Sepsis 3 José L. González, MD 2017-2018.

Sepsis 3 José L. González, MD

What is sepsis?

Figure 1. The Host Response in Severe Sepsis
Figure 1. The Host Response in Severe Sepsis. The host response to sepsis is characterized by both proinflammatory responses (top of panel, in red) and antiinflammatory immunosuppressive responses (bottom of panel, in blue). The direction, extent, and duration of these reactions are determined by both host factors (e.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (e.g., microbial load and virulence). Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern-recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding oligomerization domain–like receptors [NLRs]). The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation at least in part by acting on the same pattern-recognition receptors that are triggered by pathogens.

Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria. Sepsis is associated with microvascular thrombosis caused by concurrent activation of coagulation (mediated by tissue factor) and impairment of anticoagulant mechanisms as a consequence of reduced activity of endogenous anticoagulant pathways (mediated by activated protein C, antithrombin, and tissue factor pathway inhibitor owing to enhanced release of plasminogen activator inhibitor type 1 (PAI-1). The capacity to generate activated protein C is impaired at least in part by reduced expression of two endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated by neutrophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypoperfusion, which is aggravated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired by the loss of barrier function of the endothelium owing to a loss of function of vascular endothelial (VE) cadherin, alterations in endothelial cell-to-cell tight junctions, high levels of angiopoietin 2, and a disturbed balance between sphingosine-1 phosphate receptor 1 (S1P1) and S1P3 within the vascular wall, which is at least in part due to preferential induction of S1P3 through protease activated receptor 1 (PAR1) as a result of a reduced ratio of activated protein C to thrombin. Oxygen use is impaired at the subcellular level because of damage to mitochondria from oxidative stress.

What is sepsis?

From a dysregulated host response Secondary to infection
What is sepsis? Organ dysfunction From a dysregulated host response Secondary to infection Leading to increased mortality

Sepsis 2 Criteria SIRS (2 or more of the following):
T> 38°or <36° HR > 90 bpm RR > 20 bpm or PaCO2 < 32 WBC > 12k, <4k or >10% bands Sepsis = SIRS + infection Severe Sepsis = Sepsis + Organ Dysfunction or Hypoperfusion (high lactate, low UOP, low BP) Septic Shock = Severe Sepsis + Persistent Hypotension Different terms are not clinically useful: Sepsis vs severe sepsis vs septic sock No diff in the way you tx Doesn’t predict or prognosticate anything Lead to discrepancy in clinical data Persistent hypotension??

What is sepsis? Organ dysfunction From a dysregulated host response Secondary to infection Leading to increased mortality Problems w/ old criteria: poor sens and spec: Specificty: SIRS criteria may be a normal response to a variety of illnesses, pyrexia and neutrophilia don’t necessarily indicate a dysregulated, life-threatening response. Sensitivity: some patients w/ organ failure and infection didn’t fulfill the SIRS criteria In new criteria we do away with pyrexia, neutrophilia, focus on ABNORMAL host response to infection

Sensitivity of Various Scoring Systems on Hospital Mortality:
SOFA LODS SIRS ICU 0.74 0.75 0.64 Non-ICU 0.79 0.76 SOFA was picked because it is more widely known and simpler than LODS Criteria development: - EMR data from 1.3million 12community and academic hospitals - 149k pts w/ suspected infections (body fluid sampling and having received abx) - 2 outcomes: hospital mortality & ICU stay ≥ 3d used to assess predictive validity - a) AUC b) comparing pts w/ < 2points vs those w/ > 2pts - 3 contenders: sensitivity of the following three methods of predicting 2 outcomes SOFA = ∆SOFA ≥ 2: Sequential (Sepsis-Related) Organ Failure Assessment LODS = Logistic Organ Dysfunction System SOFA was chosen because it is a better known scoring system

Sequential Organ Failure Assessment / Sepsis-Related Organ Failure Assessment
SOFA Score 1 2 3 4 Respiratory: PaO2/FiO2 >400 ≤400 ≤300 ≤200* ≤100* Coagulation: Platelets >150 ≤150 ≤100 ≤50 ≤20 Liver: Bilirubin <1.2 >12.0 CV: Hypotension MAP≥70 MAP<70 Dopa>5 Dopa Dopa>15 CNS: GCS score 15 13-14 10-12 6-9 <6 Renal: Cr or UOP or <500 >5 or <200 *On respiratory support A system that already existed, good for predicting mortality in the ICU Assume baseline score is 0 unless otherwise known A change of 2 points correlates with an increase in mortality by 10% above the general hospital population w/ suspected infection to put that into context: overall mortality of pts w/ STEMI = 8.1% Criticisms: SOFA requires labs CV score is affected by iatrogenic interventions i.e. IVF for hypotension Developed based on retrospective analysis

