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This medical talks about Sepsis, a potentially life-threatening condition that occurs when the bodys response to infection causes inflammation throughout the body, leading to organ dysfunction and failure. The management of sepsis involves prompt recognition and diagnosis, aggressive resuscitation, and appropriate antimicrobial therapy.

Tags : Management of Sepsis, Sepsis, organ dysfunction, management of sepsis, Emergency Medicine, Emergency Medicine

Published on : Apr 14, 2023 | Views : 2500 | Downloads : 4

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Slide 1-

Management of Sepsis Bryan D. Kraft, M.D. Assistant Professor of Medicine Pulmonary, Allergy, & Critical Care Medicine Duke University Medical Center
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Disclosures None
Slide 3-

Objectives Define sepsis Learn basic sepsis pathophysiology Understand central venous O2 saturation Review literature on fluid resuscitation Discuss approach to treatment
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Definitions of SIRS and sepsis Systemic Inflammatory Response Syndrome: Requires ≥ 2 of the following: Temperature > 38°C or < 36°C Respiratory rate > 20/min, or PaCO2 < 32 mmHg Heart rate > 90 bpm WBC count >12,000 or <4,000 cells/µL, or > 10% bands Sepsis: ≥ 2 SIRS criteria + evidence of infection ACCP/SCCM Consensus Conference. Crit Care Med 1992;20(6):864–74.
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Severe Sepsis Sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following): Hypotension (SBP < 90 mmHg, MAP < 70 mmHg, or SBP of 40 mmHg below baseline) Elevated lactate UOP < 0.5 mL/kg/hr x 2 hours, despite adequate IVF Creatinine > 2 mg/dL PaO2/FIO2 < 250 in absence of PNA as source PaO2/FIO2 < 200 in presence of PNA as source Bilirubin > 2 mg/dL Platelets < 100,000/µL Coagulopathy (INR > 1.5) Levy MM, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:1250-1256.
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Shock in general is a state of cellular and tissue hypoxia due to: Reduced O2 delivery (e.g. anemia, hypoxemia); Outstripped O2 consumption (e.g. thyrotoxicosis); and/or Impaired utilization (e.g. mitochondrial dysfunction) Septic shock commonly manifests with #1 and #3 concurrently in a patient Most common clinical definition of septic shock is presence of severe sepsis + hypotension refractory to intravenous fluids alone i.e. the patient requires vasopressors generally hypotension is mean arterial pressure (MAP) < 65 mmHg Watch out for shock in a chronically hypertensive patient with “normal BP” that is significantly below baseline Some argue presence of elevated lactate (>4 mmol/L) also indicates shock regardless of MAP Septic shock
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This model of sepsis suggests it is a linear spectrum of disease: Linear Model of Sepsis
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This model of sepsis suggests it is a linear spectrum of disease: Is this really true? For example, can patients have severe sepsis without meeting SIRS criteria? Linear Model of Sepsis
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Kaukonen K et al. N Engl J Med 2015;372:1629-1638. This study analyzed > 100,000 patients with severe sepsis and stratified by SIRS status (< 2 vs. ≥ 2 criteria) How useful are these definitions?
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Kaukonen K et al. N Engl J Med 2015;372:1629-1638. This study analyzed > 100,000 patients with severe sepsis and stratified by SIRS status (< 2 vs. ≥ 2 criteria) How useful are these definitions? 12% of patients with severe sepsis (1 in 8) met only 0 or 1 SIRS criterion This was especially true of older patients, use of β-blockers, etc.
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Kaukonen K et al. N Engl J Med 2015;372:1629-1638. The same study then asked whether there was anything special about meeting 2 SIRS criteria, i.e. the cut-off used How useful are these definitions?
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Kaukonen K et al. N Engl J Med 2015;372:1629-1638. The same study then asked whether there was anything special about meeting 2 SIRS criteria, i.e. the cut-off used How useful are these definitions? They found a cut-off of “2” was not associated with a step-up in mortality, but rather there was a linear relationship between SIRS and mortality. So the sicker you are (i.e. more SIRS criteria you meet) the worse your prognosis is.
