User login
Background
Sepsis is a clinical syndrome with systemic effects that can progress to severe sepsis and/or septic shock. The incidence of severe sepsis and septic shock is rising in the United States, and these syndromes are associated with significant morbidity and a mortality rate as high as 25% to 35%.1 In fact, sepsis is one of the 10 leading causes of death in the U.S., accounting for 2% of hospital admissions but 17% of in-hospital deaths.1
The main principles of effective treatment for severe sepsis and septic shock are timely recognition and early aggressive therapy. Launched in 2002, the Surviving Sepsis Campaign (SSC) was the result of a collaboration of three professional societies. The goal of the SSC collaborative was to reduce mortality from severe sepsis and septic shock by 25%. To that end, the SSC convened representatives from several international societies to develop a set of evidence-based guidelines as a means of guiding clinicians in optimizing management of patients with severe sepsis and septic shock. Since the original publication of the SSC guidelines in 2004, there have been two updates—one in 2008 and one in February 2013.2
Guideline Updates
Quantitative, protocol-driven initial resuscitation in the first six hours for patients with severe sepsis and septic shock remains a high-level recommendation, but SSC has added normalization of the lactate level as a resuscitation goal. This new suggestion is based on two studies published since the 2008 SCC guidelines that showed noninferiority to previously established goals and absolute mortality benefit.3,4
There is a new focus on screening for sepsis and the use of hospital-based performance-improvement programs, which were not previously addressed in the 2008 SCC guidelines. Patients with suspected infections and who are seriously ill should be screened in order to identify sepsis early during the hospital course. Additionally, it is recommended that hospitals implement performance-improvement measures by which multidisciplinary teams can address treatment of sepsis by improving compliance with the SSC bundles, citing their own data as the model but ultimately leaving this recommendation as ungradable in regards to the quality of available supporting evidence.5
Cultures drawn before antibiotics and early imaging to confirm potential sources are still recommended, but the committee has added the use of one: 3 beta D-glucan and the mannan antigen and anti-mannan antibody assays when considering invasive candidiasis as your infective agent. They do note the known risk of false positive results with these assays and warn that they should be used with caution.
Early, broad-spectrum antibiotic administration within the first hour of presentation was upgraded for severe sepsis and downgraded for septic shock. The decision to initiate double coverage for suspected gram-negative infection is not recommended specifically but can be considered in situations when highly antibiotic resistant pathogens are potentially present. Daily assessment of the appropriate antibiotic regimen remains an important tenet, and the use of low procalcitonin levels as a tool to assist in the decision to discontinue antibiotics has been introduced. Source control is still strongly recommended in the first 12 hours of treatment.
The SSC 2012 guidelines specifically address the rate of fluid administered and the type of fluid that should be used. It is now recommended that a fluid challenge of 30 mL/kg be used for initial resuscitation, but the guidelines leave it up to the clinician to give more fluid if needed. There is a strong push for use of crystalloids rather than colloids during initial resuscitation and thereafter. Disfavor for colloids stemmed from trials showing increased mortality when comparing resuscitation with hydroxyethyl starch versus crystalloid for patients in septic shock.6,7 Albumin, on the other hand, is recommended to resuscitate patients with severe sepsis and septic shock in cases for which large amounts of crystalloid are required.
The 2012 SSC guidelines recommend norepinephrine (NE) alone as the first-line vasopressor in sepsis and no longer include dopamine in this category. In fact, the use of dopamine in septic shock has been downgraded and should only to be considered in patients at low risk of tachyarrhythmia and in bradycardia syndromes. Epinephrine is now favored as the second agent or as a substitute to NE. Phenylephrine is no longer recommended unless there is contraindication to using NE, the patient has a high cardiac output, or it is used as a salvage therapy. Vasopressin is considered only an adjunctive agent to NE and should never be used alone.
Recommendations regarding corticosteroid therapy remain largely unchanged from 2008 SCC guidelines, which only support their use when adequate volume resuscitation and vasopressor support has failed to achieve hemodynamic stability. Glucose control is recommended but at the new target of achieving a level of <180 mg/dL, up from a previous target of <150 mg/dL.
