Cleveland Clinic Journal of Medicine

In this issue of the Journal, Alraies et al comment on how extensively we should look for the cause of an initial episode of pericarditis.

The pericardium, like the pleura, peritoneum, and synovium, can be affected in a number of inflammatory and infectious disorders. The mechanisms by which these tissues are affected are not fully understood, nor is the process by which different diseases seem to selectively target the joint or pericardium. Why are the joints only minimally inflamed in systemic lupus erythematosus (SLE), while lupus pericarditis, in the uncommon occurrence of significant effusion, is often quite inflammatory, with a neutrophil predominance in the fluid? Why is pericardial involvement so often demonstrable by imaging in patients with SLE and rheumatoid arthritis, yet an acute pericarditis presentation with audible pericardial rubs is so seldom recognized?

Although nuances like these are not well understood, in medical school we all learned the association between connective tissue disease and pericarditis. The importance of recalling these associations is repeatedly reinforced during residency and in disease-focused review articles. During my training, woe to the resident who presented a patient at rounds who was admitted with unexplained pericarditis and was not evaluated for SLE with at least an antinuclear antibody (ANA) test, even if there were no other features to suggest the disease. Ordering the test reflected that we knew that, occasionally, pericardial disease is the sole presenting manifestation of lupus.

Such is the plight of the internist. Pericarditis can be the initial manifestation of an autoimmune or inflammatory disease, but this is more often relevant on certification examinations and in medical education than in everyday practice. We are now charged with ordering tests in a more cost-effective manner than in the past. This means that we should not order tests simply because of an epidemiologic association, but only when the result is likely to influence decisions about testing or treatment. But that creates the intellectual dissonance of knowing of a potential relationship (which someone, someday, may challenge us about) but not looking for it. There is an inherent conflict between satisfying intellectual curiosity and the need to be thorough while at the same time containing costs and avoiding the potential harm inherent in overtesting.

A partial solution is to try to define the immediate risk of not recognizing a life- or organ-threatening disease process that can be suggested by a positive nonspecific test (eg, ANA), and to refine the pretest likelihood of specific diagnoses by obtaining an accurate and complete history and performing a focused physical examination. For example, if we suspect that SLE may be the cause of an initial episode of symptomatic pericarditis, our initial evaluation should focus on the patient’s clinical picture. Is there bitemporal hair-thinning? New-onset Raynaud symptoms? Mild generalized adenopathy or lymphopenia? A borderline-low platelet count, or any proteinuria or microhematuria (which should warrant a prompt examination of a fresh urine sediment sample by a physician at the point of care to look for cellular casts indicative of glomerulonephritis)?

As internists, we should try to fulfill our need to be thorough and compulsive by using our honed skills as careful observers and historians—taking a careful history from the patient and family, performing a focused physical examination, and appropriately using disease-defining or staging tests before ordering less specific serologic or other tests. Practicing medicine in a conscientious and compulsive manner does not mean that every diagnostic possibility must be tested for at initial presentation.

Reading how experienced clinicians approach the problem of pericarditis in a specialized clinic provides a useful prompt to self-assess how we approach analogous clinical scenarios.

In this issue of the Journal, Alraies et al comment on how extensively we should look for the cause of an initial episode of pericarditis.

The pericardium, like the pleura, peritoneum, and synovium, can be affected in a number of inflammatory and infectious disorders. The mechanisms by which these tissues are affected are not fully understood, nor is the process by which different diseases seem to selectively target the joint or pericardium. Why are the joints only minimally inflamed in systemic lupus erythematosus (SLE), while lupus pericarditis, in the uncommon occurrence of significant effusion, is often quite inflammatory, with a neutrophil predominance in the fluid? Why is pericardial involvement so often demonstrable by imaging in patients with SLE and rheumatoid arthritis, yet an acute pericarditis presentation with audible pericardial rubs is so seldom recognized?

Although nuances like these are not well understood, in medical school we all learned the association between connective tissue disease and pericarditis. The importance of recalling these associations is repeatedly reinforced during residency and in disease-focused review articles. During my training, woe to the resident who presented a patient at rounds who was admitted with unexplained pericarditis and was not evaluated for SLE with at least an antinuclear antibody (ANA) test, even if there were no other features to suggest the disease. Ordering the test reflected that we knew that, occasionally, pericardial disease is the sole presenting manifestation of lupus.

Such is the plight of the internist. Pericarditis can be the initial manifestation of an autoimmune or inflammatory disease, but this is more often relevant on certification examinations and in medical education than in everyday practice. We are now charged with ordering tests in a more cost-effective manner than in the past. This means that we should not order tests simply because of an epidemiologic association, but only when the result is likely to influence decisions about testing or treatment. But that creates the intellectual dissonance of knowing of a potential relationship (which someone, someday, may challenge us about) but not looking for it. There is an inherent conflict between satisfying intellectual curiosity and the need to be thorough while at the same time containing costs and avoiding the potential harm inherent in overtesting.

A partial solution is to try to define the immediate risk of not recognizing a life- or organ-threatening disease process that can be suggested by a positive nonspecific test (eg, ANA), and to refine the pretest likelihood of specific diagnoses by obtaining an accurate and complete history and performing a focused physical examination. For example, if we suspect that SLE may be the cause of an initial episode of symptomatic pericarditis, our initial evaluation should focus on the patient’s clinical picture. Is there bitemporal hair-thinning? New-onset Raynaud symptoms? Mild generalized adenopathy or lymphopenia? A borderline-low platelet count, or any proteinuria or microhematuria (which should warrant a prompt examination of a fresh urine sediment sample by a physician at the point of care to look for cellular casts indicative of glomerulonephritis)?

As internists, we should try to fulfill our need to be thorough and compulsive by using our honed skills as careful observers and historians—taking a careful history from the patient and family, performing a focused physical examination, and appropriately using disease-defining or staging tests before ordering less specific serologic or other tests. Practicing medicine in a conscientious and compulsive manner does not mean that every diagnostic possibility must be tested for at initial presentation.

Reading how experienced clinicians approach the problem of pericarditis in a specialized clinic provides a useful prompt to self-assess how we approach analogous clinical scenarios.

In this issue of the Journal, Alraies et al comment on how extensively we should look for the cause of an initial episode of pericarditis.

The pericardium, like the pleura, peritoneum, and synovium, can be affected in a number of inflammatory and infectious disorders. The mechanisms by which these tissues are affected are not fully understood, nor is the process by which different diseases seem to selectively target the joint or pericardium. Why are the joints only minimally inflamed in systemic lupus erythematosus (SLE), while lupus pericarditis, in the uncommon occurrence of significant effusion, is often quite inflammatory, with a neutrophil predominance in the fluid? Why is pericardial involvement so often demonstrable by imaging in patients with SLE and rheumatoid arthritis, yet an acute pericarditis presentation with audible pericardial rubs is so seldom recognized?

Although nuances like these are not well understood, in medical school we all learned the association between connective tissue disease and pericarditis. The importance of recalling these associations is repeatedly reinforced during residency and in disease-focused review articles. During my training, woe to the resident who presented a patient at rounds who was admitted with unexplained pericarditis and was not evaluated for SLE with at least an antinuclear antibody (ANA) test, even if there were no other features to suggest the disease. Ordering the test reflected that we knew that, occasionally, pericardial disease is the sole presenting manifestation of lupus.

Such is the plight of the internist. Pericarditis can be the initial manifestation of an autoimmune or inflammatory disease, but this is more often relevant on certification examinations and in medical education than in everyday practice. We are now charged with ordering tests in a more cost-effective manner than in the past. This means that we should not order tests simply because of an epidemiologic association, but only when the result is likely to influence decisions about testing or treatment. But that creates the intellectual dissonance of knowing of a potential relationship (which someone, someday, may challenge us about) but not looking for it. There is an inherent conflict between satisfying intellectual curiosity and the need to be thorough while at the same time containing costs and avoiding the potential harm inherent in overtesting.

A partial solution is to try to define the immediate risk of not recognizing a life- or organ-threatening disease process that can be suggested by a positive nonspecific test (eg, ANA), and to refine the pretest likelihood of specific diagnoses by obtaining an accurate and complete history and performing a focused physical examination. For example, if we suspect that SLE may be the cause of an initial episode of symptomatic pericarditis, our initial evaluation should focus on the patient’s clinical picture. Is there bitemporal hair-thinning? New-onset Raynaud symptoms? Mild generalized adenopathy or lymphopenia? A borderline-low platelet count, or any proteinuria or microhematuria (which should warrant a prompt examination of a fresh urine sediment sample by a physician at the point of care to look for cellular casts indicative of glomerulonephritis)?

As internists, we should try to fulfill our need to be thorough and compulsive by using our honed skills as careful observers and historians—taking a careful history from the patient and family, performing a focused physical examination, and appropriately using disease-defining or staging tests before ordering less specific serologic or other tests. Practicing medicine in a conscientious and compulsive manner does not mean that every diagnostic possibility must be tested for at initial presentation.

Reading how experienced clinicians approach the problem of pericarditis in a specialized clinic provides a useful prompt to self-assess how we approach analogous clinical scenarios.

To the Editor: We previously addressed whether VKORC1 and CYP2C9 pharmacogenomic testing should be considered when prescribing warfarin.¹ Our recommendation, based on available evidence at that time, was that physicians should consider pharmacogenomic testing for any patient who is started on warfarin therapy.

Since the publication of this recommendation, two major trials, COAG (Clarification of Optimal Anticoagulation Through Genetics)² and EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin),³ were published along with commentaries debating the clinical utility of warfarin pharmacogenomics.^4–15 Based on these publications, we would like to update our recommendations for pharmacogenomic testing for warfarin therapy.

COAG compared the efficacy of a clinical algorithm or a clinical algorithm plus VKORC1 and CYP2C9 genotyping to guide warfarin dosage. At the end of 4 weeks, the mean percentage of time within the therapeutic international normalized ratio (INR) range was 45.4% for those in the clinical algorithm arm and 45.2% for those in the genotyping arm (95% confidence interval [CI] –3.4 to 3.1, P = .91). For both treatment groups, clinical data that included body surface area, age, target INR, concomitantly prescribed drugs, and smoking status were used to predict warfarin dose, with the genotyping arm including VKORC1 and CYP2C9. Although VKORC1 and CYP2C9 genotyping offered no additional benefit, caution should be used when extrapolating this conclusion to clinical settings in which warfarin therapy is initiated using a standardized starting dose (eg, 5 mg daily) instead of a clinical dosing algorithm.

Of interest, in the COAG trial, among black patients, the mean percentage of time in the therapeutic INR range was significantly less for those in the genotype-guided arm than for those in the clinically guided arm—ie, 35.2% vs 43.5% (95% CI –15.0 to –2.0, P = .01). The percentage of time with therapeutic INR has been identified as a surrogate marker for poor outcomes such as death, stroke, or major hemorrhage, with those with a lower percentage of time in therapeutic INR being at greater risk of an adverse event.¹⁶ Wan et al¹⁷ demonstrated that a 6.9% improvement of time in therapeutic INR decreased the risk of major hemorrhage by one event per 100 patient-years.¹⁷ Therefore, black patients in the COAG genotyping arm may have been at greater risk for an adverse event because of a lower observed percentage of time within the therapeutic INR range.