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Singer M, et al. Sepsis-3. JAMA. 2016;315(8):801-10. In 2016, the Society of Critical Care Medicine and European Society of Intensive Care Medicine released a consensus statement redefining the sepsis syndrome. “SIRS” and “severe sepsis” were eliminated “Septic shock” was redefined as hypotension despite adequate IVF requiring vasopressors to maintain MAP > 65 mmHg, and serum lactate > 2 mmol/L. New Definitions of Sepsis?
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Emphasis was placed on organ failure (SOFA score), especially the “quick SOFA” or qSOFA score: Presence of altered mental status Systolic blood pressure ≤100 mmHg Respiratory rate ≥ 22/minute A score of ≥ 2 reflects high risk for organ failure and mortality and should prompt appropriate intervention New Definitions of Sepsis? Singer M, et al. Sepsis-3. JAMA. 2016;315(8):801-10.
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While these definitions may prove to be clinically useful, they are not yet validated, so should be used cautiously. For example, while SIRS sacrifices specificity for sensitivity, qSOFA is likely under-sensitive, which is problematic for a screening test because it may miss septic patients. New Definitions of Sepsis? Singer M, et al. Sepsis-3. JAMA. 2016;315(8):801-10. Additional reading on Sepsis-3 definitions: Simpson SQ. New Sepsis Criteria: A Change We Should Not Make. Chest. 2016;149(5):1117-8.
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Incidence of Sepsis is Rising Benchmarking the Incidence and Mortality of Severe Sepsis in the United States Gaieski, D; Edwards, J; Kallan, M; Carr, B. Crit Care Med 41(5):1167-1174, 2013. Sepsis Severe sepsis Septic shock ICD-9 codes: Mortality: 10.6% 36.9% 42.2% Total cases (n)
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Severe Sepsis—Mortality Mackenzie, I. et al. BMJ 335:929-932, 2007 Deaths/100,000/year 0 50 100 150 200 250 300 15-24 25-44 45-64 >65 Age Age-related Mortality 0 20 40 60 80 100 0 1 2 3 4 5 Number of Failing Organs Mortality by Organ Failure % Two of the most important factors affecting prognosis are organ failure and age: Patients with sepsis generally die from multiple organ failure. Age is a major factor, especially after age 65
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Severe Sepsis—Outcomes Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. What are the outcomes of patients severe sepsis or shock compared to general population?
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Severe Sepsis—Outcomes Declining Functional Reserve Death Time  Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. The Y-axis is worsening functional status towards death. The X-axis is time. What are the outcomes of patients severe sepsis or shock compared to general population?
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Severe Sepsis—Outcomes Declining Functional Reserve Death Time  No sepsis Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. These patients are the general public that do not get sepsis. There is a steady decline in functional status due to aging, but it is slow.
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Severe Sepsis—Outcomes Declining Functional Reserve Death Time  Severe sepsis No sepsis Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. These patients with severe sepsis get an initial, significant drop in functional status, but survive their illness and mostly recover, but not back to baseline.
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Severe Sepsis—Outcomes Declining Functional Reserve Death Time  Refractory Shock Severe sepsis No sepsis Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. These patients with refractory shock typically come in with overwhelming bacteremia and die within the first few days due to shock, acidosis, and/or hypoxemia.
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Severe Sepsis—Outcomes Declining Functional Reserve Death Time  Refractory Shock Chronic critical illness and immune suppression Severe sepsis No sepsis Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. These patients survive the acute illness but their organ failure never recovers and they remain life support-dependent. Older patients get trapped in ICU. Their ICU course waxes and wanes with complications such as infections due to VRE or Candida, organisms which are otherwise not very virulent.
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Severe Sepsis—Outcomes Declining Functional Reserve Death Time  Refractory Shock Chronic critical illness and immune suppression Severe sepsis No sepsis Yende S, Iwashyna TJ, and Angus DC. Interplay between sepsis and chronic health Trends in Molecular Medicine, 20, 4 , 2014. These patients survive the acute illness but their organ failure never recovers and they remain life support-dependent. Older patients get trapped in ICU. Their ICU course waxes and wanes with complications such as infections due to VRE or Candida, organisms which are otherwise not very virulent. Additional reading on chronic critical illness: Nelson JE, et al. Chronic critical illness. Am J Respir Crit Care Med. 2010; 182(4):446-54.
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So how can sepsis outcomes be improved?
