Update on Sepsis Management
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Given at the 2016 Alabama Society of Physician Assistants CME conference
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Update on Sepsis Management
- 1. Kristopher R. Maday, MS, PA-C, CNSC University of Alabama at Birmingham
- 2. • Identify the sign and symptoms of sepsis • Describe the common complications of sepsis • Introduce the new Sepsis-III definition • Critically evaluate landmark Early Goal Directed Therapy study • Appraise current literature on sepsis management
- 4. • 2-4% of all diagnoses – 6th most common principle reason for hospitalization • Single most expensive condition treated – $15.4 billion spent on sepsis in 2009 • $18,500-33,900 per case Hall MJ. NCHS Data Brief. 2011;62. Elixhauser A. HCUP Statistical Brief. 2011;112.
- 5. Hall MJ. NCHS Data Brief. 2011;62.
- 6. Hall MJ. NCHS Data Brief. 2011;62.
- 7. Hall MJ. NCHS Data Brief. 2011;62.
- 8. Hall MJ. NCHS Data Brief. 2011;62.
- 9. Disposition Sepsis All Other Diagnoses Percent Routine 39 79 Transfer to other short-term facility 6 3 Transfer to long-term care facility 30 10 In-hospital mortality 17 2 Other or not stated 8 6 Total 100 100 Hall MJ. NCHS Data Brief. 2011;62. Elixhauser A. HCUP Statistical Brief. 2011;112.
- 10. • Initiated in 2002 • International joint collaborative between: – Society of Critical Care Medicine – European Society of Intensive Care Medicine • Mission Statement – “reducing mortality from severe sepsis and septic shock worldwide” • Developed guidelines and bundles for sepsis management Surviving Sepsis Campaign. Accessed February 17, 2015, from http://www.survivingsepsis.org/Pages/default.aspx.
- 11. sipsi
- 12. Infectious Source Total (%) Urinary Tract 34.5 Respiratory Tract 28.7 Gastrointestinal Tract 5 Soft Tissue 6.6 Other 25.2 Ani C. Critical Care Medicine. 2015;43(1):65-77
- 13. Angus DC. NEJM. 2013;369(9):840-851
- 14. Marino PL. Infection, Inflammation, and Multiorgan Injury. In: The ICU Book. 4e. 2013.
- 15. Temperature > 38o C (100.4o F) or < 36o C (96.8o F) Heart Rate > 90 beats/minute Respiratory Rate >20 breaths/minute or PaCO2 < 32 mmHg Prognosis Mortality 2 Criteria 5% 3 Criteria 10% 4 Criteria 20% Chen CL. Patient Safety. In: Schwartz’s Principles of Surgery. 10e. 2014. White Blood Cell Count > 12,000 or < 4,000 or > 10% bands
- 16. Angus DC. NEJM. 2013;369(9):840-851
- 17. • Multiple Organ Dysfunction Syndrome – Acute reversible physiologic derangement of at least 1 organ system 0 20 40 60 80 100 0 1 2 3 4 5 6 Qureshi K. BJMP. 2008;1(2):7-12 # of Organ Systems Affected %Mortality Marshall J. Critical Care Medicine. 1995;10:1638-1652
- 18. • Altered Mental Status • Hyperglycemia • Lactic Acidosis • Hypoxemia • Acute Kidney Injury • Coagulopathy • Paralytic Ileus • Hyperbilirubinemia • Elevated troponin • Hypotension
- 19. Howell MD. Intensive Care Medicine. 2007;33:1892-1899
- 21. Brown T. Journal of Critical Care. 2015;30:71-77
- 22. Kumar A. Critical Care Medicine. 2006;34:1589-1596 7.6% increase in mortality PER HOUR Odds Ratio < 1 if antibiotics started within 1st hr
- 23. 5.3% increase in mortality EVERY HOUR Bai X. Critical Care. 2014;18:532
- 24. • No more “severe sepsis” • Sequential Organ Failure Assessment Score Singer M and Sepsis-3 Group. JAMA. 2016;315(8):801-810