In the COAG trial, genotyping was done for only one VKORC1 variant and for two CYP2C9 alleles (CYP2C9*2, and CYP2C9*3). Other genetic variants are of clinical importance for warfarin dosing in black patients, and the lack of genotyping for these additional variants may explain why black patients in the genotyping arm performed worse.^5,7,11 In particular, CYP2C9*8 may be an important predictor of warfarin dose in black patients.¹⁸

EU-PACT compared the efficacy of standardized warfarin dosing and that of a clinical algorithm.³ Patients in the standardized dosing arm were prescribed warfarin 10 mg on the first day of treatment (5 mg for those over age 75), and 5 mg on days 2 and 3, with subsequent dosing adjustments based on INR. Patients in the genotyping arm were prescribed warfarin based on an algorithm that incorporated clinical data that included body surface area, age, and concomitantly prescribed drugs, as well as VKORC1 and CYP2C9 genotypes. At the end of 12 weeks, the mean percentage of time in the therapeutic INR range was 60.3% for those in the standardized-dosing arm and 67.4% for those in the genotyping arm (95% CI 3.3 to 10.6, P < .001).² The approximate 7% improvement in percentage of time in the therapeutic INR range may predict a lower risk of hemorrhage for those in the genotyping arm.¹⁷ Although patients in the genotyping arm had a higher percentage of time in the therapeutic INR range, it is unclear whether genotyping alone is superior to standardized dosing because the dosing algorithm used both clinical data and genotype data.

There are substantial differences between the COAG and EU-PACT trials, including dosing schemes, racial diversity, and trial length, and these differences could have contributed to the conflicting results. Based on these two trials, a possible conclusion is that genotype-guided warfarin dosing may be superior to standardized dosing, but may be no better than utilizing a clinical algorithm in white patients. For black patients, additional studies are needed to determine which genetic variants are of importance for guiding warfarin dosing.

We would like to update the recommendations we made in our previously published article,¹ to state that genotyping for CYP2C9 and VKORC1 may be of clinical utility in white patients depending on whether standardized dosing or a clinical algorithm is used to initiate warfarin therapy. Routine genotyping in black patients is not recommended until further studies clarify which genetic variants are of importance for guiding warfarin dosing.

The ongoing Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis may bring much needed clarity to the clinical utility of warfarin pharmacogenomics. We hope to publish a more detailed update of our 2013 article after completion of that trial.

To the Editor: We previously addressed whether VKORC1 and CYP2C9 pharmacogenomic testing should be considered when prescribing warfarin.¹ Our recommendation, based on available evidence at that time, was that physicians should consider pharmacogenomic testing for any patient who is started on warfarin therapy.

Since the publication of this recommendation, two major trials, COAG (Clarification of Optimal Anticoagulation Through Genetics)² and EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin),³ were published along with commentaries debating the clinical utility of warfarin pharmacogenomics.^4–15 Based on these publications, we would like to update our recommendations for pharmacogenomic testing for warfarin therapy.

COAG compared the efficacy of a clinical algorithm or a clinical algorithm plus VKORC1 and CYP2C9 genotyping to guide warfarin dosage. At the end of 4 weeks, the mean percentage of time within the therapeutic international normalized ratio (INR) range was 45.4% for those in the clinical algorithm arm and 45.2% for those in the genotyping arm (95% confidence interval [CI] –3.4 to 3.1, P = .91). For both treatment groups, clinical data that included body surface area, age, target INR, concomitantly prescribed drugs, and smoking status were used to predict warfarin dose, with the genotyping arm including VKORC1 and CYP2C9. Although VKORC1 and CYP2C9 genotyping offered no additional benefit, caution should be used when extrapolating this conclusion to clinical settings in which warfarin therapy is initiated using a standardized starting dose (eg, 5 mg daily) instead of a clinical dosing algorithm.

Of interest, in the COAG trial, among black patients, the mean percentage of time in the therapeutic INR range was significantly less for those in the genotype-guided arm than for those in the clinically guided arm—ie, 35.2% vs 43.5% (95% CI –15.0 to –2.0, P = .01). The percentage of time with therapeutic INR has been identified as a surrogate marker for poor outcomes such as death, stroke, or major hemorrhage, with those with a lower percentage of time in therapeutic INR being at greater risk of an adverse event.¹⁶ Wan et al¹⁷ demonstrated that a 6.9% improvement of time in therapeutic INR decreased the risk of major hemorrhage by one event per 100 patient-years.¹⁷ Therefore, black patients in the COAG genotyping arm may have been at greater risk for an adverse event because of a lower observed percentage of time within the therapeutic INR range.

In the COAG trial, genotyping was done for only one VKORC1 variant and for two CYP2C9 alleles (CYP2C9*2, and CYP2C9*3). Other genetic variants are of clinical importance for warfarin dosing in black patients, and the lack of genotyping for these additional variants may explain why black patients in the genotyping arm performed worse.^5,7,11 In particular, CYP2C9*8 may be an important predictor of warfarin dose in black patients.¹⁸

EU-PACT compared the efficacy of standardized warfarin dosing and that of a clinical algorithm.³ Patients in the standardized dosing arm were prescribed warfarin 10 mg on the first day of treatment (5 mg for those over age 75), and 5 mg on days 2 and 3, with subsequent dosing adjustments based on INR. Patients in the genotyping arm were prescribed warfarin based on an algorithm that incorporated clinical data that included body surface area, age, and concomitantly prescribed drugs, as well as VKORC1 and CYP2C9 genotypes. At the end of 12 weeks, the mean percentage of time in the therapeutic INR range was 60.3% for those in the standardized-dosing arm and 67.4% for those in the genotyping arm (95% CI 3.3 to 10.6, P < .001).² The approximate 7% improvement in percentage of time in the therapeutic INR range may predict a lower risk of hemorrhage for those in the genotyping arm.¹⁷ Although patients in the genotyping arm had a higher percentage of time in the therapeutic INR range, it is unclear whether genotyping alone is superior to standardized dosing because the dosing algorithm used both clinical data and genotype data.

There are substantial differences between the COAG and EU-PACT trials, including dosing schemes, racial diversity, and trial length, and these differences could have contributed to the conflicting results. Based on these two trials, a possible conclusion is that genotype-guided warfarin dosing may be superior to standardized dosing, but may be no better than utilizing a clinical algorithm in white patients. For black patients, additional studies are needed to determine which genetic variants are of importance for guiding warfarin dosing.

We would like to update the recommendations we made in our previously published article,¹ to state that genotyping for CYP2C9 and VKORC1 may be of clinical utility in white patients depending on whether standardized dosing or a clinical algorithm is used to initiate warfarin therapy. Routine genotyping in black patients is not recommended until further studies clarify which genetic variants are of importance for guiding warfarin dosing.

The ongoing Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis may bring much needed clarity to the clinical utility of warfarin pharmacogenomics. We hope to publish a more detailed update of our 2013 article after completion of that trial.

To the Editor: We previously addressed whether VKORC1 and CYP2C9 pharmacogenomic testing should be considered when prescribing warfarin.¹ Our recommendation, based on available evidence at that time, was that physicians should consider pharmacogenomic testing for any patient who is started on warfarin therapy.

Since the publication of this recommendation, two major trials, COAG (Clarification of Optimal Anticoagulation Through Genetics)² and EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin),³ were published along with commentaries debating the clinical utility of warfarin pharmacogenomics.^4–15 Based on these publications, we would like to update our recommendations for pharmacogenomic testing for warfarin therapy.

COAG compared the efficacy of a clinical algorithm or a clinical algorithm plus VKORC1 and CYP2C9 genotyping to guide warfarin dosage. At the end of 4 weeks, the mean percentage of time within the therapeutic international normalized ratio (INR) range was 45.4% for those in the clinical algorithm arm and 45.2% for those in the genotyping arm (95% confidence interval [CI] –3.4 to 3.1, P = .91). For both treatment groups, clinical data that included body surface area, age, target INR, concomitantly prescribed drugs, and smoking status were used to predict warfarin dose, with the genotyping arm including VKORC1 and CYP2C9. Although VKORC1 and CYP2C9 genotyping offered no additional benefit, caution should be used when extrapolating this conclusion to clinical settings in which warfarin therapy is initiated using a standardized starting dose (eg, 5 mg daily) instead of a clinical dosing algorithm.

Of interest, in the COAG trial, among black patients, the mean percentage of time in the therapeutic INR range was significantly less for those in the genotype-guided arm than for those in the clinically guided arm—ie, 35.2% vs 43.5% (95% CI –15.0 to –2.0, P = .01). The percentage of time with therapeutic INR has been identified as a surrogate marker for poor outcomes such as death, stroke, or major hemorrhage, with those with a lower percentage of time in therapeutic INR being at greater risk of an adverse event.¹⁶ Wan et al¹⁷ demonstrated that a 6.9% improvement of time in therapeutic INR decreased the risk of major hemorrhage by one event per 100 patient-years.¹⁷ Therefore, black patients in the COAG genotyping arm may have been at greater risk for an adverse event because of a lower observed percentage of time within the therapeutic INR range.

In the COAG trial, genotyping was done for only one VKORC1 variant and for two CYP2C9 alleles (CYP2C9*2, and CYP2C9*3). Other genetic variants are of clinical importance for warfarin dosing in black patients, and the lack of genotyping for these additional variants may explain why black patients in the genotyping arm performed worse.^5,7,11 In particular, CYP2C9*8 may be an important predictor of warfarin dose in black patients.¹⁸

EU-PACT compared the efficacy of standardized warfarin dosing and that of a clinical algorithm.³ Patients in the standardized dosing arm were prescribed warfarin 10 mg on the first day of treatment (5 mg for those over age 75), and 5 mg on days 2 and 3, with subsequent dosing adjustments based on INR. Patients in the genotyping arm were prescribed warfarin based on an algorithm that incorporated clinical data that included body surface area, age, and concomitantly prescribed drugs, as well as VKORC1 and CYP2C9 genotypes. At the end of 12 weeks, the mean percentage of time in the therapeutic INR range was 60.3% for those in the standardized-dosing arm and 67.4% for those in the genotyping arm (95% CI 3.3 to 10.6, P < .001).² The approximate 7% improvement in percentage of time in the therapeutic INR range may predict a lower risk of hemorrhage for those in the genotyping arm.¹⁷ Although patients in the genotyping arm had a higher percentage of time in the therapeutic INR range, it is unclear whether genotyping alone is superior to standardized dosing because the dosing algorithm used both clinical data and genotype data.

There are substantial differences between the COAG and EU-PACT trials, including dosing schemes, racial diversity, and trial length, and these differences could have contributed to the conflicting results. Based on these two trials, a possible conclusion is that genotype-guided warfarin dosing may be superior to standardized dosing, but may be no better than utilizing a clinical algorithm in white patients. For black patients, additional studies are needed to determine which genetic variants are of importance for guiding warfarin dosing.

We would like to update the recommendations we made in our previously published article,¹ to state that genotyping for CYP2C9 and VKORC1 may be of clinical utility in white patients depending on whether standardized dosing or a clinical algorithm is used to initiate warfarin therapy. Routine genotyping in black patients is not recommended until further studies clarify which genetic variants are of importance for guiding warfarin dosing.

The ongoing Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis may bring much needed clarity to the clinical utility of warfarin pharmacogenomics. We hope to publish a more detailed update of our 2013 article after completion of that trial.

To the Editor: I read with avid interest the IM Board Review by Pagán et al on a man with pheochromocytoma.¹ The article stated that the classic triad is headache, hypertension, and hyperglycemia. I found this to be incorrect. And Harrison’s Principles of Internal Medicine² states that the classic triad is palpitations, headaches, and profuse sweating. I hope you will clarify this in the interest of the readers as it is a board review article.

To the Editor: I read with avid interest the IM Board Review by Pagán et al on a man with pheochromocytoma.¹ The article stated that the classic triad is headache, hypertension, and hyperglycemia. I found this to be incorrect. And Harrison’s Principles of Internal Medicine² states that the classic triad is palpitations, headaches, and profuse sweating. I hope you will clarify this in the interest of the readers as it is a board review article.

To the Editor: I read with avid interest the IM Board Review by Pagán et al on a man with pheochromocytoma.¹ The article stated that the classic triad is headache, hypertension, and hyperglycemia. I found this to be incorrect. And Harrison’s Principles of Internal Medicine² states that the classic triad is palpitations, headaches, and profuse sweating. I hope you will clarify this in the interest of the readers as it is a board review article.