Screening for Sepsis: qSOFA
Altered Mental Status: GCS < 15 qSOFA developed using multiple logistics regression analysis, identified that 2/3 variables qSOFA outside the ICU: 0.81 predictive validity vs 0.79 for SOFA vs insude the ICU, qSOFA = 0.66 AUROC (are under the receiver operating characteristic curve) Addition of lactate to qSOFA did not increase its sensitivity Quick & easy, no labs

Altered Mental Status: GCS < 15 Respiratory Rate > 22 qSOFA developed using multiple logistics regression analysis, identified that 2/3 variables qSOFA outside the ICU: 0.81 predictive validity vs 0.79 for SOFA vs insude the ICU, qSOFA = 0.66 AUROC (are under the receiver operating characteristic curve) Addition of lactate to qSOFA did not increase its sensitivity Quick & easy, no labs

Altered Mental Status: GCS < 15 Respiratory Rate > 22 Systolic Blood Pressure < 100 mmHg qSOFA developed using multiple logistics regression analysis, identified that 2/3 variables qSOFA ~ SOFA: predicts 81% of full SOFA score Addition of lactate to qSOFA did not increase its sensitivity Quick & easy, no labs

Glasgow Coma Scale (3-15) Eyes Verbal Motor 4 opens eyes spontaneously
3 opens eyes in response to voice 2 opens eyes in response to painful stimuli 1 does not open eyes Verbal 5 oriented 4 confused conversation 3 inappropriate words 2 incomprehensible sounds 1 none Motor 6 obeys commands 5 localizes to pain 4 normal withdrawal from pain 3 decorticate posturing 2 decerebrate posturing 1 no motor response

Glasgow Coma Scale in qSOFA
Eyes opens eyes spontaneously Verbal oriented Motor obeys commands 2 out of 3 is okay 1 out of 3 is not okay Eyes: spontaneously vs to command Verbal: oriented vs confused Motor: obeys commands vs localizes to pain

Septic Shock Definition: Diagnosis:
Subset of sepsis in pts w/ higher predicted mortality (40% vs 10%) Diagnosis: Lactate > 2 AND Vassopressor-dependence for MAP > 65 mmHg p IVF resuscitation Septic Shock now has predictive validity too!

Summary of Sepsis 3 Organ dysfunction
Use SOFA score Use qSOFA score to screen (instead of SIRS) From a dysregulated host response Not a normal rxn to infection (WBC, fever) Secondary to infection Confirmed or suspected (unchanged) Leading to increased mortality 10% predictive mortality 40% if septic shock Instead of 4 terms: SIRS, sepsis, severe sepsis & septic shock We have 2 terms: sepsis and septic shock And 1 screening tool: qSOFA

Screening & Diagnosing
Screen for Sepsis qSOFA Vital Signs (SBP, RR) Check GCS SOFA CBC (plts) CMP (Cr, Tbili) ABG (PaO2/FiO2 ) lactate (severe sepsis)

Treatment Surviving Sepsis Campaign 2003 2008 2012 -----Sepsis 3-----
2016 Guidelines: Use sepsis-2 terms, definitions and thresholds are super confusing in that they are for severe sepsis (sepsis + organ dysfunction or elevated lactate) = a category that no longer exists. It says to give 30ml/Kg of IVF after initial fluid bolus fails to improve perfusion. Implying that the first step is to give IVF bolus at an unspecified rate… Sepsis bundle is a summary of the sepsis guidelines and gives cutoffs for when interventions should be done.

Treatment

Initial Resuscitation: 1. IV Fluids
How much? Starches = hydroxyethyl starches = hetastarch 3 studies published in 2014, 2014 and 2015 did not demonstrate superiority of requiring use of central venous catheter, so revised bundle is iffy, saying do focused exam OR use 2 of 4 of the following: measure CVP measure ScvO2 bedside cardiovascular US dynamic assessment w/ IVF challenge or passive leg test SvO2 = PA measurement, blood from IVC and SVC ScvO2 = SVC measurement only = higher O2 extraction from brain But in sepsis SvO2 is lower then ScvO2 due to higher extraction What if a patient has heart failure? – ideally pt would stop improving (stroke volume would stop improving) and by definition you would stop What if a patient is in respiratory distress? – intubate if necessary, stop if no improvement in stroke volume