- 25. Singer M and Sepsis-3 Group. JAMA. 2016;315(8):801-810 qSOFA RR ≥ 22/min GCS ≤ 13 SBP ≤ 100 mmHg
- 28. • Published in 2001 by Dr. Emanuel Rivers • Single academic tertiary hospital • EGDT vs Standard Care • Primary Outcome – In-hospital mortality • Secondary Outcome – 28-day and 60-day mortality Rivers E. NEJM. 2001;345(19):1368-1377
- 29. Rivers E. NEJM. 2001;345(19):1368-1377
- 30. Rivers E. NEJM. 2001;345(19):1368-1377
- 31. • Fluid difference • Transfusion difference • Vasopressor difference Outcome EGDT Usual Care ARR 95% CI p In-hospital Mortality 30.5% 46.5% 15.13% 3.62-26.64% 0.015 28-day Mortality 33.3% 49.2% 15.1% 3.33-26.3% 0.017 60-day Mortality 44.3% 56.9% 14.2% 2.1-25.6% 0.029 Rivers E. NEJM. 2001;345(19):1368-1377
- 32. Levy MM. Critical Care Medicine. 2015;43(1):3-12
- 33. Ani C. Critical Care Medicine. 2015;43(1):65-77
- 34. Since 2001, Early Goal Directed Therapy has become the … Standard Of Care for sepsis managemen
- 35. The Sepsis Trilogy TRISS Trial SEPSISPAM Trial
- 37. • 1351 patients across 31 academic US hospitals • 2 Intervention Groups – EGDT protocol – Protocol-based standard therapy • Control Group – Usual care • Primary Outcome – 60-day mortality • Results – No difference in mortality between all groups The Process Investigators. NEJM. 2014;370:1683-1693
- 38. STRIKE ONE!!!
- 39. • 1600 patients across 51 international hospitals • Intervention Group – EGDT protocol • Control Group – Usual resuscitation care • Primary Outcome – 90-day mortality • Results – No difference in mortality The ARISE Investigators. NEJM. 2014;371:1496-1506
- 40. STRIKE TWO!!!
- 41. • 1260 patients across 56 UK hospitals • Intervention group – EGDT protocol • Control group – Usual care • Primary Outcome – All-cause 90-day mortality • Results – No difference in mortality The ProMISe Investigators. NEJM. 2015;371:1496-1506
- 42. EGDT IS OUT
- 43. Comparison of EGDT Studies EGDT (Rivers) ProCESS ARISE ProMISe Location US US Australasia UK Patient # 263 1351 1600 1260 SEPSIS DEFINITION Suspected/Actual Infection Yes Yes Yes Yes ≥ 2 SIRS Criteria Yes Yes Yes Yes SBP < 90 or lactate > 4 Yes Yes Yes Yes PROTOCOL Fluid before randomization 20-30 mL/kg ~20-30 mL/kg 1000 mL 1000 mL Intervention EGDT 6 hours EGDT 6 hours EGDT 6 hours EGDT 6 hours Control Usual therapy 1) Protocol usual support 2) Usual therapy Usual therapy Usual therapy Primary Outcome In-hospital mortality 60-day mortality 90-day mortality 90-day mortality PRIMARY OUTCOME Intervention 30.5% 21% 18.6% 29.5% Control 46.5% 1) 18.2% 2) 18.9% 18.8% 29.2%
- 44. • 998 patients across 32 Scandinavian ICUs • Treatment – Transfusion threshold ≤ 7mg/dL • Control – Transfusion threshold ≤ 9mg/dL • Primary Outcome – 90-day mortality • Results – No difference in mortality Holst LB. NEJM. 2014;371:1381-1391
- 45. • 776 patients across 29 French hospitals • Treatment Group – Target MAP 80-85 • Control Group – Target MAP 65-70 • Primary Outcome – 28-day mortality • Results – No difference in mortality Asfer P. NEJM. 2014;370:1583-1593
- 48. • Vigilant early identification of sepsis • Baseline lactic acid • Antibiotics within 1st hour of hypotension • Identify infectious source (cultures, imaging) Keegan J. Emerg Med Clin N Am. 2014;32:759-776 Marik P. CHEST. 2014;145(6):1407-1418
- 50. • 20-30 cc/kg initial crystalloid bolus • 500cc bolus thereafter Keegan J. Emerg Med Clin N Am. 2014;32:759-776 Marik P. CHEST. 2014;145(6):1407-1418 Raghunathan K. Critical Care Medicine. 2014;42:1585-1591