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.

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.

A 57-year-old woman presented to the emergency department with left lower quadrant pain, which had started 1 week earlier and was constant, dull, aching, and nonradiating. There were no aggravating or alleviating factors. The pain was associated with low-grade fever and nausea. She reported no vomiting, no change in bowel habits, and no hematemesis, hematochezia, or melena. She did not have urinary urgency, frequency, or dysuria. She had no cardiac, respiratory, or neurologic symptoms.

Her medical history included hypothyroidism, type 2 diabetes mellitus, diverticulosis, and chronic obstructive pulmonary disease. Her medications included metformin, insulin, levothyroxine, and inhaled tiotropium. She had no allergies. She had never undergone surgery, including cesarean delivery. She was postmenopausal. She had two children, both of whom had been born vaginally at full term. She denied using alcohol, tobacco, and illicit drugs. Her family history was noncontributory.

On examination, she was not in acute distress. Her temperature was 36.7°C (98.1°F), blood pressure 130/90 mm Hg, heart rate 86 beats per minute and regular, respiratory rate 16 breaths per minute, and oxygen saturation 98% on ambient air. Examination of her head and neck was unremarkable. Cardiopulmonary examination was normal. Abdominal examination revealed normal bowel sounds, mild tenderness in the left lower quadrant with localized guarding, and rebound tenderness. Neurologic examination was unremarkable.

Initial laboratory data showed mild leukocytosis. Computed tomography with contrast of the abdomen and pelvis suggested acute diverticulitis.

ATRIAL FIBRILLATION, AND THEN A TURN FOR THE WORSE

The patient was admitted with an initial diagnosis of acute diverticulitis. She was started on antibiotics, hydration, and pain medications, and her abdominal pain gradually improved.

On the third hospital day, she suddenly experienced shortness of breath and palpitations. At the time of admission her electrocardiogram had been normal, but it now showed atrial fibrillation with a rapid ventricular response. She also developed elevated troponin levels, which were thought to represent type 2 non-ST-elevation myocardial infarction.

She was started on aspirin, clopidogrel, and anticoagulation with heparin bridged with warfarin for the new-onset atrial fibrillation. Her heart rate was controlled with metoprolol, and her shortness of breath improved. An echocardiogram was normal.

On the seventh hospital day, she developed severe right-sided lower abdominal pain and bruising. Her blood pressure was 90/60 mm Hg, heart rate 110 beats per minute and irregularly irregular, respiratory rate 22 breaths per minute, and oxygen saturation 97% on room air. Her abdomen was diffusely tender with a palpable mass in the right lower quadrant and hypoactive bowel sounds. Ecchymosis was noted (Figure 1).

DIFFERENTIAL DIAGNOSIS

1. What is the likely cause of her decompensation?

• Acute mesenteric ischemia
• Perforation of the gastrointestinal tract
• Rectus sheath hematoma
• Abdominal compartment syndrome due to acute pancreatitis

Acute mesenteric ischemia

Signs and symptoms of acute mesenteric ischemia can be vague. Moreover, when it leads to bowel necrosis the mortality rate is high, ranging from 30% to 65%.¹ Hence, one should suspect it and try to diagnose it early.

Most patients with this condition have comorbidities; risk factors include atherosclerotic disease, cardiac conditions (congestive heart failure, recent myocardial infarction, and atrial fibrillation), systemic illness, and inherited or acquired hypercoagulable states.²

The four major causes are:

• Acute thromboembolic occlusion of the superior mesenteric artery (the most common site of occlusion because of the acute angle of origin from the aorta)
• Acute thrombosis of the mesenteric vein
• Acute thrombosis of the mesenteric artery
• Nonocclusive disease affecting the mesenteric vessels²

Nonocclusive disease is seen in conditions in which the mesenteric vessels are already compromised due to background stenosis owing to atherosclerosis. Also, conditions such as septic and cardiogenic shock can compromise these arteries, leading to ischemia, which, if it persists, can lead to bowel infarction. Ischemic colitis falls under this category. It commonly involves the descending and sigmoid colon.³

The initial symptom of ischemia may be abdominal pain that is brought on by eating large meals (“postprandial intestinal angina.”² When the ischemia worsens to infarction, patients may have a diffusely tender abdomen and constant pain that does not vary with palpation. Surprisingly, patients do not exhibit peritoneal signs early on. This gives rise to the description of “pain out of proportion to the physical findings” traditionally associated with acute mesenteric ischemia.²

Diagnosis. Supportive laboratory data include marked leukocytosis, elevated hematocrit due to hemoconcentration, metabolic acidosis, and elevated lactate.⁴ Newer markers such as serum alpha-glutathione S-transferase (alpha-GST) and intestinal fatty acid-binding protein (I-FABP) may be used to support the diagnosis.

Elevated alpha-GST has 72% sensitivity and 77% specificity in the diagnosis of acute mesenteric ischemia.⁵ The caveat is that it cannot reliably differentiate ischemia from infarction. Its sensitivity can be improved to 97% to 100% by using the white blood cell count and lactate levels in combination.⁵

An I-FABP level higher than 100 ng/mL has 100% sensitivity for diagnosing mesenteric infarction but only 25% sensitivity for bowel strangulation.⁶

Early use of abdominal computed tomography with contrast can aid in recognizing this diagnosis.⁷ Thus, it should be ordered in suspected cases, even in patients who have elevated creatinine levels (which would normally preclude the use of contrast), since early diagnosis followed by endovascular therapy is associated with survival benefit, and the risk of contrast-induced nephropathy appears to be small.⁸ Computed tomography helps to determine the state of mesenteric vessels and bowel perfusion before ischemia progresses to infarction. It also helps to rule out other common diagnoses. Findings that suggest acute mesenteric ischemia include segmental bowel wall thickening, intestinal pneumatosis with gas in the portal vein, bowel dilation, mesenteric stranding, portomesenteric thrombosis, and solid-organ infarction.⁹

Treatment. If superior mesenteric artery occlusion is diagnosed on computed tomography, the next step is to determine if there is peritonitis.¹⁰ In patients who have evidence of peritonitis, exploratory laparotomy is performed. For emboli in such patients, open embolectomy followed by on-table angiography is carried out in combination with damage-control surgery. For patients with peritonitis and acute thrombosis, stenting along with damage-control surgery is preferred.¹⁰

On the other hand, if there is no peritonitis, the thrombosis may be amenable to endovascular intervention. For patients with acute embolic occlusion with no contraindications to thrombolysis, aspiration embolectomy in combination with local catheter-directed thrombolysis with recombinant tissue plasminogen activator can be performed. This can be combined with endovascular mechanical embolectomy for more complete management.¹⁰ Patients with contraindications to thrombolysis can be treated either with aspiration and mechanical embolectomy or with open embolectomy with angiography.¹⁰

During laparotomy, the surgeon carefully inspects the bowel for signs of necrosis. Signs that bowel is still viable include pink color, bleeding from cut surfaces, good peristalsis, and visible pulsations in the arterial arcade of the mesentery.

On day 7 she developed acute decompensation—what was the cause?

Acute mesenteric artery thrombosis arising from chronic atherosclerotic disease can be treated with stenting of the stenotic lesion.¹⁰ Patients with this condition would also benefit from aggressive management of atherosclerotic disease with statins along with antiplatelet agents.¹⁰

Mesenteric vein thrombosis requires prompt institution of anticoagulation. However, in advanced cases leading to bowel infarction, exploratory laparotomy with resection of the necrotic bowel may be required. Anticoagulation should be continued for at least 6 months, and further therapy should be determined by the underlying precipitating condition.¹⁰

Critically ill patients who develop mesenteric ischemia secondary to persistent hypotension usually respond to adequate volume resuscitation, cessation of vasopressors, and overall improvement in their hemodynamic status. These patients must be closely monitored for development of gangrene of the bowel because they may be intubated and not able to complain. Any sudden deterioration in their condition should prompt physicians to consider bowel necrosis developing in these patients. Elevation of lactate levels out of proportion to the degree of hypotension may be corroborative evidence.⁴

Our patient had risk factors for acute mesenteric ischemia that included atrial fibrillation and recent non-ST-elevation myocardial infarction. She could have had arterial emboli due to atrial fibrillation, in situ superior mesenteric arterial thrombosis, or splanchnic arterial vasoconstriction due to the myocardial infarction associated with transient hypotension.

Arguing against this diagnosis, although she had a grossly distended abdomen, abdominal bruising usually is not seen. Also, a palpable mass in the right lower quadrant is uncommon except when acute mesenteric ischemia occurs due to segmental intestinal strangulation, as with strangulated hernia or volvulus. She also had therapeutic international normalized ratio (INR) levels constantly while on anticoagulation. Nevertheless, acute mesenteric ischemia should be strongly considered in the initial differential diagnosis of this patient’s acute decompensation.

Perforation of the gastrointestinal tract

Diverticulitis is the acute inflammation of one or more diverticula, which are small pouches created by herniation of the mucosa into the wall of the colon. The condition is caused by microscopic or macroscopic perforation of the diverticula. Microscopic perforation is usually self-limited (uncomplicated diverticulitis) and responds to conservative treatment, whereas macroscopic perforation can be associated with fecal or purulent peritonitis, abscess, enteric fistula, bowel obstruction, and stricture (complicated diverticulitis), in which case surgery may be necessary.

Signs and symptoms of acute mesenteric ischemia can be vague

Patients with peritonitis due to free perforation present with generalized tenderness with rebound tenderness and guarding on abdominal examination. The abdomen may be distended and tympanic to percussion, with diminished or absent bowel sounds. Patients may have hemodynamic compromise.

Plain upright abdominal radiographs may show free air under the diaphragm. Computed tomography may show oral contrast outside the lumen and detect even small amounts of free intraperitoneal air (more clearly seen on a lung window setting).

Our patient initially presented with acute diverticulitis. She later developed diffuse abdominal tenderness with hypoactive bowel sounds. Bowel perforation is certainly a possibility at this stage, though it is usually not associated with abdominal bruising. She would need additional imaging to rule out this complication.

Other differential diagnoses to be considered in this patient with right lower-quadrant pain include acute appendicitis, incarcerated inguinal hernia, volvulus (particularly cecal volvulus), small-bowel obstruction, pyelonephritis, and gynecologic causes such as adnexal torsion, ruptured ovarian cyst, and tubo-ovarian abscess. Computed tomography helps to differentiate most of these causes.

Rectus sheath hematoma

Rectus sheath hematoma is relatively uncommon and often not considered in the initial differential diagnosis of an acute abdomen. This gives it the rightful term “a great masquerader.” It usually results from bleeding into the rectus sheath from damage to the superior (more common) or inferior epigastric arteries and occasionally from a direct tear of the rectus abdominis muscle. Predisposing factors include anticoagulant therapy (most common), advanced age, hypertension, previous abdominal surgery, trauma, paroxysmal coughing, medication injections, pregnancy, blood dyscrasias, severe vomiting, violent physical activity, and leukemia.¹¹

Clinical manifestations include acute abdominal pain, often associated with fever, nausea, and vomiting. Physical examination may reveal signs of hypovolemic shock, a palpable nonpulsatile abdominal mass, and signs of local peritoneal irritation. The Carnett sign¹¹ (tenderness within the abdominal wall that persists and does not improve with raising the head) and the Fothergill sign¹¹ (a tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath) may be elicited.

Computed tomography is more sensitive than abdominal ultrasonography in differentiating rectus sheath hematoma from an intra-abdominal pathology.¹¹ In addition, computed tomography also helps to determine if the bleeding is active or not, which has therapeutic implications.