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70 1. The Rapid Choice of the Right Antibiotic(s) Morell MR et al. The Management of Severe Sepsis and Septic ShockInfectious Disease Clinics of North America 23 (3): 485-501, 2009 60 50 40 30 20 10 0 Mortality (%) Appropriate Inappropriate Kang et al. Micek et al. Khatib et al. Schramm et al. Garey et al. Tumbarello et al. Cheong et al. Early, broad-spectrum antibiotics are absolutely critical. Failure to treat up front with the right antibiotics increases mortality by 10-20 percentage points.
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1. The Rapid Choice of the Right Antibiotics Review of risk factors for certain infections E.g., recent bowel surgery should make you think about gram-negatives, anaerobes, and Candida. Identification of source(s) or suspected source(s) E.g., comprehensive work-up based on risk factors, history, physical, laboratory, and imaging studies Correct stratification of patients as hospital-acquired, health-care associated, or community-acquired E.g., recent hospitalization, SNF patient, etc. Review of prior infection history and prior microbiological cultures and sensitivities E.g., urine culture from 2 months ago grew Zosyn-resistant E. coli Early (within 60 minutes of diagnosis) delivery of antibiotics What does this look like in action? 1. The Rapid Choice of the Right Antibiotic(s)
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1. The Rapid Choice of the Right Antibiotics This means EARLY involvement of procedural and surgical colleagues for adequate source control: E.g. inserting chest tubes for empyemas, biliary tubes for biliary obstructions, nephrostomy tubes for obstructing kidney stones, joint wash-out for septic arthritis, ex-laps for bowel perfs, etc. One caveat – patients much be stabilized for these procedures, which means they need to be fluid resuscitated first (see next slide). It is also common for patients to transiently worsen following source control procedure (classically drainage of liver abscess) due to “stirring up infection”. Anticipate this and stay on top of it with fluids and vasopressors! Consider inadequate source control in a patient who fails to improve with fluids and antibiotics alone Antibiotics will not effectively penetrate undrained abscesses 2. Achieve Adequate Source Control
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3. Fluid resuscitation: Central tenet of therapy 2012 Surviving Sepsis Campaign recommends specific physiologic goals for fluid resuscitation: MAP > 65 mmHg CVP 8-12 mmHg (or 12-15 during mechanical vent) Central venous O2 sat > 65% or Mixed venous > 70% Urine output > 0.5 ml/kg/h Normalization of lactate It is important to note that these goals are for the first 6 hours of sepsis therapy We are going to dive deeper into fluids and central venous O2 saturation (ScvO2) in a few slides
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First-line: Norepinephrine (dose: 0.01 - 1 µg/kg/min) Increases MAP mainly by vasoconstriction, but also is a mild inotrope which is important for sepsis-mediated cardiac stunning Low doses improve cardiac output, and cerebral, renal, and splanchnic blood flow Compared to dopamine: Less tachycardia, fewer arrhythmias, lower RR of death (0.91; 0.83–0.99) Second-line: Vasopressin (dose: 0.01 – 0.04 units/min) Goal is to decrease dose of NE Reasonable to start when NE dose gets to 0.2 µg/kg/min Some say dose is “fixed” at 0.04, but in reality you can adjust. 4. Maintain Blood Pressure Support
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Third-line: Epinephrine (dose: 0.01 - 1 µg/kg/min) Same dosing regimen as norepinephrine FYI on Epinephrine: If patient is dead, the dose is 1 mg IV q3min. If patient is alive but hypotensive, the dose is 10 mcg IV (or 1 ml of 1:100,000 concentration) q1min prn. Don’t give 1 mg! Can use Phenylephrine infusion in certain situations, e.g. avoidance of beta-adrenergic activation if patient has rapid Afib. 4. Maintain Blood Pressure Support
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Let’s get back to discussing fluid resuscitation goals in sepsis and what the literature says By now you have heard of the 2001 NEJM paper on Early Goal Directed Therapy by Manny Rivers (next slide) A bit of background, “Early” refers to the first 6 hours (pre-ICU). The studies done pre-Rivers looked at “Goal Directed Therapy” for sepsis, which targeted physiologic endpoints once patients arrived in the ICU but not before, and did not show a difference in outcomes. We’ll come back to that concept later. Severe Sepsis – Fluid therapy
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Severe Sepsis – Fluid therapy
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Prospective, single center, randomized, controlled trial 263 adult patients presenting to a tertiary care center ED with severe sepsis or septic shock Sepsis defined as: ≥ 2 SIRS criteria, AND SBP ≤ 90 after 20-30 ml/kg (~1.5 – 2 L) IVF bolus over 30 min OR blood lactate ≥ 4 mmol/L Notable exclusion criteria included immunosuppression, active cancer, & need for urgent surgery Rivers E, et al. NEJM 2001. Rivers E et al. N Engl J Med 2001;345:1368-1377.
