The Treatment of Sepsis: Early Goal Directed Therapy and Beyond
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Transcript of The Treatment of Sepsis: Early Goal Directed Therapy and Beyond
The Treatment of Sepsis:Early Goal Directed Therapy
and BeyondAnthony J. Hericks, D.O.
South DakotaACP
Scientific MeetingSeptember 13th, 2013
A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis: hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004; 320(Suppl):S595-S597
Surviving Sepsis CampaignSponsoring Organizations
American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians Australian and New Zealand Intensive Care Society Asia Pacific Association of Critical Care Medicine American Thoracic Society Brazilian Society of Critical Care(AIMB) Canadian Critical Care Society Emirates Intensive Care SocietyEuropean Respiratory Society European Society of Clinical Microbiology and Infectious DiseasesEuropean Society of Intensive Care Medicine European Society of Pediatric and Neonatal Intensive Care
Infectious Diseases Society of America Indian Society of Critical Care Medicine Japanese Association for Acute Medicine Japanese Society of Intensive Care Medicine Latin American Sepsis Institute Pan Arab Critical Care Medicine Society Pediatric Acute Lung Injury and Sepsis Investigators Society for Academic Emergency MedicineSociety of Critical Care Medicine Society of Hospital Medicine Surgical Infection Society World Federation of Critical Care Nurses World Federation of Societies of Intensive and Critical Care MedicineGerman Sepsis Society
Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe
Sepsis and Septic ShockDellinger RP, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32:858-873.Dellinger RP, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 Crit Care Med 2008, 36:296-327. Levy MM, et al. Surviving Sepsis Campaign: Results of an international guidelines performance improvement program targeting severe sepsis. Crit Care Med 2010, 38:367-374.Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013, 41(2):580-637.Angus DC, et al. Severe Sepsis and Septic Shock. NEJM 2013; 369(9): 840-851
Surviving Sepsis Campaign Conclusions
Strong agreement among a large cohort of international expertsMany level 1 recommendationsSignificant number of recommendations with relatively weak recommendationsEvidence-based recommendations are the foundation of improved outcomes
Dellinger RP, CCM 2013
Grading of Recommendations(Grading of Recommendations Assessment, Develop and Evaluation – GRADE)
A 82 year old white female present to the emergency department with complaints of dysuria, frequency and
urgency. Her temperature is 100.4 F, HR 92, RR 21 and BP 122/86. What should she be classified as?
1. Systemic Inflammatory Response Syndrome
2. Sepsis 3. Severe Sepsis4. Septic Shock 5. Multi-Organ
Dysfunction/Failure Syndrome
A 82 year old white female present to the emergency department with complaints of dysuria, frequency and
urgency. Her temperature is 100.4 F, HR 92, RR 21 and BP 122/86. What should she be classified as?
1. Systemic Inflammatory Response Syndrome
2. Sepsis 3. Severe Sepsis4. Septic Shock 5. Multi-Organ
Dysfunction/Failure Syndrome
Identification of Sepsis: Definitions
Systemic Inflammatory Response (SIRS)SepsisSevere SepsisSeptic ShockMulti-Organ Failure Syndrome (MOFS)Death
SIRS
Heart Rate > 90Respiratory Rate > 20WBC > 12K or < 4KTemp > 38 C (100.4 F) or < 36 C (96.8 F)
Any two of the aboveVery nonspecific
Sepsis
SIRS + signs of a suspected or known infection– WBC’s in normally sterile fluid– Infiltrate on chest x-ray– Bacteria in normally sterile fluid
Diagnostic
Criteria for
Sepsis
Severe SepsisSepsis + sepsis-induced tissue hypoperfusion or organ dysfunction
Sepsis Induced Hypotension
SBP < 90 mmHgOR
MAP < 70 mmHgOR
SBP > 40 mmHg < 2 SD below the nml for age
Septic Shock
Severe Sepsis or sepsis-induced hypoperfusion persistent despite:– Adequate/initial fluid challenge/resuscitation– Lactate > 4 mmol– Addition of pressors
Sepsis-induced hypoperfusion = infection-induced hypotension, elevated lactate or oliguria
MOFS
Altered organ function, involving two or more organs, in an acutely ill patient requiring medical intervention to achieve homeostasis
Death
The permanent the cessation of all vital functions in an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem
Severe Sepsis/Septic Shock mortality = ~30-46%
Consideration for Limitation of Support
“We recommend that the goals of care and prognosis be discussed with patients and families and these be incorporated into the patients treatment along with end-of-life care planning and utilizing palliative care principles.”– Re-address goals as earlier as feasible, but
no later than 72 hours of admit
Grade 1B
Grade 2C
Incidence of Severe Sepsis
Estimated to be:– 2% of all patients admitted to the hospital– 10% of all patients in the ICU– < 750,000 cases per year and rising– Mortality rate of 20-30%
NEJM 369(9): 840-851
Pathophysiology of Sepsis
Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955.
Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours?
1. CVP of 8-12 unventilated/12-15 ventilated
2. MAP >65 3. Cardiac Output > 8 LPM4. Hemoglobin > 10 gm/dL 5. ScvO2 > 70%
Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours?
1. CVP of 8-12 unventilated/12-15 ventilated
2. MAP >65 3. Cardiac Output > 8 LPM4. Hemoglobin > 10 gm/dL 5. ScvO2 > 70%
Initial Resuscitation:Goals of Early Goal Directed Therapy
CVP 8-12 cmH2O– 12-15 cmH2O on the ventilator
MAP > 65 mmHg– May need to be higher in patients with HTN
UOP > 0.5 mL/Kg /hourScvO2 > 70%– SvO2 > 65%
Goal: Normalize lactate
Goal in the first 6 hours after diagnosis 16-17% decrease in mortality
Rivers E. N Engl J Med 2001; 345:1368-77
Grade 1C
Grade 2C
Central Venous Pressure
Crystalloid or Colloid?
Volume?
Goal?
Crystalloid or ColloidSAFE Study– Crystalloid (NS) = Colloid
(4% Albumin)Less volume, more PRBC’s, higher CVP and Albumin
– No difference in mortality (p = 0.87)
Trend for increased risk of death in Trauma (0.06)Trend for decreased risk of death in Severe Sepsis (0.09)
Finfer S. N Engl J Med 2004; 350:2247–2256Grade 1B
SSC Recommendations
Crystalloids
Albumin– If substantial fluid is required
Grade 1B
Grade 2C
Hydroxyethyl Starch (HES)
Increased risk of acute kidney injury and death in sepsis– Variable findings depending on studies
Schortgen G. