best practices based on evidence from the literature. The campaign published its first management guidelines in 2004.

In this article, I review the most recent guidelines^1,2 (published in 2013) and discuss the campaign’s ongoing performance-improvement program.

DEFINING SEPSIS

Sepsis is a known or suspected infection plus systemic manifestations of infection. This includes the sepsis inflammatory response syndrome. Criteria include:

• Tachycardia (heart rate > 90 beats per minute)
• Tachypnea (> 20 breaths/minute or Paco₂ < 32 mm Hg)
• Fever (temperature > 38.3°C [100.9°F]) or hypothermia (core temperature < 36°C [96.8°F])
• High or low white blood cell count (> 12.0 × 10⁹/L or < 4.0 × 10⁹/L), or a normal count with more than 10% immature cells.

The definition of sepsis was broadened in 2002 to include other systemic manifestations of infection, such as changes in blood glucose level and organ dysfunction.

Severe sepsis is defined as sepsis plus either acute organ dysfunction or tissue hypoperfusion due to infection, with tissue hypoperfusion defined as:

• Hypotension (systolic blood pressure < 90 mm Hg, or a drop in systolic blood pressure of > 40 mm Hg)
• Elevated lactate
• Low urine output
• Altered mental status.

In severe sepsis, organ dysfunction is caused by blood-borne toxins and involves acute lung and kidney injury, coagulopathy (thrombocytopenia and increased international normalized ratio), and liver dysfunction.

Septic shock is present when a patient requires vasopressors after adequate intravascular volume repletion.

SEPSIS IS DEADLY AND COSTLY

Severe sepsis is the leading cause of hospital death. Patients admitted with severe sepsis are eight times more likely to die than those admitted with other conditions.³ The economic burden is enormous: it is the most expensive condition treated in US hospitals, costing an estimated $20.3 billion in 2011, of which $12.7 billion came from Medicare.

THE SURVIVING SEPSIS CAMPAIGN

The Surviving Sepsis Campaign is a global effort to reduce the rate of death from severe sepsis. The campaign’s methods include:

Patients with severe sepsis are eight times more likely to die than those with other conditions

• Educating physicians, the public, the media, and government about the high rates of morbidity and death in severe sepsis
• Creating evidence-based guidelines for managing sepsis and establishing global best-practice standards
• Facilitating the transfer of knowledge by developing performance-improvement programs to change bedside practice.

The campaign is funded with a grant from the Gordon and Betty Moore Foundation. The campaign’s guidelines are not associated with any direct or indirect industry support. The 2013 guidelines were backed by 30 international organizations.^1,2

All recommendations are ranked with numerical and letter scores, according to the GRADE system: 1 indicates a strong recommendation and 2 a weak one. The letters A through D reflect the quality of evidence, ranging from high (A) to very low (D).

GIVING ANTIBIOTICS EARLY IMPROVES OUTCOMES

A number of studies have suggested that starting appropriate antibiotics early improves outcomes in severe sepsis and septic shock. The death rate increases with each hour of delay.⁴

Recommendation. Intravenous antibiotic therapy should be started as soon as possible, and within the first hour after recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C).

The feasibility of achieving this goal has not been scientifically validated, and the recommendation should not be misinterpreted as the current standard of care. Even hospitals that participate in performance-improvement programs often struggle to start antibiotics, even within 6 hours of recognition. Nevertheless, the goal is a good one.

Some have questioned the early antibiotic recommendation because of concerns about antibiotic overuse and resistance. For a patient with some manifestation of systemic inflammation, such as organ dysfunction or hypotension with no clear cause, the campaign’s position is to provide empiric antibiotics early and then, if a noninfectious cause is found, to stop the antibiotics. Moreover, as soon as a causative pathogen has been identified, the regimen should be switched to the most appropriate antimicrobial that covers the pathogen and is safe and cost-effective. Collaboration with an antimicrobial stewardship program, if available, is encouraged.

FIND THE INFECTION SOURCE PROMPTLY: SOURCE CONTROL MAY BE REQUIRED

Recommendation. A specific anatomic diagnosis of infection (eg, necrotizing soft-tissue infection, peritonitis complicated by intra-abdominal infection, cholangitis, intestinal infarction) requiring consideration of emergency source control should be confirmed or excluded as soon as possible. If needed, surgical drainage should be undertaken for source control within the first 12 hours after a diagnosis is made (grade 1C).

FLUID THERAPY: CRYSTALLOIDS FIRST

Recommendation. In fluid resuscitation of severe sepsis, use crystalloids first (grade 1B).

Mortality risk increases with each hour of delay in starting antibiotics

No head-to-head trial has shown albumin to be superior to crystalloids, and crystalloids are less expensive. However, normal saline has a higher chloride content than plasma, which leads to non-anion-gap metabolic acidosis. It is called an unbalanced crystalloid, having a high chloride content and no buffer. There is concern that this reduces renal blood flow and the glomerular filtration rate, creating the potential for acute kidney injury. Although no high-level evidence supports this concern, some animal studies and historical control studies suggest that a balanced crystalloid such as Ringer’s lactate, Ringer’s acetate, or PlasmaLyte (having a chloride content close to that of plasma and the buffers acetate or lactate) may be associated with better outcome in resuscitation of severe sepsis.

Use albumin solution if necessary

Recommendation. Albumin should be used in the fluid resuscitation of severe sepsis and septic shock for patients who require substantial amounts of crystalloids (grade 2C).

Finfer et al⁵ compared the effect of fluid resuscitation with either an albumin or saline solution in nearly 7,000 patients in intensive care and found that death rates over 28 days were nearly identical between the two groups. Although this study was not designed to measure an effect in subsets of patients, the subgroup with severe sepsis had a lower mortality rate with albumin (relative risk 0.87, 95% confidence interval 0.74–1.02). In a meta-analysis of 17 studies of albumin vs crystalloids or albumin vs saline, Delaney et al⁶ found a significant survival advantage with an albumin solution in patients with sepsis and severe septic shock.

Sometimes, in patients admitted to intensive care with septic shock and receiving two or three vasopressors and large amounts of a crystalloid solution, vasopressors can be reduced when fluid is being given, but as soon as the fluid infusion rate is decreased, the need for increasing vasopressors returns. This scenario is an indication for changing to an albumin solution.

Recommendation. Initial fluid challenge in sepsis-induced tissue hypoperfusion (as evidenced by hypotension or elevated lactate) with suspicion of hypovolemia should be a minimum of 30 mL/kg of crystalloids, a portion of which can be an albumin equivalent. Some patients require more rapid administration and greater amounts of fluid (grade 1B).

Other fluid resuscitation considerations

Recommendation. Hydroxyethyl starch (hetastarch) should not be used for fluid resuscitation of severe sepsis and septic shock (grade 1B).

Five large clinical trials^7–11 compared hetastarch with crystalloids in the resuscitation of severe sepsis or septic shock. None found an advantage to using hetastarch, and three found it to be associated with higher rates of acute kidney injury and renal-replacement therapy.

Blood is not considered a resuscitation fluid.

Full fluid replacement is still needed in heart or kidney disease

Often, doctors hesitate to administer full fluid resuscitation to patients with septic shock or sepsis-induced hypotension who have baseline cardiomyopathy with a low ejection fraction or who have end-stage renal disease and are anuric. However, these patients’ baseline intravascular volume status has changed because of venodilation and capillary leak leading to reduced blood return to the heart. They require the same amount of fluids as other patients to return to their baseline state.

To avoid fluid overload in these patients, however, we recommend providing fluid in smaller boluses. For a young, previously healthy patient, 2 L of crystalloid should be provided as quickly as possible. Patients with heart or kidney disease should receive smaller (250- or 500-mL) boluses, with oxygen saturation checked after each dose, as hypoxemia is one of only two potential downsides of aggressive fluid resuscitation (the other being the further raising of intra-abdominal pressure in the intra-abdominal compartment syndrome).

WHAT DRIVES HYPOTENSION IN SEPTIC SHOCK?

In septic shock, mechanisms that can lower the blood pressure include capillary leakage (loss of intravascular volume), decreased arteriolar resistance, decreased cardiac contractility, increased ventricular compliance, and increased venous capacitance (loss of intra-arterial volume).