At least 30mL/kg Starches = hydroxyethyl starches = hetastarch 3 studies published in 2014, 2014 and 2015 did not demonstrate superiority of requiring use of central venous catheter, so revised bundle is iffy, saying do focused exam OR use 2 of 4 of the following: measure CVP measure ScvO2 bedside cardiovascular US dynamic assessment w/ IVF challenge or passive leg test SvO2 = PA measurement, blood from IVC and SVC ScvO2 = SVC measurement only = higher O2 extraction from brain But in sepsis SvO2 is lower then ScvO2 due to higher extraction What if a patient has heart failure? – ideally pt would stop improving (stroke volume would stop improving) and by definition you would stop What if a patient is in respiratory distress? – intubate if necessary, stop if no improvement in stroke volume

At least 30mL/kg What type? Starches = hydroxyethyl starches = hetastarch 3 studies published in 2014, 2014 and 2015 did not demonstrate superiority of requiring use of central venous catheter, so revised bundle is iffy, saying do focused exam OR use 2 of 4 of the following: measure CVP measure ScvO2 bedside cardiovascular US dynamic assessment w/ IVF challenge or passive leg test SvO2 = PA measurement, blood from IVC and SVC ScvO2 = SVC measurement only = higher O2 extraction from brain But in sepsis SvO2 is lower then ScvO2 due to higher extraction What if a patient has heart failure? – ideally pt would stop improving (stroke volume would stop improving) and by definition you would stop What if a patient is in respiratory distress? – intubate if necessary, stop if no improvement in stroke volume

At least 30mL/kg Crystalloids over colloids How soon? Starches = hydroxyethyl starches = hetastarch 3 studies published in 2014, 2014 and 2015 did not demonstrate superiority of requiring use of central venous catheter, so revised bundle is iffy, saying do focused exam OR use 2 of 4 of the following: measure CVP measure ScvO2 bedside cardiovascular US dynamic assessment w/ IVF challenge or passive leg test SvO2 = PA measurement, blood from IVC and SVC ScvO2 = SVC measurement only = higher O2 extraction from brain But in sepsis SvO2 is lower then ScvO2 due to higher extraction What if a patient has heart failure? – ideally pt would stop improving (stroke volume would stop improving) and by definition you would stop What if a patient is in respiratory distress? – intubate if necessary, stop if no improvement in stroke volume

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Starches = hydroxyethyl starches = hetastarch 3 studies published in 2014, 2014 and 2015 did not demonstrate superiority of requiring use of central venous catheter, so revised bundle is iffy, saying do focused exam OR use 2 of 4 of the following: measure CVP measure ScvO2 bedside cardiovascular US dynamic assessment w/ IVF challenge or passive leg test SvO2 = PA measurement, blood from IVC and SVC ScvO2 = SVC measurement only = higher O2 extraction from brain But in sepsis SvO2 is lower then ScvO2 due to higher extraction What if a patient has heart failure? – ideally pt would stop improving (stroke volume would stop improving) and by definition you would stop What if a patient is in respiratory distress? – intubate if necessary, stop if no improvement in stroke volume

At least 30mL/kg Crystalloids over colloids Within the first 3 hours How do you assess for improvement? A) CVP 8-12 B) MAP > 65 C) UOP > 0.5mL/kg/hr D) SCV O2 > 70% E) clinically Starches = hydroxyethyl starches = hetastarch 3 studies published in 2014, 2014 and 2015 did not demonstrate superiority of requiring use of central venous catheter, so revised bundle is iffy, saying do focused exam OR use 2 of 4 of the following: measure CVP measure ScvO2 bedside cardiovascular US dynamic assessment w/ IVF challenge or passive leg test SvO2 = PA measurement, blood from IVC and SVC ScvO2 = SVC measurement only = higher O2 extraction from brain But in sepsis SvO2 is lower then ScvO2 due to higher extraction What if a patient has heart failure? – ideally pt would stop improving (stroke volume would stop improving) and by definition you would stop What if a patient is in respiratory distress? – intubate if necessary, stop if no improvement in stroke volume

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables Fluid challenges against stroke volume measurements Variation in systolic pressure Pulse pressure differences Stroke volume to changes in intrathoracic pressure Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables to determine efficacy Normalize lactate if abnormal Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables to determine efficacy Normalize lactate if abnormal What if your patient is not getting better? Types of shock. Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables to determine efficacy Normalize lactate if abnormal Types of shock: Distributive Cardiogenic Hypovolemic Obstructive Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91 Distributive: septic, SIRS, neurogenic, anaphylactic, drug-induced and toxin-induced, endocrine Cardiogenic: cardiomyopathic, arrhythmic, mechanical Hypovolemic: hemorrhagic, non-hemorrhagic Obstructive: pulmonary vascular or mechanical (tamponode, tension pneumo, constrictive or restrictive pericarditis)