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Rivers E et al. N Engl J Med 2001;345:1368-1377. Here is the enrollment and randomization schema for the study Enrollment and Resuscitation Algorithm
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Enrollment and Resuscitation Algorithm Here is the enrollment and randomization schema for the study You will notice that the only difference between the 2 groups was the use of central venous saturation (ScvO2) as a surrogate for oxygen delivery to guide resuscitation. Rivers E et al. N Engl J Med 2001;345:1368-1377.
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Enrollment and Resuscitation Algorithm Here is the enrollment and randomization schema for the study You will notice that the only difference between the 2 groups was the use of central venous saturation (ScvO2) as a surrogate for oxygen delivery to guide resuscitation. So let’s review ScvO2 and what it means… Rivers E et al. N Engl J Med 2001;345:1368-1377.
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Central venous vs. Mixed venous O2 sat Central venous oxyhemoglobin saturation (ScvO2) is measured here Mixed venous oxyhemoglobin saturation (MvO2) is measured here
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Central venous vs. Mixed venous O2 sat Central venous oxyhemoglobin saturation (ScvO2) is measured here Mixed venous oxyhemoglobin saturation (MvO2) is measured here What’s the difference? ScvO2 reflects tissue O2 extraction from only the upper extremities and brain, missing what the visceral organs (including coronary sinus, which empties into the RA) and lower extremities are doing. Visceral organs typically have higher extraction ratios and therefore lower venous O2 saturations. The MvO2 is therefore lower than the ScvO2 and reflects the average O2 extraction for the entire body. It is called “mixed” because the venous return from the SVC, IVC, and coronary sinus is mixed by the RV.
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Central venous vs. Mixed venous O2 sat Central venous oxyhemoglobin saturation (ScvO2) is measured here Mixed venous oxyhemoglobin saturation (MvO2) is measured here What’s the difference? ScvO2 reflects tissue O2 extraction from only the upper extremities and brain, missing what the visceral organs (including coronary sinus, which empties into the RA) and lower extremities are doing. Visceral organs typically have higher extraction ratios and therefore lower venous O2 saturations. The MvO2 is therefore lower than the ScvO2 and reflects the average O2 extraction for the entire body. It is called “mixed” because the venous return from the SVC, IVC, and coronary sinus is mixed by the RV. We tend to check ScVO2 rather than MvO2 because the latter requires a PA catheter. What are they supposed to represent? They are surrogates for oxygen delivery (DO2) and oxygen uptake (VO2). This is derived from the Fick Equation…
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Volume of O2 in Volume of O2 out CvO2 CaO2 The Fick Principle
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Volume of O2 in Volume of O2 out CvO2 CaO2 The Fick Principle Venous Oxygen Content: (Hb)(MVO2 %)(1.34) + (0.003)(PvO2) Arterial Oxygen Content: (Hb)(SaO2 %)(1.34) + (0.003)(PaO2)
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Volume of O2 in Volume of O2 out CvO2 CaO2 The Fick Principle So the concept then is that by measuring MvO2 (or ScvO2), you can make assumptions about tissue oxygenation. For example, if the MvO2 is high (e.g. > 65%), then the tissue oxygen extraction is not maxed out and therefore O2 delivery is adequate. If the MvO2 is low (e.g. < 50%), then the tissues are extracting more oxygen suggesting delivery is inadequate. The assumption, then, based on the Rivers paper, is that RBC transfusion (to increase Hb) or Dobutamine (to increase CO), will then improve oxygen uptake. (Fick equation above). There are 2 major problems with this assumption. First, while measuring the venous O2 content may be helpful, it isn’t enough because of the two other independent variables (CO and VO2). For example, VO2 may be depressed due to cytopathic hypoxia from sepsis rather than poor CO or anemia. Second, the MvO2 is a weighted average of the entire body. Each organ has a specific CO and VO2…
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75% 20% 75% 20% 75% 20% 90% 10% 60% 10% 75% 20% C.O.= 5 lpm MvO2 is weighted average of entire body Each circle is an organ. The top number is the organ-specific SvO2% and the bottom number is organ blood flow as a % of the total cardiac output. Healthy Kidney Liver Brain Heart Gut Muscle 75% Mixed venous
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75% 20% 75% 20% 20% 10% 70% 5% 60% 15% 75% 20% 75% 20% 75% 20% 75% 20% 90% 10% 60% 10% SvO2= %CO/OBF= 75% 20% Severe sepsis Pre-resuscitation Healthy C.O.= 5 lpm C.O.= 7.5 lpm Gut Mixed venous What happens during severe sepsis? = SvO2 =%CO/OBF 75% Kidney 61%
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75% 20% 75% 20% 20% 10% 70% 5% 60% 15% 75% 20% 75% 20% 75% 20% 75% 20% 90% 10% 60% 10% SvO2= %CO/OBF= 75% 20% Severe sepsis Pre-resuscitation Healthy C.O.= 5 lpm C.O.= 7.5 lpm Gut Mixed venous Kidney What happens during severe sepsis? = SvO2 =%CO/OBF 75% 61% But blood flow to the gut and kidney has decreased. This has lowered the venous saturations due to higher extraction and caused an overall decrease in MvO2. This is why we resuscitate. What has happened in the septic patient? CO has increased due to catecholamine stimulation.
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What happens during severe sepsis? 75% 20% 75% 20% 60% 20% 90% 10% 60% 15% 75% 15% C.O.= 10 lpm Kidney Gut 71% Severe sepsis Post-resuscitation = SvO2 =%CO/OBF With fluid resuscitation, blood flow has been largely restored to vital organs and CO has continued to increase. There is also a rise in MvO2 from 61% to 71%.
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What happens during severe sepsis? 75% 20% 75% 20% 60% 20% 90% 10% 60% 15% 75% 15% C.O.= 10 lpm Kidney Gut 71% Severe sepsis Post-resuscitation = SvO2 =%CO/OBF But what happens if you drop out a unit? For example, the patient develops gut ischemia… With fluid resuscitation, blood flow has been largely restored to vital organs and CO has continued to increase. There is also a rise in MvO2 from 61% to 71%.
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75% 20% 75% 20% 0% 0% 90% 10% 60% 20% 75% 30% VO2/Q dropout 75% 20% 75% 20% 60% 20% 90% 10% 60% 15% 75% 15% C.O.= 10 lpm C.O.= 10 lpm Kidney Gut Gut Gut ischemia 71% 74% Severe sepsis Post-resuscitation = SvO2 =%CO/OBF = SvO2 =%CO/OBF
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75% 20% 75% 20% 0% 0% 90% 10% 60% 20% 75% 30% VO2/Q dropout 75% 20% 75% 20% 60% 20% 90% 10% 60% 15% 75% 15% C.O.= 10 lpm C.O.= 10 lpm Kidney Gut Gut Gut ischemia 71% 74% Severe sepsis Post-resuscitation = SvO2 =%CO/OBF = SvO2 =%CO/OBF Here the gut becomes under-perfused and the MvO2 actually goes up because blood flow is redistributed. So a rise in MvO2 doesn’t necessarily mean oxygen delivery has been improved. Additional reading: Roberts JK, al. Oxygen Delivery in Septic Shock. Ann Am Thorac Soc. 2015;12(6):952-5.
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Rivers E et al. N Engl J Med 2001;345:1368-1377. Protocol for Early Goal-Directed Therapy 500 ml q30 min Back to Rivers’ paper… Here was the algorithm
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Baseline patient characteristics Rivers E et al. N Engl J Med 2001;345:1368-1377.
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Treatments Administered Rivers E et al. N Engl J Med 2001;345:1368-1377.
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Treatments Administered Rivers E et al. N Engl J Med 2001;345:1368-1377. Patients randomized to EGDT got more fluid in the first 6 hours. The Standard therapy group then played catch up with fluid between 7-72 hours.
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Treatments Administered Rivers E et al. N Engl J Med 2001;345:1368-1377. But total fluid administration was the same at 72 hours…
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Outcomes Rivers E et al. N Engl J Med 2001;345:1368-1377. Even though total fluids were the same at 72 hours, there was still more death and organ failure in Standard therapy group. This suggests that fluids during the first 6 hours is critical and if you get behind you can’t make it up later.