Capillary leakage ranges from moderate to severe, and it is difficult to know the severity early on during resuscitation. The extent of capillary leakage is often apparent only after 24 hours of fluid resuscitation, when the large amount of fluid needed to maintain intravascular volume produces significant tissue edema. Within the first 24 hours of resuscitation of a patient with septic shock or in the presence of ongoing inflammation, one cannot use intake and output to judge the adequacy of fluid resuscitation.

Reduced arteriolar resistance may be an advantage in the nonhypotensive severely septic patient, compensating for the decreased ejection fraction, but it becomes problematic in the presence of hypotension. In addition, venodilation increases venous capacitance, producing a “sink” for blood and inadequate return of blood volume to the heart.

Decreased contractility of the left and right ventricles leads to compensatory sinus tachycardia.¹² Reduced heart contractility can be seen by radionuclide angiography: little difference in chamber size is apparent in systole (immediately before contraction) vs diastole (immediately after contraction) (Figure 1).

Images courtesy of Joseph E. Parrillo, MD.

NOREPINEPHRINE IS THE FIRST-CHOICE VASOPRESSOR

If a patient remains hypotensive after replacement of intravascular volume, the hypotension is due to a combination of vasodilation and reduced contractility, and a combined inotrope-vasopressor is an appropriate drug to raise blood pressure. Therefore, the drug of first choice for raising blood pressure should be a combined inotrope-vasopressor.

There are three combined inotrope-vasopressors: dopamine, norepinephrine, and epinephrine. Head-to-head comparisons of norepinephrine and dopamine have supported a survival advantage with norepinephrine in patients with shock, including septic shock.¹³ A meta-analysis of six randomized trials totaling 2,768 patients also supports norepinephrine over dopamine in septic shock. Dopamine has been associated with a higher incidence of tachyarrhythmic events.¹⁴

Recommendations. Norepinephrine is the first choice for vasopressor therapy (grade 1B). If an additional agent is needed to maintain blood pressure, epinephrine should be added to norepinephrine (grade 2B). Alternatively, vasopressin (0.03 U/minute) can be added to norepinephrine to raise mean arterial pressure to target or to decrease the norepinephrine dose (ungraded recommendation).

Dopamine is not recommended as empiric or additive therapy for septic shock. It may be considered, however, in the presence of septic shock with sinus bradycardia.

Phenylephrine for special cases

Phenylephrine is a pure vasopressor: it decreases stroke volume and is particularly disadvantageous in patients with low cardiac output.

Recommendation. Phenylephrine is not recommended as empiric or additive therapy in the treatment of septic shock, with these exceptions (grade 1C):

• In unusual cases in which norepinephrine is associated with serious tachyarrhythmia, phenylephrine would be the least likely vasopressor to exacerbate arrhythmia
• If cardiac output is known to be high and blood pressure is persistently low
• If it is used as salvage therapy when combined inotrope-vasopressor drugs and low-dose vasopressin have failed to achieve the mean arterial pressure target.

RESUSCITATION OF SEPSIS-INDUCED TISSUE HYPOPERFUSION

A more severe form of sepsis-induced tissue hypoperfusion occurs in patients with severe sepsis, who require vasopressors after fluid challenge or have a lactate level of at least 4 mmol/L (36 mg/dL). Initial resuscitation is of utmost importance in these patients and often is done in the emergency department or regular hospital unit. These patients are targeted for “quantitative resuscitation,” ie, a protocol of fluid therapy and vasoactive agent support to achieve predefined end points.

Rivers et al¹⁵ published a landmark study of “early goal-directed therapy” targeting the early management of sepsis-induced tissue hypoperfusion (vasopressor requirement after fluid resuscitation or lactate > 4 mmol/L) and reported significant improvement in the survival rate when resuscitation was targeted to a superior vena cava oxygen saturation of 70%. Both control-group and active-treatment-group patients had central venous pressure targets of 8 mm Hg or greater. The Surviving Sepsis Campaign adopted these targets as recommendations in the original 2004 guidelines and continued through the 2013 guidelines, although the campaign’s sepsis management “bundles” that had originally included specific targets for central venous pressure and central venous oxygen saturation as above were changed in the 2013 guidelines to only measuring these variables (see discussion below).