Notably, recombinant human activated protein C was completely omitted from the 2012 guidelines, prompted by the voluntary removal of the drug by the manufacturer after failing to show benefit. Use of selenium and intravenous immunoglobulin received comment, but there is insufficient evidence supporting their benefit at the current time. They also encourage clinicians to incorporate goals of care and end-of-life issues into the treatment plan and discuss this with patients and/or surrogates early in treatment.
Guideline Analysis
Prior versions of the SSC guidelines have been met with a fair amount of skepticism.8 Much of the criticism is based on the industry sponsorship of the 2004 version, the lack of transparency regarding potential conflicts of interest of the committee members, and that the bundle recommendations largely were based on only one trial and, therefore, not evidenced-based.9 The 2012 SSC committee seems to have addressed these issues as the guidelines are free of commercial sponsorship in the 2008 and current versions. They also rigorously applied the GRADE system to methodically assess the strength and quality of supporting evidence. The result is a set of guidelines that are partially evidence-based and partially based on expert opinion, but this is clearly delineated in these newest guidelines. This provides clinicians with a clear and concise recommended approach to the patient with severe sepsis and septic shock.
The guidelines continue to place a heavy emphasis on three- and six-hour treatment bundles, and with the assistance of the Institute for Health Care Improvement efforts to improve implementation of the bundle, they are already are widespread with an eye to expand across the country. The components of the three-hour treatment bundle (lactate measurement, blood cultures prior to initiation of antibiotics, broad-spectrum antibiotics, and IV crystalloids for hypotension or for a lactate of >4 mmol/L) recommended by the SSC have not changed substantially since 2008. The one exception is the rate at which IV crystalloid should be administered of 30 mL/kg, which is up from 20 mL/kg. Only time will tell how this change will affect bundle compliance or reduce mortality. But this does pose a significant challenge to quality and performance improvement groups accustomed to tracking compliance with IV fluid administration under the old standard and the educational campaigns associated with a change.
It appears that the SSC is here to stay, now in its third iteration. The lasting legacy of the SSC guidelines might not rest with the content of the guidelines, per se, but in raising awareness of severe sepsis and septic shock in a way that had not previously been considered.
HM Takeaways
The revised 2012 SCC updates bring some new tools to the clinician for early recognition and effective management of patients with sepsis. The push for institutions to adopt screening and performance measures reflects a general trend in health care to create high-performance systems. As these new guidelines are put into practice, there are several changes that might require augmentation of quality metrics being tracked at institutions nationally and internationally.
Dr. Pendharker is assistant professor of medicine in the division of hospital medicine at the University of California San Francisco and San Francisco General Hospital. Dr. Gomez is assistant professor of medicine in the division of pulmonary and critical care medicine at UCSF and San Francisco General Hospital.
References
- Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011:1-8.
- Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.
- Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752-761.
- Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303:739-746.
- Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38:367-374.
- Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012;16:R94.
- Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124-134.
- Marik PE. Surviving sepsis: going beyond the guidelines. Ann Intensive Care. 2011;1:17.
- Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
Background
Sepsis is a clinical syndrome with systemic effects that can progress to severe sepsis and/or septic shock. The incidence of severe sepsis and septic shock is rising in the United States, and these syndromes are associated with significant morbidity and a mortality rate as high as 25% to 35%.1 In fact, sepsis is one of the 10 leading causes of death in the U.S., accounting for 2% of hospital admissions but 17% of in-hospital deaths.1
The main principles of effective treatment for severe sepsis and septic shock are timely recognition and early aggressive therapy. Launched in 2002, the Surviving Sepsis Campaign (SSC) was the result of a collaboration of three professional societies. The goal of the SSC collaborative was to reduce mortality from severe sepsis and septic shock by 25%. To that end, the SSC convened representatives from several international societies to develop a set of evidence-based guidelines as a means of guiding clinicians in optimizing management of patients with severe sepsis and septic shock. Since the original publication of the SSC guidelines in 2004, there have been two updates—one in 2008 and one in February 2013.2
Guideline Updates
Quantitative, protocol-driven initial resuscitation in the first six hours for patients with severe sepsis and septic shock remains a high-level recommendation, but SSC has added normalization of the lactate level as a resuscitation goal. This new suggestion is based on two studies published since the 2008 SCC guidelines that showed noninferiority to previously established goals and absolute mortality benefit.3,4
There is a new focus on screening for sepsis and the use of hospital-based performance-improvement programs, which were not previously addressed in the 2008 SCC guidelines. Patients with suspected infections and who are seriously ill should be screened in order to identify sepsis early during the hospital course. Additionally, it is recommended that hospitals implement performance-improvement measures by which multidisciplinary teams can address treatment of sepsis by improving compliance with the SSC bundles, citing their own data as the model but ultimately leaving this recommendation as ungradable in regards to the quality of available supporting evidence.5
Cultures drawn before antibiotics and early imaging to confirm potential sources are still recommended, but the committee has added the use of one: 3 beta D-glucan and the mannan antigen and anti-mannan antibody assays when considering invasive candidiasis as your infective agent. They do note the known risk of false positive results with these assays and warn that they should be used with caution.