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Suggestion that the Standard group algorithm was not followed as well as EGDT algorithm: Control group received less fluid over first 6 hours despite same hemodynamic triggers (CVP 8 -12, MAP > 65). The CVP and MAP both lower in control group at 6 hours 14% of the control group (compared to <1% of EGDT group) did not reach combined physiologic end points for CVP, MAP, and UOP Could not conclude which components of the algorithm were more most crucial for observed survival benefit ~ 10% of patients in the study did not receive Abx within 6 hours Other observations and criticisms
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Barriers to EGDT implementation Concern of the lack of generalizability of the study Translation from a highly controlled research environment to diverse clinical care setting? Need for timely insertion of a central venous catheter which is cumbersome and resource heavy Time and resources required to implement the protocol in general are high Currently EGDT is only followed strictly in ~ 10% of candidate patients Carlbom DJ, et al. Crit Care Med 2007;35:2525-2532. Jones AE, et al. Acad Emerg Med 2007;14:1072-1078.
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There have been 3 major follow-up studies to Rivers EGDT to address some of these concerns ProCESS (NEJM 2014) – U.S. ARISE (NEJM 2014) – Australia/NZ ProMISe (NEJM 2015) – U.K. These studies evaluated EGDT vs. usual care in patients with early severe sepsis or septic shock Follow-up Studies The ProCESS Investigators. N Engl J Med 2014; 370:1683-1693. The ARISE Investigators and the ANZICS Clinical Trials Group. N Engl J Med 2014; 371:1496-1506. Mouncey PR, et al. for the ProMISe Investigators N Engl J Med 2015; 372:1301-1311.
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Multicenter, prospective, randomized, controlled trials of patients with severe sepsis and septic shock ≥ 2 SIRS criteria, AND Evidence of hypotension or hypoperfusion (1 of the following): SBP < 90 or MAP < 65 after fluid bolus (0.5 - 1 L or 20-30 ml/kg over 30-60 min) Requiring vasopressors to achieve BP goals Lactate > 4 mmol/l ProCESS, ARISE, & ProMISe trials
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Acute CVA Acute coronary syndrome Acute pulmonary edema Status asthmaticus Major cardiac arrhythmia Seizure Drug overdose Burn or trauma Emergent surgery CD4 count < 50/mm2 *Active bleeding *Desired limited care *CVC contraindicated *Refusal of blood *Imminent death *Pregnancy *Age < 18 yrs ProCESS, ARISE, & ProMISe trials Exclusion criteria similar to Rivers study: *ARISE only
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ProCESS, ARISE, & ProMISe trials Study groups Early goal-directed therapy compared with usual care (and protocol driven standard therapy in ProCESS trial) For Usual Care group, decisions about diagnosis, monitoring, treatment were made by treating clinical team ScvO2 measurements were not permitted during the first 6-hour intervention
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ProCESS Trial 1,341 patients randomized in ED at 1:1:1 439 protocol-based EGDT, 446 protocol-based standard therapy, 456 usual care (UC) 60 day mortality 21%, 18.2% and 18.9%, respectively (P=NS) No differences in 90 day or 1 year mortality or need for organ support for: EGDT vs. Standard Protocol Both Protocols vs. UC
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ARISE Trial 1,600 patients (796 EGDT, 804 UC) EGDT group received ~250 ml more IVF in first 6 h (1964 vs. 1713 ml) 90 day mortality of 18.6 vs. 18.8% for EGDT vs. UC respectively (P=NS) No differences in survival time, duration of organ support, LOS
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ProMISe Trial 1,260 patients (630 EGDT, 630 UC) EGDT group received ~200 ml more IVF in first 6 h (2000 vs. 1784 ml) 90 day mortality of 29.5% vs. 29.2% for EGDT vs. UC respectively (P=NS) No differences in duration of organ support, length of hospital stay
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Clinical Characteristics Across Studies UC=Usual Care R=randomization
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Clinical Characteristics Across Studies UC=Usual Care R=randomization ARISE cohort not as sick
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Clinical Characteristics Across Studies UC=Usual Care R=randomization Most patients got 4-5 L of IVF
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Criticisms Mortalities in ProCESS and ARISE were lower than expected (~ 18%) Raises the possibility of a lack of treatment effect in less sick patients ProMISe mortality ~ 29% (Rivers - 46%) ? Bias in usual care groups’ treatment due to knowledge of Rivers study: 4-8% transfused, 1-8% got Dobutamine All patients given ~ 2L IVF pre-randomization