Jones et al¹⁶ analyzed studies that involved early (within 24 hours of presentation) vs late (after 24 hours or unknown) quantitative resuscitation for sepsis-induced tissue hypoperfusion and found a significant reduction in the rate of death with early resuscitation but no difference with late resuscitation compared with standard therapy.

ALTERNATIVES TO MEASURING PRESSURE TO PREDICT RESPONSE TO FLUID

The campaign recognizes the limitation of pressure measurements to predict the response to fluid resuscitation. Some clinicians have objected to the guidelines, arguing that new bedside technology provides better information than central venous pressure or superior vena cava oxygen saturation.

It is useful to recall the Starling principle, which is based on the behavior of isolated myocardial fibrils that are put under the strain of graduated weights and then are stimulated to contract, modeling the contractility of the heart. The more the fibril is stretched, the more intense the contraction. Increased contractility explains why fluid resuscitation increases cardiac output; it is not simply a matter of increasing fluid volume in the veins. Increased volume in the left ventricle increases stretch, causing more intense contractility and higher stroke-volume cardiac output.

Crystalloids should be used for initial fluid resuscitation

The guidelines are based on pressure measurements, but volume is the important measure that drives contractility. For this reason, the 2013 guidelines encourage the use of alternative measures if a hospital has the capability to assess and use them. These alternative measures include changes in pulse pressure, systolic pressure, and stroke volume during the respiratory cycle or with fluid bolus. The greater the variation in these measures, the more likely the patient will respond to additional fluid therapy.¹⁷ Normal values:

• Pulse pressure variation: < 13%
• Systolic pressure variation: < 10 mm Hg
• Stroke volume variation: < 10%.

The problem with the more sophisticated technologies is that they tend to be available only in academic centers and not at hospitals doing the critical early resuscitation of septic shock.

The serum lactate level

Measuring serum lactate levels is an alternative method for monitoring resuscitation of early septic shock. This method is widely available even with point-of-care testing. If the lactate level is elevated, quantitative resuscitation, fluids, inotropes, and oxygen delivery can be targeted to lactate clearance.

Recommendation. In patients in whom elevated lactate levels are used as a marker of tissue hypoperfusion, resuscitation should be targeted to normalize lactate as rapidly as possible (grade 2C).

STEROID THERAPY IS CONTROVERSIAL

Corticosteroid therapy for septic shock remains controversial. Although it has been deemphasized, it likely has a role in select patients.

Recommendation. Intravenous corticosteroids should not be used in adults with septic shock if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability (grade 2C). However, a patient on high doses of multiple vasopressors after adequate fluid resuscitation would likely benefit.

Recommendation. If corticosteroid therapy is used, hydrocortisone 200 mg should be given over 24 hours, preferentially by continuous intravenous infusion but alternatively 50 mg every 6 hours (grade 2D). This regimen can be continued for up to 7 days or tapered when shock resolves.

SURVIVING SEPSIS CAMPAIGN PERFORMANCE-IMPROVEMENT PROGRAM

By themselves, guidelines change bedside care very slowly. To effect change, protocols must be put in place and quality indicators must be measured. Beginning in 2005, the Surviving Sepsis Campaign converted its guidelines to selected sets of quality indicators, ie, severe sepsis bundles. The campaign published tools that hospitals could use to initiate performance improvement programs for diagnosis and management of severe sepsis and septic shock. The information was disseminated worldwide with a free software program. The program allowed data collection at the bedside to record performance with quality indicators.

In addition, the campaign requested user data so that performance could be tracked over time. In 2010, data on more than 10,000 patients in participating hospitals showed improved ability to achieve quality indicators. The longer a hospital continued the program, the better its compliance with management bundles; in addition, there was a concomitant reduction in hospital mortality rates.¹⁸

Among participants, mortality rates decreased from 37% in the first quarter to 26% in the 16th

At this time, the database holds records for more than 30,000 patients. Mortality rates among campaign participants decreased from 37% in the first quarter to 26% in the 16th quarter worldwide, with a reduced relative risk of mortality of 28%.¹⁹ To assess whether background factors unrelated to campaign participation were contributing to the reduced rates, mortality rates of long-term participants were compared with those of new program participants; the finding supported the association with program participation.

Bundles revised

The campaign published updated performance bundles in the 2013 guidelines.