In our patient, rectus sheath hematoma is a possibility because of her ongoing anticoagulation, findings of localized abdominal bruising, and palpable right lower-quadrant mass, and it is high on the list of differential diagnoses. Rectus sheath hematoma should be considered in the differential diagnosis of lower abdominal pain particularly in elderly women who are on anticoagulation and in whom the onset of pain coincides with a paroxysm of cough.¹² Women are twice as likely as men to develop rectus sheath hematoma, owing to their different muscle mass.¹³ In addition, anterior abdominal wall muscles are stretched during pregnancy.¹³

Abdominal compartment syndrome

Abdominal compartment syndrome has been classically associated with surgical patients. However, it is being increasingly recognized in critically ill medical patients, in whom detecting and treating it early may result in significant reduction in rates of morbidity and death.¹⁴

Abdominal compartment syndrome is of three types: primary, secondary, and recurrent. Primary abdominal compartment syndrome refers to the classic surgical patients with evidence of direct injury to the abdominal or pelvic organs through major trauma or extensive abdominal surgeries. Secondary abdominal compartment syndrome refers to its development in critically ill intensive care patients in whom the pathology does not directly involve the abdominal or pelvic organs.

Various medical conditions can culminate in abdominal compartment syndrome and result in multiorgan failure. Recurrent abdominal compartment syndrome refers to its development after management of either primary or secondary intra-abdominal hypertension or abdominal compartment syndrome.¹⁵ Clinicians thus must be aware of secondary and recurrent abdominal compartment syndrome occurring in critically ill patients.

The normal intra-abdominal pressure is around 5 to 7 mm Hg, even in most critically ill patients. Persistent elevation, ie, higher than 12 mm Hg, is referred to as intra-abdominal hypertension.^16–18 Intra-abdominal hypertension is subdivided into four grades:

• Grade I: 12–15 mm Hg
• Grade II: 16–20 mm Hg
• Grade III: 21–25 mm Hg
• Grade IV: > 25 mm Hg.

The World Society of the Abdominal Compartment Syndrome (WSACS) defines abdominal compartment syndrome as pressure higher than 20 mm Hg along with organ damage.¹⁸ It may or may not be associated with an abdominal perfusion pressure less than 60 mm Hg.¹⁸

Risk factors associated with abdominal compartment syndrome include conditions causing decreased gut motility (gastroparesis, ileus, and colonic pseudo-obstruction), intra-abdominal or retroperitoneal masses or abscesses, ascites, hemoperitoneum, acute pancreatitis, third-spacing due to massive fluid resuscitation with transfusions, peritoneal dialysis, and shock.^18,19

Microscopic perforation is usually self-limited, whereas macroscopic perforation may need surgery

Physical examination has a sensitivity of only 40% to 60% in detecting intra-abdominal hypertension.²⁰ The gold-standard method of measuring the intra-abdominal pressure is the modified Kron technique,¹⁸ using a Foley catheter in the bladder connected to a pressure transducer. With the patient in the supine position, the transducer is zeroed at the mid-axillary line at the level of the iliac crest, and 25 mL of normal saline is instilled into the bladder and maintained for 30 to 60 seconds to let the detrusor muscle relax.¹⁵ Pressure tracings are then recorded at the end of expiration. Factors that are known to affect the transbladder pressure include patient position, respiratory movement, and body mass index, and should be taken into account when reading the pressure recordings.^15,21 Other techniques that can be used include intragastric, intra-inferior vena cava, and intrarectal approaches.¹⁵

The WSACS recommends that any patient admitted to a critical care unit or in whom new organ failure develops should be screened for risk factors for intra-abdominal hypertension and abdominal compartment syndrome. If a patient has at least two of the risk factors suggested by WSACS, a baseline intra-abdominal pressure measurement should be obtained. Patients at risk for intra-abdominal hypertension should have the intra-abdominal pressure measured every 4 to 6 hours. However, in the face of hemodynamic instability and worsening multiorgan failure, the pressure may need to be measured hourly.¹⁸

Clinicians managing patients in the intensive care unit should think of intra-abdominal pressure alongside blood pressure, urine output, and mental status when evaluating hemodynamic status. Clinical manifestations of abdominal compartment syndrome reflect the underlying organ dysfunction and include hypotension, refractory shock, decreased urine output, intracranial hypertension, progressive hypoxemia and hypercarbia, elevated pulmonary peak pressures, and worsening of metabolic acidosis.²²

Treatment. The standard treatment for primary abdominal compartment syndrome is surgical decompression. According to WSACS guidelines, insertion of a percutaneous drainage catheter should be advocated in patients with gross ascites and in whom decompressive surgery is not feasible. A damage-control resuscitation strategy used for patients undergoing damage-control laparotomy has been found to increase the 30-day survival rate.²³ A damage-control resuscitation strategy consists of increasing the use of plasma and platelet transfusions over packed red cell transfusions, limiting the use of crystalloid solutions in early fluid resuscitation, and allowing for permissive hypotension.

Rectus sheath hematoma is relatively uncommon and is not often considered in the initial differential diagnosis of an acute abdomen

Secondary abdominal compartment syndrome is treated conservatively in most cases, since patients with this condition are very poor surgical candidates owing to their comorbidities.¹⁸ However, in patients with progressive organ dysfunction in whom medical management has failed, surgical decompression should be considered.¹⁸ Medical management of secondary abdominal compartment syndrome depends on the underlying etiology. Strategies include nasogastric or colonic decompression, use of prokinetic agents, paracentesis in cases with gross ascites, and maintaining a cumulative negative fluid balance. The WSACS does not recommend routine use of diuretics, albumin infusion, or renal replacement strategies. Pain should be adequately controlled to improve abdominal wall compliance.^18,24 Neuromuscular blockade agents may be used to aid this process. Neostigmine may be used to treat colonic pseudo-obstruction when other conservative methods fail. Use of enteral nutrition should be minimized.¹⁸

Our patient might have abdominal compartment syndrome, but a definitive diagnosis cannot be made at this point without measuring the intra-abdominal pressure.

WHICH IMAGING TEST WOULD BE BEST?

2. Which imaging test would be best for establishing the diagnosis in this patient?

• Plain abdominal radiography
• Abdominal ultrasonography
• Computed tomography of the abdomen and pelvis with contrast
• Magnetic resonance imaging of the abdomen and pelvis

Plain abdominal radiography

Plain abdominal radiography can help to determine if there is free gas under the diaphragm (due to bowel perforation), obstructed bowel, sentinel loop, volvulus, or fecoliths causing the abdominal pain. It cannot diagnose rectus sheath hematoma or acute mesenteric ischemia.

Abdominal ultrasonography

Abdominal ultrasonography can be used as the first diagnostic test, as it is widely available, safe, effective, and tolerable. It does not expose the patient to radiation or intravenous contrast agents. It helps to diagnose rectus sheath hematoma and helps to follow its maturation and resolution once a diagnosis is made. It can provide a rapid assessment of the size, location, extent, and physical characteristics of the mass.

Ultrasonography is widely available, safe, effective, and tolerable

Rectus sheath hematoma appears spindle-shaped on sagittal sections and ovoid on coronal sections. It often appears sonolucent in the early stages and sonodense in the late stage, but the appearance may be heterogeneous depending on the combined presence of clot and fresh blood. These findings are sufficient to make the diagnosis.

Abdominal ultrasonography has 85% to 96% sensitivity in diagnosing rectus sheath hematoma.²⁵ It can help diagnose other causes of the abdominal pain, such as renal stones and cholecystitis. It is the preferred imaging test in pediatric patients, pregnant patients, and those with renal insufficiency.

Abdominal computed tomography

Abdominal computed tomography has a sensitivity and specificity of 100% for diagnosing acute rectus sheath hematoma with a duration of less than 5 days.²⁵ It not only helps to determine the precise location and extent, but also helps to determine if there is active extravasation. Even in patients with renal insufficiency, noncontrast computed tomography will help to confirm the diagnosis, although it may not show extravasation or it may miss certain abdominal pathologies because of the lack of contrast.

Acute rectus sheath hematoma appears as a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement. Chronic rectus sheath hematoma appears isodense or hypodense relative to the surrounding muscle. Above the arcuate line, rectus sheath hematoma has a spindle shape; below the arcuate line, it is typically spherical.

In 1996, Berná et al²⁶ classified rectus sheath hematoma into three grades based on findings of computed tomography:

• Grade I is intramuscular and unilateral
• Grade II may involve bilateral rectus muscles without extension into the prevesicular space
• Grade III extends into the peritoneum and prevesicular space

Magnetic resonance imaging

Magnetic resonance imaging is useful to differentiate chronic rectus sheath hematoma (greater than 5-day duration) from an anterior abdominal wall mass. Chronic rectus sheath hematoma will have high signal intensity on both T1- and T2-weighted images up to 10 months after the onset of the hematoma.²⁷

Back to our patient

Since our patient’s symptoms are acute and of less than 5 days’ duration, computed tomography of the abdomen and pelvis would be the best diagnostic test, with therapeutic implications if there is ongoing extravasation.

Computed tomography of the abdomen with contrast showed a new hematoma, measuring 25 by 14 by 13.5 cm, in the right rectus sheath (Figure 2), with no other findings. The hematoma was grade I, since it was intramuscular and unilateral without extension elsewhere.

Laboratory workup showed that the patient’s hematocrit was falling, from 34% to 24%, and her INR was elevated at 2.5. She was resuscitated with fluids, blood transfusion, and fresh-frozen plasma. Anticoagulation was withheld. In spite of resuscitation, her hematocrit kept falling, though she remained hemodynamically stable.

THE WAY FORWARD

3. At this point, what would be the best approach to management in this patient?

• Serial clinical examinations and frequent monitoring of the complete blood cell count
• Urgent surgical consult for exploratory laparotomy with evaluation of the hematoma and ligation of the bleeding vessel
• Repeat computed tomographic angiography to identify a possible bleeding vessel; consideration of radiographically guided arterial embolization
• Measuring the intra-abdominal pressure using the intrabladder pressure for abdominal compartment syndrome and consideration of surgical drainage

The key clinical concern in a patient with a rectus sheath hematoma who is hemodynamically stable is whether the hematoma is expanding. This patient responded to initial resuscitation, but her falling hematocrit was evidence of ongoing bleeding leading to an expanding rectus sheath hematoma. Thus, serial clinical examinations and frequent monitoring of the complete blood cell count would not be enough, as it could miss fatal ongoing bleeding.

Radiographically guided embolization with Gelfoam, thrombin, or coils should be attempted first, as this is less invasive than exploratory laparotomy.²⁸ It can achieve hemostasis, decrease the size of the hematoma, limit the need for blood products, and prevent rupture into the abdomen. If this is unsuccessful, the next step is ligation of the bleeding vessel.²⁹

Surgical treatment includes evacuation of the hematoma, repair of the rectus sheath, ligation of bleeding vessels, and abdominal wall closure. Surgical evacuation or guided drainage of a rectus sheath hematoma on its own is not normally indicated and may indeed cause persistent bleeding by diminishing a potential tamponade effect. However, it may become necessary if the hematoma is very large or infected, if it causes marked respiratory impairment, or if abdominal compartment syndrome is suspected.

Abdominal compartment syndrome is very rare but is associated with a 50% mortality rate.³⁰ It should be suspected in patients with oliguria, low cardiac output, changes in minute ventilation, and altered splanchnic blood flow. The diagnosis is confirmed with indwelling catheter manometry of the bladder to measure intra-abdominal pressure. Intra-abominal pressure above 25 mm Hg should be treated with decompressive laparotomy.³⁰ However, the clinical suspicion of abdominal compartment syndrome was low in this patient.

The best choice at this point would be urgent computed tomographic angiography to identify a bleeding vessel, along with consideration of radiographically guided arterial embolization.