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Criticisms Mortalities in ProCESS and ARISE were lower than expected (~ 18%) Raises the possibility of a lack of treatment effect in less sick patients ProMISe mortality ~ 29% (Rivers - 46%) ? Bias in usual care groups’ treatment due to knowledge of Rivers study: 4-8% transfused, 1-8% got Dobutamine All patients given ~ 2L IVF pre-randomization This is not trivial – it will dilute out a treatment effect because it will make absolute differences between the 2 treatments smaller. Imagine studying ASA for STEMI and patients in both control (placebo) and intervention (ASA 325 mg) groups were given 81 mg before randomization…
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Use of Lactate to Guide Resuscitation So the routine use of ScvO2 is not necessary… Experts have also called for the use of lactate “clearance” as a non-invasive guide for IVF resuscitation (Of course “clearance” is a misnomer because can’t measure production and elimination, only random points in time…) Lactate levels may be clinically relevant though: Mortality rate for septic pts with lactate > 4 mmol/L ~ 30% and is up to 46% if also hypotensive Surviving Sepsis Campaign guidelines: Suggestion: Targeting resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion (grade 2C) Levy et al. Crit Care Med 2010
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Jansen, et al. looked at using lactate to guide IVF therapy in a RCT in 2010 Used EGDT/physiologic endpoints to target ~ 10% lactate reduction per hour Compared with a non-lactate based approach Study outcomes included organ severity (SOFA), mortality, length of stay, etc. Use of Lactate to Guide Resuscitation Jansen et al. Am J Resp Crit Care Med, 2010
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(A) Treatment algorithm, control group and lactate group. The goal for central venous pressure (CVP) was 12 to 15 mm Hg in mechanically ventilated patients. Besides the static CVP goals, CVP was used as a dynamic safety limit during fluid challenges. Both crystalloids and colloids could be used at the discretion of the clinician. Albumin was not a standard resuscitation fluid in the participating centers. The goal for hemoglobin was 10 g/dl in patients with cardiac ischemia. (B) Additional treatment algorithm, lactate group. If the lactate level became less than or equal to 2.0 mEq/L, a further decrease was no longer required. Fluid responsiveness was assessed by a fluid challenge of 200 ml crystalloids or colloids. The goal was an increase in blood pressure, ScvO2, or stroke volume, or a decrease in heart rate. CVP was used as a dynamic safety limit: if CVP increased less than or equal to 2 mm Hg, fluid administration was continued; if CVP increased more than 2 and less than or equal to 5 mm Hg, the fluid challenge was repeated after waiting for 10 minutes; if CVP increased greater than or equal to 5 mm Hg, fluid administration was stopped. Before administration of vasodilators, fluid responsiveness was assessed and fluids were infused if necessary. The recommended dose for nitroglycerin was 2 mg in 1/2 hour followed by 2 mg per hour. MAP = mean arterial pressure; NTG = nitroglycerin; RBCs = red blood cell transfusions; SaO2 = arterial oxygen saturation; ScvO2 = central venous oxygen saturation; T = time; UP = urine production. But Jansen study algorithm quite complex Lactate checked q2h in Lactate Group If lactate remained > 3 mmol/L All of these are designed to improve O2 delivery
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Lower adjusted mortality by 10 percentage points (adj. HR 0.61; P=0.006) Lower SOFA scores (i.e. organ failure) at 72 hours (6.4 vs. 7.0, p=0.009) Shorter time to weaning from mechanical ventilation and inotropes (but not from vasopressors or dialysis) Shorter ICU length of stay Jansen Study Clinical Outcomes Compared to Control group, the Lactate group had:
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Use of Lactate to Guide Resuscitation Jansen et al. Am J Resp Crit Care Med, 2010;182(6):752-61. Why was this?
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Use of Lactate to Guide Resuscitation Jansen et al. Am J Resp Crit Care Med, 2010;182(6):752-61. Interestingly, there was no difference in lactate levels between control and “lactate-driven protocol” Why was this?
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Use of Lactate to Guide Resuscitation Jansen et al. Am J Resp Crit Care Med, 2010;182(6):752-61. Interestingly, there was no difference in lactate levels between control and “lactate-driven protocol” Why was this?