The 3-hour bundle remains the same. Within the first 3 hours of presentation with sepsis:

• Measure the serum lactate level.
• Obtain blood cultures before starting antibiotics.
• Start broad-spectrum antibiotics.
• Give a crystalloid (30 mL/kg) for hypotension or for lactate ≥ 4 mmol/L.

The 6-hour bundle has changed somewhat. Within 6 hours of presentation:

• If hypotension does not respond to initial fluid resuscitation, apply vasopressors to maintain mean arterial pressure ≥ 65 mm Hg.
• In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L, measure central venous pressure and central venous oxygen saturation.
• Remeasure lactate if the initial lactate level was elevated.

In light of the campaign’s recognition of alternatives to central venous pressure and central venous oxygen saturation for quantitative resuscitation targets, specific targets for these measures were not defined, allowing institutions the flexibility to base decisions on other technologies, such as inferior vena cava ultrasonography, systolic pressure variation, and changes in flow measures or estimates with fluid boluses if they have the capability.

Moreover, the second point in the 6-hour bundle is being further revised. The Protocolized Care for Early Septic Shock (ProCESS) trial²⁰ and the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial,²¹ both published in 2013, demonstrated that measuring central venous pressure and central venous oxygen saturation, although safe, is not necessary for successful resuscitation of patients with septic shock. Therefore, newer versions of the 6-hour bundle propose that physicians reassess intravascular volume status and tissue perfusion, after initial 30 mL/kg crystalloid administration, in the event of persistent hypotension (mean arterial pressure < 65 mm Hg, ie, vasopressor requirement) or an initial lactate level of 4 mmol/L or higher, and then document the findings. To meet the requirements, one must document either a repeat focused examination by a licensed independent practitioner (to include vital signs, cardiopulmonary, capillary refill, pulse, and skin findings) or two alternative items from the following options: central venous pressure, central venous oxygen saturation, bedside cardiovascular ultrasonography,  and dynamic assessment of fluid responsiveness with passive leg-raising or fluid challenge.

Of interest, the ProCESS²⁰ and ARISE²¹ trials supported early identification of septic shock, early use of antibiotics, and early aggressive fluid resuscitation as the likely reasons for the reduced mortality rates across all treatment groups in these studies.

REDUCING HOSPITAL MORTALITY RATES

Phase 3 of the campaign involves data from 30,000 patients with severe sepsis or septic shock in emergency departments (52%), medical and surgical units (35%), and critical care units (13%).

Hospital mortality rates were 28% for those who presented to the emergency department with sepsis vs 47% for those who developed it in the hospital.²² The reason for the substantial difference is unclear; possibly, diagnosis takes longer in medical and surgical units because of a lower nurse-to-patient ratio, leading to delay in diagnosis and treatment.

Phase 4 of the campaign: Improve recognition of sepsis in the hospital

The finding of the greater risk of dying from sepsis in those who develop severe sepsis on medical and surgical floors has led to initiation of phase 4 of the campaign, conducted in four US-based collaborative groups in California, Illinois, New Jersey, and Florida, with 12 to 20 sites per collaborative. The collaborative is funded by the Moore Foundation and sponsored by the Society of Critical Care Medicine and the Society of Hospital Medicine. The purpose is to improve early recognition of severe sepsis through nurse screening of every patient during every shift of every day of hospitalization. The program empowers nurses to recognize and report sepsis, severe sepsis, and septic shock. The response differs depending on the hospital: some employ a rapid response or “sepsis alert,” others have a designated hospitalist on each shift who is informed, and hospitals that use private doctors may have a call-in system.

MUCH REMAINS TO BE DONE

The Surviving Sepsis Campaign has come far since the initial guidelines published in 2004. Thirty international organizations now sponsor and support the evidence-based guidelines. The sepsis performance improvement program deployed internationally has been associated with significant improvement in outcome in patients with severe sepsis.

How much of this is related to the campaign as opposed to other changes in health care cannot be clearly ascertained. In addition, how much of the Surviving Sepsis Campaign’s performance-improvement program effect is from attention to this patient group or from precise indicators is difficult to deduce. However, most experts in the field believe the Surviving Sepsis Campaign has significantly improved outcomes since its inception in 2002. Much still needs to be done as new evidence evolves.