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables to determine efficacy Normalize lactate if abnormal Hemodynamic assessment if dx is unclear Pt w/ cirrhosis s/p 3L IVF bolus. BP is now 90/60 up from 80/50, what now? Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91 Distributive: septic, SIRS, neurogenic, anaphylactic, drug-induced and toxin-induced, endocrine Cardiogenic: cardiomyopathic, arrhythmic, mechanical Hypovolemic: hemorrhagic, non-hemorrhagic Obstructive: pulmonary vascular or mechanical (tamponode, tension pneumo, constrictive or restrictive pericarditis)

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables to determine efficacy Normalize lactate if abnormal Hemodynamic assessment if dx is unclear IVF as long as there is improvement. Can consider colloids Do not use hydroxy-ethyl starches, do not use gelatins Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91 Distributive: septic, SIRS, neurogenic, anaphylactic, drug-induced and toxin-induced, endocrine Cardiogenic: cardiomyopathic, arrhythmic, mechanical Hypovolemic: hemorrhagic, non-hemorrhagic Obstructive: pulmonary vascular or mechanical (tamponode, tension pneumo, constrictive or restrictive pericarditis)

At least 30mL/kg Crystalloids over colloids Within the first 3 hours Use dynamic variables to determine efficacy Normalize lactate if abnormal Hemodynamic assessment if dx is unclear Continue IVF as long as there is improvement What’s next after fluids? Static variable = CVP, SCVO2, MAP, UOP When CVP is normal (8-12) there is limited ability to predict a response to IVF Stroke volume is calculated using TTE by subtracting end-diastolic volume from end-systolic volume CO = SV x HR Pulse pressure in predicting fluid responsiveness = sensitivity of 0.72, specificity of 0.91 Distributive: septic, SIRS, neurogenic, anaphylactic, drug-induced and toxin-induced, endocrine Cardiogenic: cardiomyopathic, arrhythmic, mechanical Hypovolemic: hemorrhagic, non-hemorrhagic Obstructive: pulmonary vascular or mechanical (tamponode, tension pneumo, constrictive or restrictive pericarditis)

2. Identify Infection, Source Control, IV Abx

Initial Resuscitation: 2a. IV Antibiotics
What can we do before giving antibiotics? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible BD glucan used for disseminated candidiasis and invasive aspergillosis In stem cell xplant pts, solid organ xplants or heme malignancy

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics 1,3 β-D glucan assay, mannan and anti-mannan Ab assays 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics Galactomannan assays ? Pan-culture? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Initial Resuscitation: 2. IV Antibiotics
Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx How soon? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Which ones? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one (broad spectrum) Septic shock: empiric combination therapy (at least 2 classes) How do you dose them? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one (broad spectrum) Septic shock: empiric combination therapy (at least 2 classes) Use pharmacokinetic data 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one (broad spectrum) Septic shock: empiric combination therapy (at least 2 classes) Pt’s blood cultures positive for e-coli, sensitive to ceftriaxone. What now? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one Septic shock: empiric combination therapy (at least 2 classes) Narrow therapy once pathogen is identified and sensitivities are established 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one Septic shock: empiric combination therapy (at least 2 classes) Narrow therapy once pathogen is identified and sensitivities are established Cultures are negative, pt’s lipase comes back as 3400, what now? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one Septic shock: empiric combination therapy (at least 2 classes) Narrow therapy once pathogen is identified and sensitivities are established Do not give abx in non-infectious inflammatory states All studies are negative, patient no longer meets criteria for sepsis 3 days later, pt is extubated, what next? 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Appropriate microbiologic cultures if doing so causes no significant delay in administering antibiotics IV abx Within 1 hour Sepsis: at least one Septic shock: empiric combination therapy (at least 2 classes) Narrow therapy once pathogen is identified and sensitivities are established Do not give abx in non-infectious inflammatory states De-escalate if clinically improving, assess daily, stop after 7-10 days 1,3 β-D glucan assay, mannan and anti-mannan Ab assays - if systemic fungal infection is suspected Result much sooner than cultures But significantly higher rate of false positives Imaging Studies If suspected source of infection Also sample them if possible

Initial Resuscitation: 2b. Identify Infection
Imaging if necessary to identify or exclude source ASAP Worse outcomes if it takes longer than 6-12hrs for source control Give abx for longer period of time if source is not completely drainable

Imaging if necessary to identify or exclude source ASAP Drainage within 6-12 hours if possible Worse outcomes if it takes longer than 6-12hrs for source control Give abx for longer period of time if source is not completely drainable

Imaging if necessary to identify or exclude source ASAP Drainage within 6-12 hours if possible What if you can’t completely drain a source? Worse outcomes if it takes longer than 6-12hrs for source control Give abx for longer period of time if source is not completely drainable

Imaging if necessary to identify or exclude source ASAP Drainage within 6-12 hours if possible Prolonged course of antibiotics is reasonable if source is undrainable. Worse outcomes if it takes longer than 6-12hrs for source control Give abx for longer period of time if source is not completely drainable

Imaging if necessary to identify or exclude source ASAP Drainage within 6-12 hours if possible Remove IV access if it is suspicious for infectious source Worse outcomes if it takes longer than 6-12hrs for source control Give abx for longer period of time if source is not completely drainable

Imaging if necessary to identify or exclude source ASAP Drainage within 6-12 hours if possible Remove IV access if it is suspicious for infectious source After IVF hydration, IV abx, what’s next? Worse outcomes if it takes longer than 6-12hrs for source control Give abx for longer period of time if source is not completely drainable

Initial Resuscitation: 3. Vasopressors
Norepinephrine should be first choice Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias

Norepinephrine Add vasopressin or epinephrine Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias

Norepinephrine Add vasopressin or epinephrine +/- Dopamine Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias

Norepinephrine Add vasopressin or epinephrine +/- Dopamine To what goal? Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias

Norepinephrine Add vasopressin or epinephrine +/- Dopamine MAP 65mmHg Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias

Norepinephrine Add vasopressin or epinephrine +/- Dopamine MAP 65mmHg How to you measure it? Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias

Norepinephrine Add vasopressin or epinephrine +/- Dopamine MAP ≥ 65mmHg All patients on vassopressors should have an arterial catheter placed Dopamine has more cardiac activity thus it can be used in patients w/ bradycardia any may lead to tachyarrrhythmias Worse outcomes with higher MAPs

4. Adjunctive Therapy Corticosteroids?
Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts

4. Adjunctive Therapy Don’t use steroids unless nothing else works
Hgb transfusion goals? Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts

4. Adjunctive Therapy Steroids as a last resort
Transfuse pRBCs only if Hgb < 7.0 Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts Exceptions: MI, hypoxemia, active bleeding

Transfuse pRBCs only if Hgb < 7.0 Plt transfusion goal? Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts Exceptions: MI, hypoxemia, active bleeding

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts Exceptions: MI, hypoxemia, active bleeding

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent or continuous sedation? Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts Exceptions: MI, hypoxemia, active bleeding

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent preferred to continuous sedation Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts Exceptions: MI, hypoxemia, active bleeding

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent preferred to continuous sedation Glucose control <110 vs <180? Transfusion Requirement in Critical Care Trial = goal 7-9 vs not associated w/ increased mortality in ICU pts Exceptions: MI, hypoxemia, active bleeding

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent preferred to continuous sedation Protocolized glucose control to maintain < 180 mg/dL Glucose monitoring q1-2hours Use arterial glucose monitoring as POC testing is often not accurate in septic patients

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent preferred to continuous sedation Protocolized glucose control to maintain < 180 mg/dL VTE prophy w/ UHF or LMWH? Glucose monitoring q1-2hours Use arterial glucose monitoring as POC testing is often not accurate in septic patients

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent preferred to continuous sedation Protocolized glucose control to maintain < 180 mg/dL LMWH preferred over UFH for VTE prophylaxis LMWH lower incidence of PE, lower incidence of HIT, lower cost

Transfuse pRBCs only if Hgb < 7.0 Plt < 10 < 20 if at high risk of bleeding < 50 if active bleeding, active surgery or procedure planned Intermittent preferred to continuous sedation Protocolized glucose control to maintain < 180 mg/dL LMWH preferred over UFH for VTE prophylaxis Set goals of care! LMWH lower incidence of PE, lower incidence of HIT, lower cost, ease of administration (no monitoring)

Sepsis 3 Summary Screen w/ qSOFA Diagnose w/ SOFA Septic Shock Treat:
IVF Identify Infection Abx & Source control Vassopressors qSOFA: AMS, SBP < 100, RR > 22 Dx w/ SOFA Septic Shock: lactate > 2, vassopressors. Remember to get a repeat lactate level to comply w/ sepsis bundle Treat: IVF: crystalloid over colloid Identify infection: cultures, imaging Abx & Source Control

Sources Angus DC, van der Poll T. N Engl J Med 2013;369: Rhodes A, Evans L, Alhzzani W et al. Surviving Sepsis Capaign: Internaltional Guidelines for Management of Severe Sepsis and Septic Shock: Crit Care Medicine. Mar 2017; 45: Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA Feb 23;315(8):

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