- 51. Norepinephrine for MAP 65-80 mmHg Keegan J. Emerg Med Clin N Am. 2014;32:759-776 Marik P. CHEST. 2014;145(6):1407-1418 Raghunathan K. Critical Care Medicine. 2014;42:1585-1591
- 52. Dobutamine for lactate clearance or CI > 2.5 L/min/m2 Keegan J. Emerg Med Clin N Am. 2014;32:759-776 Marik P. CHEST. 2014;145(6):1407-1418 Raghunathan K. Critical Care Medicine. 2014;42:1585-1591
- 53. • Hydrocortisone 200mg if refractory hypotension after norepinephrine • Transfusion only if Hgb < 7.0 mg/dL • Transfer to ICU Keegan J. Emerg Med Clin N Am. 2014;32:759-776 Marik P. CHEST. 2014;145(6):1407-1418 Raghunathan K. Critical Care Medicine. 2014;42:1585-1591
- 54. Sepsis Septic Shock Performed by hour 3 1)Initial lactate level 2)Blood cultures 3) Broad spectrum antibiotics Performed by hour 6 1) Repeat lactate if initial lactate > 2 mmol 1) Resuscitation with 30cc/kg crystalloid 2) Vasopressors if hypotension is refractory to fluids or initial lactate ≥ 4 mmol: a) Repeat volume status and tissue perfusion assessment consisting of: a) Focused physical exam b) Any 2 of the following: i. CVP ii. ScVO2 iii. CV US iv. Passive leg raise or fluid challenge
- 57. S E P T I C end Lactic Acid arly Antibiotics ressors ransfer nfusions ultures
- 59. w w w . p a i n e p o d c a s t . c o m
Editor's Notes
- https://www.advisory.com/daily-briefing/2016/06/30/ten-most-costly-conditions-for-hospitals?wt.mc_id=email%7Cdailybriefing+headline%7Cdba%7Cdb%7C2016jun30%7Cfinaldb2016jun30%7C%7C%7C%7C#.V3VZzuXGT4M.facebook
- Hospitalization rates for septicemia or sepsis more than doubled from 2000 through 2008 2% of all diagnoses in 2008 Hospitalizations for septicemia or sepsis (as a first-listed or principal diagnosis) increased from 326,000 in 2000 to 727,000 in 2008, and the rate of these hospitalizations more than doubled from 11.6 per 10,000 population in 2000 to 24.0 per 10,000 population in 2008 (Figure 1). Overall hospitalizations did not increase during this period (10,11). Hospitalizations with septicemia or sepsis—as the first-listed, principal, or a secondary diagnosis—increased from 621,000 in 2000 to 1,141,000 in 2008, and the rate of these hospitalizations increased by 70% from 22.1 per 10,000 in 2000 to 37.7 per 10,000 in 2008 (Figure 1). This rate includes patients (a) hospitalized for septicemia or sepsis, (b) hospitalized for another diagnosis but who had septicemia or sepsis at the time they were admitted, and (c) who acquired septicemia or sepsis during their hospital stay.
- Hospitalization rates for sepsis or septicemia were similar for males and females and increased with age. The rate of hospitalizations for septicemia or sepsis was much higher for those aged 65 and over (122.2 per 10,000 population) than for those under age 65 (9.5 per 10,000 population). About two-thirds of patients hospitalized for septicemia or sepsis in 2008 were aged 65 and over and had Medicare as their expected source of payment (data not shown). This proportion has been stable over the past decade. The septicemia or sepsis hospitalization rate for those aged 85 and over (271.2 per 10,000 population) was about 30 times the rate for those under age 65, and was more than four times higher than the rate of 65.7 per 10,000 for the 65–74 age group (Figure 2).