TREATMENT IS USUALLY CONSERVATIVE

Treatment of rectus sheath hematoma is conservative in most hemodynamically stable patients, with embolization or surgical intervention reserved for unstable patients or those in whom the hematoma is expanding.

Knowledge of the grading system of Berná et al²⁶ helps to assess the patient’s risk and to anticipate potential complications. Grade I hematomas are mild and do not necessitate admission. Patients with grade II hematoma can be admitted to the floor for 24 to 48 hours for observation. Grade III usually occurs in patients receiving anticoagulant therapy and frequently requires blood products. These patients have a prolonged hospital stay and more complications, including hypovolemic shock, myonecrosis, acute coronary syndrome, arrhythmias, acute renal failure, small-bowel infarction, and abdominal compartment syndrome—all of which increases the risk of morbidity and death. Thus, patients who are on anticoagulation who develop grade III rectus sheath hematoma should be admitted to the hospital, preferably to the intensive care unit, to ensure that the hematoma is not expanding and to plan reinstitution of anticoagulation as appropriate.

In most cases, rectus sheath hematomas resolve within 1 to 3 months. Resolution of large hematomas may be hastened with the use of pulsed ultrasound.³¹ However, this treatment should be used only after the acute phase is over, when there is evidence of an organized thrombus and coagulation measures have returned to the target range. This helps to reduce the risk of bleeding and to prevent symptoms from worsening.³¹

OUR PATIENT’S COURSE

Our patient underwent urgent computed tomographic angiography, which showed a modest increase in the size of the rectus sheath hematoma. However, no definitive blush of contrast was seen to suggest active arterial bleeding. Her hematocrit stabilized, and she remained hemodynamically stable without requiring additional intervention. Most likely her bleeding was self-contained. She had normal intra-abdominal pressure on serial monitoring. She was later transferred to acute inpatient rehabilitation in view of deconditioning and is currently doing well. The hematoma persisted, decreasing only slightly in size over the next 3 weeks.

A 57-year-old woman presented to the emergency department with left lower quadrant pain, which had started 1 week earlier and was constant, dull, aching, and nonradiating. There were no aggravating or alleviating factors. The pain was associated with low-grade fever and nausea. She reported no vomiting, no change in bowel habits, and no hematemesis, hematochezia, or melena. She did not have urinary urgency, frequency, or dysuria. She had no cardiac, respiratory, or neurologic symptoms.

Her medical history included hypothyroidism, type 2 diabetes mellitus, diverticulosis, and chronic obstructive pulmonary disease. Her medications included metformin, insulin, levothyroxine, and inhaled tiotropium. She had no allergies. She had never undergone surgery, including cesarean delivery. She was postmenopausal. She had two children, both of whom had been born vaginally at full term. She denied using alcohol, tobacco, and illicit drugs. Her family history was noncontributory.

On examination, she was not in acute distress. Her temperature was 36.7°C (98.1°F), blood pressure 130/90 mm Hg, heart rate 86 beats per minute and regular, respiratory rate 16 breaths per minute, and oxygen saturation 98% on ambient air. Examination of her head and neck was unremarkable. Cardiopulmonary examination was normal. Abdominal examination revealed normal bowel sounds, mild tenderness in the left lower quadrant with localized guarding, and rebound tenderness. Neurologic examination was unremarkable.

Initial laboratory data showed mild leukocytosis. Computed tomography with contrast of the abdomen and pelvis suggested acute diverticulitis.

ATRIAL FIBRILLATION, AND THEN A TURN FOR THE WORSE

The patient was admitted with an initial diagnosis of acute diverticulitis. She was started on antibiotics, hydration, and pain medications, and her abdominal pain gradually improved.

On the third hospital day, she suddenly experienced shortness of breath and palpitations. At the time of admission her electrocardiogram had been normal, but it now showed atrial fibrillation with a rapid ventricular response. She also developed elevated troponin levels, which were thought to represent type 2 non-ST-elevation myocardial infarction.

She was started on aspirin, clopidogrel, and anticoagulation with heparin bridged with warfarin for the new-onset atrial fibrillation. Her heart rate was controlled with metoprolol, and her shortness of breath improved. An echocardiogram was normal.

On the seventh hospital day, she developed severe right-sided lower abdominal pain and bruising. Her blood pressure was 90/60 mm Hg, heart rate 110 beats per minute and irregularly irregular, respiratory rate 22 breaths per minute, and oxygen saturation 97% on room air. Her abdomen was diffusely tender with a palpable mass in the right lower quadrant and hypoactive bowel sounds. Ecchymosis was noted (Figure 1).

DIFFERENTIAL DIAGNOSIS

1. What is the likely cause of her decompensation?

• Acute mesenteric ischemia
• Perforation of the gastrointestinal tract
• Rectus sheath hematoma
• Abdominal compartment syndrome due to acute pancreatitis

Acute mesenteric ischemia

Signs and symptoms of acute mesenteric ischemia can be vague. Moreover, when it leads to bowel necrosis the mortality rate is high, ranging from 30% to 65%.¹ Hence, one should suspect it and try to diagnose it early.

Most patients with this condition have comorbidities; risk factors include atherosclerotic disease, cardiac conditions (congestive heart failure, recent myocardial infarction, and atrial fibrillation), systemic illness, and inherited or acquired hypercoagulable states.²

The four major causes are:

• Acute thromboembolic occlusion of the superior mesenteric artery (the most common site of occlusion because of the acute angle of origin from the aorta)
• Acute thrombosis of the mesenteric vein
• Acute thrombosis of the mesenteric artery
• Nonocclusive disease affecting the mesenteric vessels²

Nonocclusive disease is seen in conditions in which the mesenteric vessels are already compromised due to background stenosis owing to atherosclerosis. Also, conditions such as septic and cardiogenic shock can compromise these arteries, leading to ischemia, which, if it persists, can lead to bowel infarction. Ischemic colitis falls under this category. It commonly involves the descending and sigmoid colon.³

The initial symptom of ischemia may be abdominal pain that is brought on by eating large meals (“postprandial intestinal angina.”² When the ischemia worsens to infarction, patients may have a diffusely tender abdomen and constant pain that does not vary with palpation. Surprisingly, patients do not exhibit peritoneal signs early on. This gives rise to the description of “pain out of proportion to the physical findings” traditionally associated with acute mesenteric ischemia.²

Diagnosis. Supportive laboratory data include marked leukocytosis, elevated hematocrit due to hemoconcentration, metabolic acidosis, and elevated lactate.⁴ Newer markers such as serum alpha-glutathione S-transferase (alpha-GST) and intestinal fatty acid-binding protein (I-FABP) may be used to support the diagnosis.

Elevated alpha-GST has 72% sensitivity and 77% specificity in the diagnosis of acute mesenteric ischemia.⁵ The caveat is that it cannot reliably differentiate ischemia from infarction. Its sensitivity can be improved to 97% to 100% by using the white blood cell count and lactate levels in combination.⁵

An I-FABP level higher than 100 ng/mL has 100% sensitivity for diagnosing mesenteric infarction but only 25% sensitivity for bowel strangulation.⁶

Early use of abdominal computed tomography with contrast can aid in recognizing this diagnosis.⁷ Thus, it should be ordered in suspected cases, even in patients who have elevated creatinine levels (which would normally preclude the use of contrast), since early diagnosis followed by endovascular therapy is associated with survival benefit, and the risk of contrast-induced nephropathy appears to be small.⁸ Computed tomography helps to determine the state of mesenteric vessels and bowel perfusion before ischemia progresses to infarction. It also helps to rule out other common diagnoses. Findings that suggest acute mesenteric ischemia include segmental bowel wall thickening, intestinal pneumatosis with gas in the portal vein, bowel dilation, mesenteric stranding, portomesenteric thrombosis, and solid-organ infarction.⁹

Treatment. If superior mesenteric artery occlusion is diagnosed on computed tomography, the next step is to determine if there is peritonitis.¹⁰ In patients who have evidence of peritonitis, exploratory laparotomy is performed. For emboli in such patients, open embolectomy followed by on-table angiography is carried out in combination with damage-control surgery. For patients with peritonitis and acute thrombosis, stenting along with damage-control surgery is preferred.¹⁰

On the other hand, if there is no peritonitis, the thrombosis may be amenable to endovascular intervention. For patients with acute embolic occlusion with no contraindications to thrombolysis, aspiration embolectomy in combination with local catheter-directed thrombolysis with recombinant tissue plasminogen activator can be performed. This can be combined with endovascular mechanical embolectomy for more complete management.¹⁰ Patients with contraindications to thrombolysis can be treated either with aspiration and mechanical embolectomy or with open embolectomy with angiography.¹⁰

During laparotomy, the surgeon carefully inspects the bowel for signs of necrosis. Signs that bowel is still viable include pink color, bleeding from cut surfaces, good peristalsis, and visible pulsations in the arterial arcade of the mesentery.

On day 7 she developed acute decompensation—what was the cause?

Acute mesenteric artery thrombosis arising from chronic atherosclerotic disease can be treated with stenting of the stenotic lesion.¹⁰ Patients with this condition would also benefit from aggressive management of atherosclerotic disease with statins along with antiplatelet agents.¹⁰

Mesenteric vein thrombosis requires prompt institution of anticoagulation. However, in advanced cases leading to bowel infarction, exploratory laparotomy with resection of the necrotic bowel may be required. Anticoagulation should be continued for at least 6 months, and further therapy should be determined by the underlying precipitating condition.¹⁰

Critically ill patients who develop mesenteric ischemia secondary to persistent hypotension usually respond to adequate volume resuscitation, cessation of vasopressors, and overall improvement in their hemodynamic status. These patients must be closely monitored for development of gangrene of the bowel because they may be intubated and not able to complain. Any sudden deterioration in their condition should prompt physicians to consider bowel necrosis developing in these patients. Elevation of lactate levels out of proportion to the degree of hypotension may be corroborative evidence.⁴

Our patient had risk factors for acute mesenteric ischemia that included atrial fibrillation and recent non-ST-elevation myocardial infarction. She could have had arterial emboli due to atrial fibrillation, in situ superior mesenteric arterial thrombosis, or splanchnic arterial vasoconstriction due to the myocardial infarction associated with transient hypotension.

Arguing against this diagnosis, although she had a grossly distended abdomen, abdominal bruising usually is not seen. Also, a palpable mass in the right lower quadrant is uncommon except when acute mesenteric ischemia occurs due to segmental intestinal strangulation, as with strangulated hernia or volvulus. She also had therapeutic international normalized ratio (INR) levels constantly while on anticoagulation. Nevertheless, acute mesenteric ischemia should be strongly considered in the initial differential diagnosis of this patient’s acute decompensation.

Perforation of the gastrointestinal tract

Diverticulitis is the acute inflammation of one or more diverticula, which are small pouches created by herniation of the mucosa into the wall of the colon. The condition is caused by microscopic or macroscopic perforation of the diverticula. Microscopic perforation is usually self-limited (uncomplicated diverticulitis) and responds to conservative treatment, whereas macroscopic perforation can be associated with fecal or purulent peritonitis, abscess, enteric fistula, bowel obstruction, and stricture (complicated diverticulitis), in which case surgery may be necessary.

Signs and symptoms of acute mesenteric ischemia can be vague

Patients with peritonitis due to free perforation present with generalized tenderness with rebound tenderness and guarding on abdominal examination. The abdomen may be distended and tympanic to percussion, with diminished or absent bowel sounds. Patients may have hemodynamic compromise.

Plain upright abdominal radiographs may show free air under the diaphragm. Computed tomography may show oral contrast outside the lumen and detect even small amounts of free intraperitoneal air (more clearly seen on a lung window setting).

Our patient initially presented with acute diverticulitis. She later developed diffuse abdominal tenderness with hypoactive bowel sounds. Bowel perforation is certainly a possibility at this stage, though it is usually not associated with abdominal bruising. She would need additional imaging to rule out this complication.

Other differential diagnoses to be considered in this patient with right lower-quadrant pain include acute appendicitis, incarcerated inguinal hernia, volvulus (particularly cecal volvulus), small-bowel obstruction, pyelonephritis, and gynecologic causes such as adnexal torsion, ruptured ovarian cyst, and tubo-ovarian abscess. Computed tomography helps to differentiate most of these causes.

Rectus sheath hematoma

Rectus sheath hematoma is relatively uncommon and often not considered in the initial differential diagnosis of an acute abdomen. This gives it the rightful term “a great masquerader.” It usually results from bleeding into the rectus sheath from damage to the superior (more common) or inferior epigastric arteries and occasionally from a direct tear of the rectus abdominis muscle. Predisposing factors include anticoagulant therapy (most common), advanced age, hypertension, previous abdominal surgery, trauma, paroxysmal coughing, medication injections, pregnancy, blood dyscrasias, severe vomiting, violent physical activity, and leukemia.¹¹

Clinical manifestations include acute abdominal pain, often associated with fever, nausea, and vomiting. Physical examination may reveal signs of hypovolemic shock, a palpable nonpulsatile abdominal mass, and signs of local peritoneal irritation. The Carnett sign¹¹ (tenderness within the abdominal wall that persists and does not improve with raising the head) and the Fothergill sign¹¹ (a tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath) may be elicited.

Computed tomography is more sensitive than abdominal ultrasonography in differentiating rectus sheath hematoma from an intra-abdominal pathology.¹¹ In addition, computed tomography also helps to determine if the bleeding is active or not, which has therapeutic implications.

In our patient, rectus sheath hematoma is a possibility because of her ongoing anticoagulation, findings of localized abdominal bruising, and palpable right lower-quadrant mass, and it is high on the list of differential diagnoses. Rectus sheath hematoma should be considered in the differential diagnosis of lower abdominal pain particularly in elderly women who are on anticoagulation and in whom the onset of pain coincides with a paroxysm of cough.¹² Women are twice as likely as men to develop rectus sheath hematoma, owing to their different muscle mass.¹³ In addition, anterior abdominal wall muscles are stretched during pregnancy.¹³

Abdominal compartment syndrome

Abdominal compartment syndrome has been classically associated with surgical patients. However, it is being increasingly recognized in critically ill medical patients, in whom detecting and treating it early may result in significant reduction in rates of morbidity and death.¹⁴

Abdominal compartment syndrome is of three types: primary, secondary, and recurrent. Primary abdominal compartment syndrome refers to the classic surgical patients with evidence of direct injury to the abdominal or pelvic organs through major trauma or extensive abdominal surgeries. Secondary abdominal compartment syndrome refers to its development in critically ill intensive care patients in whom the pathology does not directly involve the abdominal or pelvic organs.

Various medical conditions can culminate in abdominal compartment syndrome and result in multiorgan failure. Recurrent abdominal compartment syndrome refers to its development after management of either primary or secondary intra-abdominal hypertension or abdominal compartment syndrome.¹⁵ Clinicians thus must be aware of secondary and recurrent abdominal compartment syndrome occurring in critically ill patients.

The normal intra-abdominal pressure is around 5 to 7 mm Hg, even in most critically ill patients. Persistent elevation, ie, higher than 12 mm Hg, is referred to as intra-abdominal hypertension.^16–18 Intra-abdominal hypertension is subdivided into four grades:

• Grade I: 12–15 mm Hg
• Grade II: 16–20 mm Hg
• Grade III: 21–25 mm Hg
• Grade IV: > 25 mm Hg.

The World Society of the Abdominal Compartment Syndrome (WSACS) defines abdominal compartment syndrome as pressure higher than 20 mm Hg along with organ damage.¹⁸ It may or may not be associated with an abdominal perfusion pressure less than 60 mm Hg.¹⁸

Risk factors associated with abdominal compartment syndrome include conditions causing decreased gut motility (gastroparesis, ileus, and colonic pseudo-obstruction), intra-abdominal or retroperitoneal masses or abscesses, ascites, hemoperitoneum, acute pancreatitis, third-spacing due to massive fluid resuscitation with transfusions, peritoneal dialysis, and shock.^18,19

Microscopic perforation is usually self-limited, whereas macroscopic perforation may need surgery

Physical examination has a sensitivity of only 40% to 60% in detecting intra-abdominal hypertension.²⁰ The gold-standard method of measuring the intra-abdominal pressure is the modified Kron technique,¹⁸ using a Foley catheter in the bladder connected to a pressure transducer. With the patient in the supine position, the transducer is zeroed at the mid-axillary line at the level of the iliac crest, and 25 mL of normal saline is instilled into the bladder and maintained for 30 to 60 seconds to let the detrusor muscle relax.¹⁵ Pressure tracings are then recorded at the end of expiration. Factors that are known to affect the transbladder pressure include patient position, respiratory movement, and body mass index, and should be taken into account when reading the pressure recordings.^15,21 Other techniques that can be used include intragastric, intra-inferior vena cava, and intrarectal approaches.¹⁵

The WSACS recommends that any patient admitted to a critical care unit or in whom new organ failure develops should be screened for risk factors for intra-abdominal hypertension and abdominal compartment syndrome. If a patient has at least two of the risk factors suggested by WSACS, a baseline intra-abdominal pressure measurement should be obtained. Patients at risk for intra-abdominal hypertension should have the intra-abdominal pressure measured every 4 to 6 hours. However, in the face of hemodynamic instability and worsening multiorgan failure, the pressure may need to be measured hourly.¹⁸

Clinicians managing patients in the intensive care unit should think of intra-abdominal pressure alongside blood pressure, urine output, and mental status when evaluating hemodynamic status. Clinical manifestations of abdominal compartment syndrome reflect the underlying organ dysfunction and include hypotension, refractory shock, decreased urine output, intracranial hypertension, progressive hypoxemia and hypercarbia, elevated pulmonary peak pressures, and worsening of metabolic acidosis.²²

Treatment. The standard treatment for primary abdominal compartment syndrome is surgical decompression. According to WSACS guidelines, insertion of a percutaneous drainage catheter should be advocated in patients with gross ascites and in whom decompressive surgery is not feasible. A damage-control resuscitation strategy used for patients undergoing damage-control laparotomy has been found to increase the 30-day survival rate.²³ A damage-control resuscitation strategy consists of increasing the use of plasma and platelet transfusions over packed red cell transfusions, limiting the use of crystalloid solutions in early fluid resuscitation, and allowing for permissive hypotension.

Rectus sheath hematoma is relatively uncommon and is not often considered in the initial differential diagnosis of an acute abdomen

Secondary abdominal compartment syndrome is treated conservatively in most cases, since patients with this condition are very poor surgical candidates owing to their comorbidities.¹⁸ However, in patients with progressive organ dysfunction in whom medical management has failed, surgical decompression should be considered.¹⁸ Medical management of secondary abdominal compartment syndrome depends on the underlying etiology. Strategies include nasogastric or colonic decompression, use of prokinetic agents, paracentesis in cases with gross ascites, and maintaining a cumulative negative fluid balance. The WSACS does not recommend routine use of diuretics, albumin infusion, or renal replacement strategies. Pain should be adequately controlled to improve abdominal wall compliance.^18,24 Neuromuscular blockade agents may be used to aid this process. Neostigmine may be used to treat colonic pseudo-obstruction when other conservative methods fail. Use of enteral nutrition should be minimized.¹⁸

Our patient might have abdominal compartment syndrome, but a definitive diagnosis cannot be made at this point without measuring the intra-abdominal pressure.

WHICH IMAGING TEST WOULD BE BEST?

2. Which imaging test would be best for establishing the diagnosis in this patient?

• Plain abdominal radiography
• Abdominal ultrasonography
• Computed tomography of the abdomen and pelvis with contrast
• Magnetic resonance imaging of the abdomen and pelvis

Plain abdominal radiography

Plain abdominal radiography can help to determine if there is free gas under the diaphragm (due to bowel perforation), obstructed bowel, sentinel loop, volvulus, or fecoliths causing the abdominal pain. It cannot diagnose rectus sheath hematoma or acute mesenteric ischemia.

Abdominal ultrasonography

Abdominal ultrasonography can be used as the first diagnostic test, as it is widely available, safe, effective, and tolerable. It does not expose the patient to radiation or intravenous contrast agents. It helps to diagnose rectus sheath hematoma and helps to follow its maturation and resolution once a diagnosis is made. It can provide a rapid assessment of the size, location, extent, and physical characteristics of the mass.

Ultrasonography is widely available, safe, effective, and tolerable

Rectus sheath hematoma appears spindle-shaped on sagittal sections and ovoid on coronal sections. It often appears sonolucent in the early stages and sonodense in the late stage, but the appearance may be heterogeneous depending on the combined presence of clot and fresh blood. These findings are sufficient to make the diagnosis.

Abdominal ultrasonography has 85% to 96% sensitivity in diagnosing rectus sheath hematoma.²⁵ It can help diagnose other causes of the abdominal pain, such as renal stones and cholecystitis. It is the preferred imaging test in pediatric patients, pregnant patients, and those with renal insufficiency.

Abdominal computed tomography

Abdominal computed tomography has a sensitivity and specificity of 100% for diagnosing acute rectus sheath hematoma with a duration of less than 5 days.²⁵ It not only helps to determine the precise location and extent, but also helps to determine if there is active extravasation. Even in patients with renal insufficiency, noncontrast computed tomography will help to confirm the diagnosis, although it may not show extravasation or it may miss certain abdominal pathologies because of the lack of contrast.

Acute rectus sheath hematoma appears as a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement. Chronic rectus sheath hematoma appears isodense or hypodense relative to the surrounding muscle. Above the arcuate line, rectus sheath hematoma has a spindle shape; below the arcuate line, it is typically spherical.

In 1996, Berná et al²⁶ classified rectus sheath hematoma into three grades based on findings of computed tomography:

• Grade I is intramuscular and unilateral
• Grade II may involve bilateral rectus muscles without extension into the prevesicular space
• Grade III extends into the peritoneum and prevesicular space

Magnetic resonance imaging

Magnetic resonance imaging is useful to differentiate chronic rectus sheath hematoma (greater than 5-day duration) from an anterior abdominal wall mass. Chronic rectus sheath hematoma will have high signal intensity on both T1- and T2-weighted images up to 10 months after the onset of the hematoma.²⁷

Back to our patient

Since our patient’s symptoms are acute and of less than 5 days’ duration, computed tomography of the abdomen and pelvis would be the best diagnostic test, with therapeutic implications if there is ongoing extravasation.

Computed tomography of the abdomen with contrast showed a new hematoma, measuring 25 by 14 by 13.5 cm, in the right rectus sheath (Figure 2), with no other findings. The hematoma was grade I, since it was intramuscular and unilateral without extension elsewhere.

Laboratory workup showed that the patient’s hematocrit was falling, from 34% to 24%, and her INR was elevated at 2.5. She was resuscitated with fluids, blood transfusion, and fresh-frozen plasma. Anticoagulation was withheld. In spite of resuscitation, her hematocrit kept falling, though she remained hemodynamically stable.

THE WAY FORWARD

3. At this point, what would be the best approach to management in this patient?

• Serial clinical examinations and frequent monitoring of the complete blood cell count
• Urgent surgical consult for exploratory laparotomy with evaluation of the hematoma and ligation of the bleeding vessel
• Repeat computed tomographic angiography to identify a possible bleeding vessel; consideration of radiographically guided arterial embolization
• Measuring the intra-abdominal pressure using the intrabladder pressure for abdominal compartment syndrome and consideration of surgical drainage

The key clinical concern in a patient with a rectus sheath hematoma who is hemodynamically stable is whether the hematoma is expanding. This patient responded to initial resuscitation, but her falling hematocrit was evidence of ongoing bleeding leading to an expanding rectus sheath hematoma. Thus, serial clinical examinations and frequent monitoring of the complete blood cell count would not be enough, as it could miss fatal ongoing bleeding.

Radiographically guided embolization with Gelfoam, thrombin, or coils should be attempted first, as this is less invasive than exploratory laparotomy.²⁸ It can achieve hemostasis, decrease the size of the hematoma, limit the need for blood products, and prevent rupture into the abdomen. If this is unsuccessful, the next step is ligation of the bleeding vessel.²⁹

Surgical treatment includes evacuation of the hematoma, repair of the rectus sheath, ligation of bleeding vessels, and abdominal wall closure. Surgical evacuation or guided drainage of a rectus sheath hematoma on its own is not normally indicated and may indeed cause persistent bleeding by diminishing a potential tamponade effect. However, it may become necessary if the hematoma is very large or infected, if it causes marked respiratory impairment, or if abdominal compartment syndrome is suspected.

Abdominal compartment syndrome is very rare but is associated with a 50% mortality rate.³⁰ It should be suspected in patients with oliguria, low cardiac output, changes in minute ventilation, and altered splanchnic blood flow. The diagnosis is confirmed with indwelling catheter manometry of the bladder to measure intra-abdominal pressure. Intra-abominal pressure above 25 mm Hg should be treated with decompressive laparotomy.³⁰ However, the clinical suspicion of abdominal compartment syndrome was low in this patient.

The best choice at this point would be urgent computed tomographic angiography to identify a bleeding vessel, along with consideration of radiographically guided arterial embolization.

TREATMENT IS USUALLY CONSERVATIVE

Treatment of rectus sheath hematoma is conservative in most hemodynamically stable patients, with embolization or surgical intervention reserved for unstable patients or those in whom the hematoma is expanding.

Knowledge of the grading system of Berná et al²⁶ helps to assess the patient’s risk and to anticipate potential complications. Grade I hematomas are mild and do not necessitate admission. Patients with grade II hematoma can be admitted to the floor for 24 to 48 hours for observation. Grade III usually occurs in patients receiving anticoagulant therapy and frequently requires blood products. These patients have a prolonged hospital stay and more complications, including hypovolemic shock, myonecrosis, acute coronary syndrome, arrhythmias, acute renal failure, small-bowel infarction, and abdominal compartment syndrome—all of which increases the risk of morbidity and death. Thus, patients who are on anticoagulation who develop grade III rectus sheath hematoma should be admitted to the hospital, preferably to the intensive care unit, to ensure that the hematoma is not expanding and to plan reinstitution of anticoagulation as appropriate.

In most cases, rectus sheath hematomas resolve within 1 to 3 months. Resolution of large hematomas may be hastened with the use of pulsed ultrasound.³¹ However, this treatment should be used only after the acute phase is over, when there is evidence of an organized thrombus and coagulation measures have returned to the target range. This helps to reduce the risk of bleeding and to prevent symptoms from worsening.³¹

OUR PATIENT’S COURSE

Our patient underwent urgent computed tomographic angiography, which showed a modest increase in the size of the rectus sheath hematoma. However, no definitive blush of contrast was seen to suggest active arterial bleeding. Her hematocrit stabilized, and she remained hemodynamically stable without requiring additional intervention. Most likely her bleeding was self-contained. She had normal intra-abdominal pressure on serial monitoring. She was later transferred to acute inpatient rehabilitation in view of deconditioning and is currently doing well. The hematoma persisted, decreasing only slightly in size over the next 3 weeks.

A 57-year-old woman presented to the emergency department with left lower quadrant pain, which had started 1 week earlier and was constant, dull, aching, and nonradiating. There were no aggravating or alleviating factors. The pain was associated with low-grade fever and nausea. She reported no vomiting, no change in bowel habits, and no hematemesis, hematochezia, or melena. She did not have urinary urgency, frequency, or dysuria. She had no cardiac, respiratory, or neurologic symptoms.

Her medical history included hypothyroidism, type 2 diabetes mellitus, diverticulosis, and chronic obstructive pulmonary disease. Her medications included metformin, insulin, levothyroxine, and inhaled tiotropium. She had no allergies. She had never undergone surgery, including cesarean delivery. She was postmenopausal. She had two children, both of whom had been born vaginally at full term. She denied using alcohol, tobacco, and illicit drugs. Her family history was noncontributory.

On examination, she was not in acute distress. Her temperature was 36.7°C (98.1°F), blood pressure 130/90 mm Hg, heart rate 86 beats per minute and regular, respiratory rate 16 breaths per minute, and oxygen saturation 98% on ambient air. Examination of her head and neck was unremarkable. Cardiopulmonary examination was normal. Abdominal examination revealed normal bowel sounds, mild tenderness in the left lower quadrant with localized guarding, and rebound tenderness. Neurologic examination was unremarkable.

Initial laboratory data showed mild leukocytosis. Computed tomography with contrast of the abdomen and pelvis suggested acute diverticulitis.

ATRIAL FIBRILLATION, AND THEN A TURN FOR THE WORSE

The patient was admitted with an initial diagnosis of acute diverticulitis. She was started on antibiotics, hydration, and pain medications, and her abdominal pain gradually improved.

On the third hospital day, she suddenly experienced shortness of breath and palpitations. At the time of admission her electrocardiogram had been normal, but it now showed atrial fibrillation with a rapid ventricular response. She also developed elevated troponin levels, which were thought to represent type 2 non-ST-elevation myocardial infarction.

She was started on aspirin, clopidogrel, and anticoagulation with heparin bridged with warfarin for the new-onset atrial fibrillation. Her heart rate was controlled with metoprolol, and her shortness of breath improved. An echocardiogram was normal.

On the seventh hospital day, she developed severe right-sided lower abdominal pain and bruising. Her blood pressure was 90/60 mm Hg, heart rate 110 beats per minute and irregularly irregular, respiratory rate 22 breaths per minute, and oxygen saturation 97% on room air. Her abdomen was diffusely tender with a palpable mass in the right lower quadrant and hypoactive bowel sounds. Ecchymosis was noted (Figure 1).

DIFFERENTIAL DIAGNOSIS

1. What is the likely cause of her decompensation?

• Acute mesenteric ischemia
• Perforation of the gastrointestinal tract
• Rectus sheath hematoma
• Abdominal compartment syndrome due to acute pancreatitis

Acute mesenteric ischemia

Signs and symptoms of acute mesenteric ischemia can be vague. Moreover, when it leads to bowel necrosis the mortality rate is high, ranging from 30% to 65%.¹ Hence, one should suspect it and try to diagnose it early.

Most patients with this condition have comorbidities; risk factors include atherosclerotic disease, cardiac conditions (congestive heart failure, recent myocardial infarction, and atrial fibrillation), systemic illness, and inherited or acquired hypercoagulable states.²

The four major causes are:

• Acute thromboembolic occlusion of the superior mesenteric artery (the most common site of occlusion because of the acute angle of origin from the aorta)
• Acute thrombosis of the mesenteric vein
• Acute thrombosis of the mesenteric artery
• Nonocclusive disease affecting the mesenteric vessels²

Nonocclusive disease is seen in conditions in which the mesenteric vessels are already compromised due to background stenosis owing to atherosclerosis. Also, conditions such as septic and cardiogenic shock can compromise these arteries, leading to ischemia, which, if it persists, can lead to bowel infarction. Ischemic colitis falls under this category. It commonly involves the descending and sigmoid colon.³

The initial symptom of ischemia may be abdominal pain that is brought on by eating large meals (“postprandial intestinal angina.”² When the ischemia worsens to infarction, patients may have a diffusely tender abdomen and constant pain that does not vary with palpation. Surprisingly, patients do not exhibit peritoneal signs early on. This gives rise to the description of “pain out of proportion to the physical findings” traditionally associated with acute mesenteric ischemia.²

Diagnosis. Supportive laboratory data include marked leukocytosis, elevated hematocrit due to hemoconcentration, metabolic acidosis, and elevated lactate.⁴ Newer markers such as serum alpha-glutathione S-transferase (alpha-GST) and intestinal fatty acid-binding protein (I-FABP) may be used to support the diagnosis.

Elevated alpha-GST has 72% sensitivity and 77% specificity in the diagnosis of acute mesenteric ischemia.⁵ The caveat is that it cannot reliably differentiate ischemia from infarction. Its sensitivity can be improved to 97% to 100% by using the white blood cell count and lactate levels in combination.⁵

An I-FABP level higher than 100 ng/mL has 100% sensitivity for diagnosing mesenteric infarction but only 25% sensitivity for bowel strangulation.⁶

Early use of abdominal computed tomography with contrast can aid in recognizing this diagnosis.⁷ Thus, it should be ordered in suspected cases, even in patients who have elevated creatinine levels (which would normally preclude the use of contrast), since early diagnosis followed by endovascular therapy is associated with survival benefit, and the risk of contrast-induced nephropathy appears to be small.⁸ Computed tomography helps to determine the state of mesenteric vessels and bowel perfusion before ischemia progresses to infarction. It also helps to rule out other common diagnoses. Findings that suggest acute mesenteric ischemia include segmental bowel wall thickening, intestinal pneumatosis with gas in the portal vein, bowel dilation, mesenteric stranding, portomesenteric thrombosis, and solid-organ infarction.⁹

Treatment. If superior mesenteric artery occlusion is diagnosed on computed tomography, the next step is to determine if there is peritonitis.¹⁰ In patients who have evidence of peritonitis, exploratory laparotomy is performed. For emboli in such patients, open embolectomy followed by on-table angiography is carried out in combination with damage-control surgery. For patients with peritonitis and acute thrombosis, stenting along with damage-control surgery is preferred.¹⁰

On the other hand, if there is no peritonitis, the thrombosis may be amenable to endovascular intervention. For patients with acute embolic occlusion with no contraindications to thrombolysis, aspiration embolectomy in combination with local catheter-directed thrombolysis with recombinant tissue plasminogen activator can be performed. This can be combined with endovascular mechanical embolectomy for more complete management.¹⁰ Patients with contraindications to thrombolysis can be treated either with aspiration and mechanical embolectomy or with open embolectomy with angiography.¹⁰

During laparotomy, the surgeon carefully inspects the bowel for signs of necrosis. Signs that bowel is still viable include pink color, bleeding from cut surfaces, good peristalsis, and visible pulsations in the arterial arcade of the mesentery.

On day 7 she developed acute decompensation—what was the cause?

Acute mesenteric artery thrombosis arising from chronic atherosclerotic disease can be treated with stenting of the stenotic lesion.¹⁰ Patients with this condition would also benefit from aggressive management of atherosclerotic disease with statins along with antiplatelet agents.¹⁰

Mesenteric vein thrombosis requires prompt institution of anticoagulation. However, in advanced cases leading to bowel infarction, exploratory laparotomy with resection of the necrotic bowel may be required. Anticoagulation should be continued for at least 6 months, and further therapy should be determined by the underlying precipitating condition.¹⁰

Critically ill patients who develop mesenteric ischemia secondary to persistent hypotension usually respond to adequate volume resuscitation, cessation of vasopressors, and overall improvement in their hemodynamic status. These patients must be closely monitored for development of gangrene of the bowel because they may be intubated and not able to complain. Any sudden deterioration in their condition should prompt physicians to consider bowel necrosis developing in these patients. Elevation of lactate levels out of proportion to the degree of hypotension may be corroborative evidence.⁴

Our patient had risk factors for acute mesenteric ischemia that included atrial fibrillation and recent non-ST-elevation myocardial infarction. She could have had arterial emboli due to atrial fibrillation, in situ superior mesenteric arterial thrombosis, or splanchnic arterial vasoconstriction due to the myocardial infarction associated with transient hypotension.