Early, broad-spectrum antibiotic administration within the first hour of presentation was upgraded for severe sepsis and downgraded for septic shock. The decision to initiate double coverage for suspected gram-negative infection is not recommended specifically but can be considered in situations when highly antibiotic resistant pathogens are potentially present. Daily assessment of the appropriate antibiotic regimen remains an important tenet, and the use of low procalcitonin levels as a tool to assist in the decision to discontinue antibiotics has been introduced. Source control is still strongly recommended in the first 12 hours of treatment.
The SSC 2012 guidelines specifically address the rate of fluid administered and the type of fluid that should be used. It is now recommended that a fluid challenge of 30 mL/kg be used for initial resuscitation, but the guidelines leave it up to the clinician to give more fluid if needed. There is a strong push for use of crystalloids rather than colloids during initial resuscitation and thereafter. Disfavor for colloids stemmed from trials showing increased mortality when comparing resuscitation with hydroxyethyl starch versus crystalloid for patients in septic shock.6,7 Albumin, on the other hand, is recommended to resuscitate patients with severe sepsis and septic shock in cases for which large amounts of crystalloid are required.
The 2012 SSC guidelines recommend norepinephrine (NE) alone as the first-line vasopressor in sepsis and no longer include dopamine in this category. In fact, the use of dopamine in septic shock has been downgraded and should only to be considered in patients at low risk of tachyarrhythmia and in bradycardia syndromes. Epinephrine is now favored as the second agent or as a substitute to NE. Phenylephrine is no longer recommended unless there is contraindication to using NE, the patient has a high cardiac output, or it is used as a salvage therapy. Vasopressin is considered only an adjunctive agent to NE and should never be used alone.
Recommendations regarding corticosteroid therapy remain largely unchanged from 2008 SCC guidelines, which only support their use when adequate volume resuscitation and vasopressor support has failed to achieve hemodynamic stability. Glucose control is recommended but at the new target of achieving a level of <180 mg/dL, up from a previous target of <150 mg/dL.
Notably, recombinant human activated protein C was completely omitted from the 2012 guidelines, prompted by the voluntary removal of the drug by the manufacturer after failing to show benefit. Use of selenium and intravenous immunoglobulin received comment, but there is insufficient evidence supporting their benefit at the current time. They also encourage clinicians to incorporate goals of care and end-of-life issues into the treatment plan and discuss this with patients and/or surrogates early in treatment.
Guideline Analysis
Prior versions of the SSC guidelines have been met with a fair amount of skepticism.8 Much of the criticism is based on the industry sponsorship of the 2004 version, the lack of transparency regarding potential conflicts of interest of the committee members, and that the bundle recommendations largely were based on only one trial and, therefore, not evidenced-based.9 The 2012 SSC committee seems to have addressed these issues as the guidelines are free of commercial sponsorship in the 2008 and current versions. They also rigorously applied the GRADE system to methodically assess the strength and quality of supporting evidence. The result is a set of guidelines that are partially evidence-based and partially based on expert opinion, but this is clearly delineated in these newest guidelines. This provides clinicians with a clear and concise recommended approach to the patient with severe sepsis and septic shock.
The guidelines continue to place a heavy emphasis on three- and six-hour treatment bundles, and with the assistance of the Institute for Health Care Improvement efforts to improve implementation of the bundle, they are already are widespread with an eye to expand across the country. The components of the three-hour treatment bundle (lactate measurement, blood cultures prior to initiation of antibiotics, broad-spectrum antibiotics, and IV crystalloids for hypotension or for a lactate of >4 mmol/L) recommended by the SSC have not changed substantially since 2008. The one exception is the rate at which IV crystalloid should be administered of 30 mL/kg, which is up from 20 mL/kg. Only time will tell how this change will affect bundle compliance or reduce mortality. But this does pose a significant challenge to quality and performance improvement groups accustomed to tracking compliance with IV fluid administration under the old standard and the educational campaigns associated with a change.
It appears that the SSC is here to stay, now in its third iteration. The lasting legacy of the SSC guidelines might not rest with the content of the guidelines, per se, but in raising awareness of severe sepsis and septic shock in a way that had not previously been considered.
HM Takeaways
The revised 2012 SCC updates bring some new tools to the clinician for early recognition and effective management of patients with sepsis. The push for institutions to adopt screening and performance measures reflects a general trend in health care to create high-performance systems. As these new guidelines are put into practice, there are several changes that might require augmentation of quality metrics being tracked at institutions nationally and internationally.
Dr. Pendharker is assistant professor of medicine in the division of hospital medicine at the University of California San Francisco and San Francisco General Hospital. Dr. Gomez is assistant professor of medicine in the division of pulmonary and critical care medicine at UCSF and San Francisco General Hospital.
References
- Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011:1-8.
- Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.
- Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752-761.
- Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303:739-746.
- Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38:367-374.
- Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012;16:R94.
- Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124-134.
- Marik PE. Surviving sepsis: going beyond the guidelines. Ann Intensive Care. 2011;1:17.
- Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
Background
Sepsis is a clinical syndrome with systemic effects that can progress to severe sepsis and/or septic shock. The incidence of severe sepsis and septic shock is rising in the United States, and these syndromes are associated with significant morbidity and a mortality rate as high as 25% to 35%.1 In fact, sepsis is one of the 10 leading causes of death in the U.S., accounting for 2% of hospital admissions but 17% of in-hospital deaths.1
The main principles of effective treatment for severe sepsis and septic shock are timely recognition and early aggressive therapy. Launched in 2002, the Surviving Sepsis Campaign (SSC) was the result of a collaboration of three professional societies. The goal of the SSC collaborative was to reduce mortality from severe sepsis and septic shock by 25%. To that end, the SSC convened representatives from several international societies to develop a set of evidence-based guidelines as a means of guiding clinicians in optimizing management of patients with severe sepsis and septic shock. Since the original publication of the SSC guidelines in 2004, there have been two updates—one in 2008 and one in February 2013.2
Guideline Updates
Quantitative, protocol-driven initial resuscitation in the first six hours for patients with severe sepsis and septic shock remains a high-level recommendation, but SSC has added normalization of the lactate level as a resuscitation goal. This new suggestion is based on two studies published since the 2008 SCC guidelines that showed noninferiority to previously established goals and absolute mortality benefit.3,4
There is a new focus on screening for sepsis and the use of hospital-based performance-improvement programs, which were not previously addressed in the 2008 SCC guidelines. Patients with suspected infections and who are seriously ill should be screened in order to identify sepsis early during the hospital course. Additionally, it is recommended that hospitals implement performance-improvement measures by which multidisciplinary teams can address treatment of sepsis by improving compliance with the SSC bundles, citing their own data as the model but ultimately leaving this recommendation as ungradable in regards to the quality of available supporting evidence.5
Cultures drawn before antibiotics and early imaging to confirm potential sources are still recommended, but the committee has added the use of one: 3 beta D-glucan and the mannan antigen and anti-mannan antibody assays when considering invasive candidiasis as your infective agent. They do note the known risk of false positive results with these assays and warn that they should be used with caution.
Early, broad-spectrum antibiotic administration within the first hour of presentation was upgraded for severe sepsis and downgraded for septic shock. The decision to initiate double coverage for suspected gram-negative infection is not recommended specifically but can be considered in situations when highly antibiotic resistant pathogens are potentially present. Daily assessment of the appropriate antibiotic regimen remains an important tenet, and the use of low procalcitonin levels as a tool to assist in the decision to discontinue antibiotics has been introduced. Source control is still strongly recommended in the first 12 hours of treatment.