- Patients hospitalized for septicemia or sepsis were more severely ill than patients hospitalized for another diagnosis. For patients under age 65, those hospitalized for septicemia or sepsis were more than twice as likely to have seven or more diagnoses than those hospitalized for other conditions (Figure 3). For those aged 65 and over, those hospitalized for septicemia or sepsis were 26% more likely to have seven or more diagnoses than those hospitalized for other conditions.
- Patients hospitalized for septicemia or sepsis stayed longer than other inpatients. Those hospitalized for septicemia or sepsis had an average length of stay that was 75% longer than those hospitalized for other conditions (Figure 4). Those under age 65 hospitalized for septicemia or sepsis had an average length of stay that was more than double that of other hospitalizations. Those aged 65 and over hospitalized for septicemia or sepsis had an average length of stay that was 43% higher than that of other patients.
- Patients hospitalized for septicemia or sepsis were more than eight times as likely to die during their hospitalization. Only 2% of hospitalizations in 2008 were for septicemia or sepsis, yet they made up 17% of in-hospital deaths (data not shown). In-hospital deaths were more than eight times as likely among patients hospitalized for septicemia or sepsis (17%) compared with other diagnoses (2%). In addition, those hospitalized for septicemia or sepsis were one-half as likely to be discharged home, twice as likely to be transferred to another short-term care facility, and three times as likely to be discharged to long-term care institutions, as those with other diagnoses (Table). For those under age 65, 13% of those hospitalized for septicemia or sepsis died in the hospital, compared with 1% of those hospitalized for other conditions (data not shown). For those aged 65 and over, 20% of septicemia or sepsis hospitalizations ended in death compared with 3% for other hospitalizations (data not shown).
- 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.
- The body’s protective mechanism to an insult actually causes harm
- 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), plus impaired fibrinolysis 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.
- Mortality linearly increases with severity Neurologic, Pulmonary, Renal, Hematologic, Cardiac, Gastrointestinal
- Hyperglycemia = > 120 without history of DM Coagulopathy = INR > 1.5, PTT > 60, Pl < 100k Lactic Acidosis = > 2 Hypoxemia = P/F < 300 Bilirubin > 4 AKI = increase Cr > 0.5md/dL or oliguria SBP < 90, MAP < 60, > 40 drop
- Severe sepsis = Lactic Acidosis, SBP <90 or SBP Drop ≥ 40 mm Hg of normal
- HOW GOOD ARE WE AT DIAGNOSING SEPSIS? Main difference in 1991 and 2001 definition is the addition of of organ dysfunction in the sepsis diagnosis Problem either the definitions are too sensitive (high false positive) or physicians are under-diagnosing sepsis Why symptoms attributed to other conditions, , low index of suspicion, atypical presentation, sub-clinical presentation We do a good job identifying the severe cases and septic shock
- 7.6% decrease in surivival/hour for the 1st 6hrs until antibiotics are given
- https://www.youtube.com/watch?v=1S8l5D2xr6w
- Inclusion – 2 SIRS criteria AND SBP<90 after 20-30mL/kg crystalloid bolus or lactate > 4 Control – standard of care and admission to ICU as soon as possible Treatment – EGDT for 6hr in ED
- CVP – 500cc fluid every 30min until CVP 8-12 If CVP adequate and MAP<65 vasopressors (epi, norepi, dopamine, phenylephrine If CVP adequate and MAP > 90 vasodilators If CVP and MAP adeauet and ScVO2 < 70% PRBC to a Hct of 30% add dobutamine if Hct > 30% and ScVO2 < 70%
- More fluids in 1st 6hr in EGDT but no difference in total fluid at 72hr More transfusions in EGDT Early inotropic use higher in EGDT Vasopressor use higher in standard care
- 2014 SSC Data Compliance with SSC bundles and guidelines and the associated decrease in mortality
- PBST relaxed protocolised care Strengths Well designed, pragmatic method Methods and statistical analysis defined and published a priori. Recruited adequate numbers as planned for 80% power to detect 6–7% mortality reduction with alpha 0.05. Weaknesses Changed inclusion criteria during trial (reduced fluid bolus required before meeting "refractory hypotension" criteria), but mean volume used was within Rivers' original definition of 20–30 ml/kg. Mortality ~20% but initial power calculation based on 30–46%, therefore interim adjustment made and recruitment target reduced. Adherence to protocol was 88.1% in EGDT group and 95.6% in protocol-based standard therapy group. Although pragmatic, this is not perfect and may reduce between group differences.
- URC may place CVL or a-line, but NO ScVO2 measurement Strengths Clinical relevance and high impact Large multi-centre study Use of original EGDT algorithm in the intervention group A pragmatic study which allowed clinician discretion in managing the 'usual care' group and also not limiting involvement of some centres because of resource limitations Information supplied regarding timing of first dose antibiotics. A sensible inclusion criteria of antimicrobials being started before enrolment addressed the potential confounding effect of late administration Subgroup analyses for variation in mortality between countries Statistical analysis plan published before recruitment was completed eliminates the risk of analytical bias Weaknesses Lower APACHE scores than ProCESS and Rivers study but this has been addressed with a subgroup analysis of those with APACHE II scores of < 25 and > 25. There was still no difference in mortality between EGDT and usual-care in the sicker group although the total numbers were small in > 25 group (n=69) Low recruitment rate per month across all centres. The largest recruiting centre (Austin Health) recruited at a mean rate of just over 2 patients per month. However, adherence with EGDT protocol was high and management of sepsis well established in usual care practice. This low rate reflects the complexities of conducting research studies. Multi-centre involvement is essential both for ensuring generalisability and appropriately powered trials
- Strengths Robust methodological approach. Consistent inclusion criteria and protocol with ARISE study Important outcome measures Cost analysis and quality-adjusted life years an important outcome measure Study population representative of critically ill patients with septic shock (mean APACHE II score 18. ARISE was 15) Trial statistical analysis plan was published prior to completion of the study Adherence to EGDT ranged from 86-95% Weaknesses Only 1/3 of eligible patients were recruited. The authors acknowledge this and provide an explanation. As in all studies that enroll patients presenting to ED, recruitment is more challenging on weekends and during out of office hours Non blinded
- Transfusion Requirements in Septic Shock EGDT had transfusion to a Hgb>10 Inclusion Criteria septic shock with Hgb<9 Strengths Randomised Blinding of investigators assessing primary outcome Multi-centre Weaknesses Non-blinding of staff - however this would be unrealistic to achieve Protocol violations mean that the study is less likely to detect a difference if there really is one. However, there was still a difference of 1.5g/dl between the daily lowest Hb levels in the intervention and the control groups. The authors also performed a per-protocol analysis which found no difference in the primary outcome.
- Sepsis and Mean Arterial Pressure (SEPSISPAM) trial Inclusion criteria refractory hypotension after 30 mL/kg fluid resuscitation Strengths Randomised Blinding of research staff Standard protocol for use of renal replacement therapy No significant difference in fluid intake between intervention and control group Clearly defined thresholds for renal replacement therapy Weaknesses Due to a lower mortality than predicted the study was under powered Frequent use of steroids and activated protein C may limit generalisability Achieved MAP was higher than target MAP, although this is common practice in many ICUs Less than 15 patients recruited per centre per year. For a common condition this is surprisingly low and may limit the external validity of the trial. The authors report 16.5% of patients in the high MAP group vs. 10.3% (P=0.01) in the low MAP group failed to achieve target BP because the attending clinician decided to limit the vasopressor infusion. Whilst this is an ethically important safety factor, this compliance bias will favour the null hypothesis.
- Vigilant early identification of sepsis Lactic Acid Drawn before resuscitation begins Antibiotics Within 1st hour of hypotension Infectious source Obtain cultures Imaging
- Preload optimization with crystalloid Retrospective cohort study in 2014 balanced solution improved in-hospital mortality
- Afterload optimization
- Inotropic optimization