Arguing against this diagnosis, although she had a grossly distended abdomen, abdominal bruising usually is not seen. Also, a palpable mass in the right lower quadrant is uncommon except when acute mesenteric ischemia occurs due to segmental intestinal strangulation, as with strangulated hernia or volvulus. She also had therapeutic international normalized ratio (INR) levels constantly while on anticoagulation. Nevertheless, acute mesenteric ischemia should be strongly considered in the initial differential diagnosis of this patient’s acute decompensation.

Perforation of the gastrointestinal tract

Diverticulitis is the acute inflammation of one or more diverticula, which are small pouches created by herniation of the mucosa into the wall of the colon. The condition is caused by microscopic or macroscopic perforation of the diverticula. Microscopic perforation is usually self-limited (uncomplicated diverticulitis) and responds to conservative treatment, whereas macroscopic perforation can be associated with fecal or purulent peritonitis, abscess, enteric fistula, bowel obstruction, and stricture (complicated diverticulitis), in which case surgery may be necessary.

Signs and symptoms of acute mesenteric ischemia can be vague

Patients with peritonitis due to free perforation present with generalized tenderness with rebound tenderness and guarding on abdominal examination. The abdomen may be distended and tympanic to percussion, with diminished or absent bowel sounds. Patients may have hemodynamic compromise.

Plain upright abdominal radiographs may show free air under the diaphragm. Computed tomography may show oral contrast outside the lumen and detect even small amounts of free intraperitoneal air (more clearly seen on a lung window setting).

Our patient initially presented with acute diverticulitis. She later developed diffuse abdominal tenderness with hypoactive bowel sounds. Bowel perforation is certainly a possibility at this stage, though it is usually not associated with abdominal bruising. She would need additional imaging to rule out this complication.

Other differential diagnoses to be considered in this patient with right lower-quadrant pain include acute appendicitis, incarcerated inguinal hernia, volvulus (particularly cecal volvulus), small-bowel obstruction, pyelonephritis, and gynecologic causes such as adnexal torsion, ruptured ovarian cyst, and tubo-ovarian abscess. Computed tomography helps to differentiate most of these causes.

Rectus sheath hematoma

Rectus sheath hematoma is relatively uncommon and often not considered in the initial differential diagnosis of an acute abdomen. This gives it the rightful term “a great masquerader.” It usually results from bleeding into the rectus sheath from damage to the superior (more common) or inferior epigastric arteries and occasionally from a direct tear of the rectus abdominis muscle. Predisposing factors include anticoagulant therapy (most common), advanced age, hypertension, previous abdominal surgery, trauma, paroxysmal coughing, medication injections, pregnancy, blood dyscrasias, severe vomiting, violent physical activity, and leukemia.¹¹

Clinical manifestations include acute abdominal pain, often associated with fever, nausea, and vomiting. Physical examination may reveal signs of hypovolemic shock, a palpable nonpulsatile abdominal mass, and signs of local peritoneal irritation. The Carnett sign¹¹ (tenderness within the abdominal wall that persists and does not improve with raising the head) and the Fothergill sign¹¹ (a tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath) may be elicited.

Computed tomography is more sensitive than abdominal ultrasonography in differentiating rectus sheath hematoma from an intra-abdominal pathology.¹¹ In addition, computed tomography also helps to determine if the bleeding is active or not, which has therapeutic implications.

In our patient, rectus sheath hematoma is a possibility because of her ongoing anticoagulation, findings of localized abdominal bruising, and palpable right lower-quadrant mass, and it is high on the list of differential diagnoses. Rectus sheath hematoma should be considered in the differential diagnosis of lower abdominal pain particularly in elderly women who are on anticoagulation and in whom the onset of pain coincides with a paroxysm of cough.¹² Women are twice as likely as men to develop rectus sheath hematoma, owing to their different muscle mass.¹³ In addition, anterior abdominal wall muscles are stretched during pregnancy.¹³

Abdominal compartment syndrome

Abdominal compartment syndrome has been classically associated with surgical patients. However, it is being increasingly recognized in critically ill medical patients, in whom detecting and treating it early may result in significant reduction in rates of morbidity and death.¹⁴

Abdominal compartment syndrome is of three types: primary, secondary, and recurrent. Primary abdominal compartment syndrome refers to the classic surgical patients with evidence of direct injury to the abdominal or pelvic organs through major trauma or extensive abdominal surgeries. Secondary abdominal compartment syndrome refers to its development in critically ill intensive care patients in whom the pathology does not directly involve the abdominal or pelvic organs.

Various medical conditions can culminate in abdominal compartment syndrome and result in multiorgan failure. Recurrent abdominal compartment syndrome refers to its development after management of either primary or secondary intra-abdominal hypertension or abdominal compartment syndrome.¹⁵ Clinicians thus must be aware of secondary and recurrent abdominal compartment syndrome occurring in critically ill patients.

The normal intra-abdominal pressure is around 5 to 7 mm Hg, even in most critically ill patients. Persistent elevation, ie, higher than 12 mm Hg, is referred to as intra-abdominal hypertension.^16–18 Intra-abdominal hypertension is subdivided into four grades:

• Grade I: 12–15 mm Hg
• Grade II: 16–20 mm Hg
• Grade III: 21–25 mm Hg
• Grade IV: > 25 mm Hg.

The World Society of the Abdominal Compartment Syndrome (WSACS) defines abdominal compartment syndrome as pressure higher than 20 mm Hg along with organ damage.¹⁸ It may or may not be associated with an abdominal perfusion pressure less than 60 mm Hg.¹⁸

Risk factors associated with abdominal compartment syndrome include conditions causing decreased gut motility (gastroparesis, ileus, and colonic pseudo-obstruction), intra-abdominal or retroperitoneal masses or abscesses, ascites, hemoperitoneum, acute pancreatitis, third-spacing due to massive fluid resuscitation with transfusions, peritoneal dialysis, and shock.^18,19

Microscopic perforation is usually self-limited, whereas macroscopic perforation may need surgery

Physical examination has a sensitivity of only 40% to 60% in detecting intra-abdominal hypertension.²⁰ The gold-standard method of measuring the intra-abdominal pressure is the modified Kron technique,¹⁸ using a Foley catheter in the bladder connected to a pressure transducer. With the patient in the supine position, the transducer is zeroed at the mid-axillary line at the level of the iliac crest, and 25 mL of normal saline is instilled into the bladder and maintained for 30 to 60 seconds to let the detrusor muscle relax.¹⁵ Pressure tracings are then recorded at the end of expiration. Factors that are known to affect the transbladder pressure include patient position, respiratory movement, and body mass index, and should be taken into account when reading the pressure recordings.^15,21 Other techniques that can be used include intragastric, intra-inferior vena cava, and intrarectal approaches.¹⁵

The WSACS recommends that any patient admitted to a critical care unit or in whom new organ failure develops should be screened for risk factors for intra-abdominal hypertension and abdominal compartment syndrome. If a patient has at least two of the risk factors suggested by WSACS, a baseline intra-abdominal pressure measurement should be obtained. Patients at risk for intra-abdominal hypertension should have the intra-abdominal pressure measured every 4 to 6 hours. However, in the face of hemodynamic instability and worsening multiorgan failure, the pressure may need to be measured hourly.¹⁸

Clinicians managing patients in the intensive care unit should think of intra-abdominal pressure alongside blood pressure, urine output, and mental status when evaluating hemodynamic status. Clinical manifestations of abdominal compartment syndrome reflect the underlying organ dysfunction and include hypotension, refractory shock, decreased urine output, intracranial hypertension, progressive hypoxemia and hypercarbia, elevated pulmonary peak pressures, and worsening of metabolic acidosis.²²

Treatment. The standard treatment for primary abdominal compartment syndrome is surgical decompression. According to WSACS guidelines, insertion of a percutaneous drainage catheter should be advocated in patients with gross ascites and in whom decompressive surgery is not feasible. A damage-control resuscitation strategy used for patients undergoing damage-control laparotomy has been found to increase the 30-day survival rate.²³ A damage-control resuscitation strategy consists of increasing the use of plasma and platelet transfusions over packed red cell transfusions, limiting the use of crystalloid solutions in early fluid resuscitation, and allowing for permissive hypotension.

Rectus sheath hematoma is relatively uncommon and is not often considered in the initial differential diagnosis of an acute abdomen

Secondary abdominal compartment syndrome is treated conservatively in most cases, since patients with this condition are very poor surgical candidates owing to their comorbidities.¹⁸ However, in patients with progressive organ dysfunction in whom medical management has failed, surgical decompression should be considered.¹⁸ Medical management of secondary abdominal compartment syndrome depends on the underlying etiology. Strategies include nasogastric or colonic decompression, use of prokinetic agents, paracentesis in cases with gross ascites, and maintaining a cumulative negative fluid balance. The WSACS does not recommend routine use of diuretics, albumin infusion, or renal replacement strategies. Pain should be adequately controlled to improve abdominal wall compliance.^18,24 Neuromuscular blockade agents may be used to aid this process. Neostigmine may be used to treat colonic pseudo-obstruction when other conservative methods fail. Use of enteral nutrition should be minimized.¹⁸

Our patient might have abdominal compartment syndrome, but a definitive diagnosis cannot be made at this point without measuring the intra-abdominal pressure.

WHICH IMAGING TEST WOULD BE BEST?

2. Which imaging test would be best for establishing the diagnosis in this patient?

• Plain abdominal radiography
• Abdominal ultrasonography
• Computed tomography of the abdomen and pelvis with contrast
• Magnetic resonance imaging of the abdomen and pelvis

Plain abdominal radiography

Plain abdominal radiography can help to determine if there is free gas under the diaphragm (due to bowel perforation), obstructed bowel, sentinel loop, volvulus, or fecoliths causing the abdominal pain. It cannot diagnose rectus sheath hematoma or acute mesenteric ischemia.

Abdominal ultrasonography

Abdominal ultrasonography can be used as the first diagnostic test, as it is widely available, safe, effective, and tolerable. It does not expose the patient to radiation or intravenous contrast agents. It helps to diagnose rectus sheath hematoma and helps to follow its maturation and resolution once a diagnosis is made. It can provide a rapid assessment of the size, location, extent, and physical characteristics of the mass.

Ultrasonography is widely available, safe, effective, and tolerable

Rectus sheath hematoma appears spindle-shaped on sagittal sections and ovoid on coronal sections. It often appears sonolucent in the early stages and sonodense in the late stage, but the appearance may be heterogeneous depending on the combined presence of clot and fresh blood. These findings are sufficient to make the diagnosis.

Abdominal ultrasonography has 85% to 96% sensitivity in diagnosing rectus sheath hematoma.²⁵ It can help diagnose other causes of the abdominal pain, such as renal stones and cholecystitis. It is the preferred imaging test in pediatric patients, pregnant patients, and those with renal insufficiency.

Abdominal computed tomography

Abdominal computed tomography has a sensitivity and specificity of 100% for diagnosing acute rectus sheath hematoma with a duration of less than 5 days.²⁵ It not only helps to determine the precise location and extent, but also helps to determine if there is active extravasation. Even in patients with renal insufficiency, noncontrast computed tomography will help to confirm the diagnosis, although it may not show extravasation or it may miss certain abdominal pathologies because of the lack of contrast.

Acute rectus sheath hematoma appears as a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement. Chronic rectus sheath hematoma appears isodense or hypodense relative to the surrounding muscle. Above the arcuate line, rectus sheath hematoma has a spindle shape; below the arcuate line, it is typically spherical.

In 1996, Berná et al²⁶ classified rectus sheath hematoma into three grades based on findings of computed tomography:

• Grade I is intramuscular and unilateral
• Grade II may involve bilateral rectus muscles without extension into the prevesicular space
• Grade III extends into the peritoneum and prevesicular space