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Use of Lactate to Guide Resuscitation Jansen et al. Am J Resp Crit Care Med, 2010;182(6):752-61. Interestingly, there was no difference in lactate levels between control and “lactate-driven protocol” Again we see more upfront IVF in the Lactate group and late catch up in the control group Why was this?
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Lactate monitoring may be beneficial in guiding sepsis resuscitation But does not accelerate lactate “clearance” compared to usual care Lactate is likely a biomarker for, rather than a “cause” of, organ failure Reinforces the principle that the first six hours is a crucial time for aggressive IVF, vasopressors, achieving physiologic goals And that playing catch up after 6 hours is insufficient to reverse organ failure What can we learn from Jansen study?
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Additional Reading on Lactate and Sepsis Suetrong B and Walley KR. Lactic Acidosis in Sepsis: It’s Not All Anaerobic: Implications for Diagnosis and Management. Chest. 2016;149(1):252-61. Nice review on lactate production and metabolism in health and sepsis. Jones AE, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-46. Jones et al. found that targeting lactate clearance of at least 10% was non-inferior to targeting SvO2 > 70%. There were no differences in mortality between the two groups.
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Summary The 3 most important components of sepsis care are: Rapid administration of the right antibiotic(s) Source control within first hospital day Aggressive resuscitation with IVF, pressors, etc. during first 6 hours of care How much fluid is enough? Most patients in Rivers, ProCESS, ARISE, and ProMISe received 4-5 L and this is likely a good estimate, acknowledging every patient is different. How do you judge fluid responsiveness? By all of these: Physical exam, straight leg raise, IVC ultrasound, CVP, MAP, UOP, lactate, ScvO2, trial and error, etc. etc.
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Summary The 3 most important components of sepsis care are: Rapid administration of the right antibiotic(s) Source control within first hospital day Aggressive resuscitation with IVF, pressors, etc. during first 6 hours of care How much fluid is enough? Most patients in Rivers, ProCESS, ARISE, and ProMISe received 4-5 L and this is likely a good estimate, acknowledging every patient is different. How do you judge fluid responsiveness? By all of these: Physical exam, straight leg raise, IVC ultrasound, CVP, MAP, UOP, lactate, ScvO2, trial and error, etc. etc. No single test will tell you what to do!
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Summary Fluids should be administered as long as the patient is fluid responsive, to a point. Avoid fluid overload (edema worsens O2 delivery due to increasing distance needed for O2 diffusion) Conversely, using high dose vasopresors in a hypovolemic patient will cause digital necrosis So the take home message is give enough fluids up front to fill the tank (~4-5 L may be sufficient) but not too much to cause significant fluid overload…
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Summary Too little fluid Too much fluid More organ injury Higher mortality Vasopressor-induced digital necrosis Worse edema Impaired oxygen diffusion Worse ARDS Finding the middle for each patient requires combining many variables: physical exam, straight leg raise, IVC ultrasound, lactate, ScvO2, urine output, trial and error, etc.
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Summary The ProCESS, ARISE, and ProMISe studies are not an assault on protocolized sepsis management However, routine use of ScvO2 > 70% for resuscitation goal cannot be recommended But ScvO2 monitoring may still be highly indicated in select patients that are not responding to non-invasive approach alone, i.e. Rising lactate despite adequate fluid resuscitation Active cardiac ischemia (heart regulates VO2 based on DO2 rather than O2 extraction)
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Summary So back to where we started – should we still try to optimize oxygen delivery as a treatment for sepsis? Yes, to a point. We know that raising DO2 to supra-physiologic levels is bad, but returning DO2 to physiologic range is still valid based on the best available data and first principles. But not everyone needs ScvO2 monitoring And each organ has different metabolic needs, so using the ScvO2 to make assumptions about local tissue oxygen delivery comes with all of the caveats discussed
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Additional Reading on Sepsis ATS Fellows Reading List NEJM 2014; 371(15):1381-91. Low vs. high Hb goals NEJM. 2014; 24;370(17):1583-93. High vs. low MAP targets Anesth Analg. 2010 Aug;111(2):444-50. Practice malalignment in RCTs, specifically as it relates to ICU transfusion goals
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Feel free to email questions: bryan.kraft@duke.edu