The SSC 2012 guidelines specifically address the rate of fluid administered and the type of fluid that should be used. It is now recommended that a fluid challenge of 30 mL/kg be used for initial resuscitation, but the guidelines leave it up to the clinician to give more fluid if needed. There is a strong push for use of crystalloids rather than colloids during initial resuscitation and thereafter. Disfavor for colloids stemmed from trials showing increased mortality when comparing resuscitation with hydroxyethyl starch versus crystalloid for patients in septic shock.6,7 Albumin, on the other hand, is recommended to resuscitate patients with severe sepsis and septic shock in cases for which large amounts of crystalloid are required.
The 2012 SSC guidelines recommend norepinephrine (NE) alone as the first-line vasopressor in sepsis and no longer include dopamine in this category. In fact, the use of dopamine in septic shock has been downgraded and should only to be considered in patients at low risk of tachyarrhythmia and in bradycardia syndromes. Epinephrine is now favored as the second agent or as a substitute to NE. Phenylephrine is no longer recommended unless there is contraindication to using NE, the patient has a high cardiac output, or it is used as a salvage therapy. Vasopressin is considered only an adjunctive agent to NE and should never be used alone.
Recommendations regarding corticosteroid therapy remain largely unchanged from 2008 SCC guidelines, which only support their use when adequate volume resuscitation and vasopressor support has failed to achieve hemodynamic stability. Glucose control is recommended but at the new target of achieving a level of <180 mg/dL, up from a previous target of <150 mg/dL.
Notably, recombinant human activated protein C was completely omitted from the 2012 guidelines, prompted by the voluntary removal of the drug by the manufacturer after failing to show benefit. Use of selenium and intravenous immunoglobulin received comment, but there is insufficient evidence supporting their benefit at the current time. They also encourage clinicians to incorporate goals of care and end-of-life issues into the treatment plan and discuss this with patients and/or surrogates early in treatment.
Guideline Analysis
Prior versions of the SSC guidelines have been met with a fair amount of skepticism.8 Much of the criticism is based on the industry sponsorship of the 2004 version, the lack of transparency regarding potential conflicts of interest of the committee members, and that the bundle recommendations largely were based on only one trial and, therefore, not evidenced-based.9 The 2012 SSC committee seems to have addressed these issues as the guidelines are free of commercial sponsorship in the 2008 and current versions. They also rigorously applied the GRADE system to methodically assess the strength and quality of supporting evidence. The result is a set of guidelines that are partially evidence-based and partially based on expert opinion, but this is clearly delineated in these newest guidelines. This provides clinicians with a clear and concise recommended approach to the patient with severe sepsis and septic shock.
The guidelines continue to place a heavy emphasis on three- and six-hour treatment bundles, and with the assistance of the Institute for Health Care Improvement efforts to improve implementation of the bundle, they are already are widespread with an eye to expand across the country. The components of the three-hour treatment bundle (lactate measurement, blood cultures prior to initiation of antibiotics, broad-spectrum antibiotics, and IV crystalloids for hypotension or for a lactate of >4 mmol/L) recommended by the SSC have not changed substantially since 2008. The one exception is the rate at which IV crystalloid should be administered of 30 mL/kg, which is up from 20 mL/kg. Only time will tell how this change will affect bundle compliance or reduce mortality. But this does pose a significant challenge to quality and performance improvement groups accustomed to tracking compliance with IV fluid administration under the old standard and the educational campaigns associated with a change.
It appears that the SSC is here to stay, now in its third iteration. The lasting legacy of the SSC guidelines might not rest with the content of the guidelines, per se, but in raising awareness of severe sepsis and septic shock in a way that had not previously been considered.
HM Takeaways
The revised 2012 SCC updates bring some new tools to the clinician for early recognition and effective management of patients with sepsis. The push for institutions to adopt screening and performance measures reflects a general trend in health care to create high-performance systems. As these new guidelines are put into practice, there are several changes that might require augmentation of quality metrics being tracked at institutions nationally and internationally.
Dr. Pendharker is assistant professor of medicine in the division of hospital medicine at the University of California San Francisco and San Francisco General Hospital. Dr. Gomez is assistant professor of medicine in the division of pulmonary and critical care medicine at UCSF and San Francisco General Hospital.
References
- Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011:1-8.
- Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.
- Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752-761.
- Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303:739-746.
- Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38:367-374.
- Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012;16:R94.
- Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124-134.
- Marik PE. Surviving sepsis: going beyond the guidelines. Ann Intensive Care. 2011;1:17.
- Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.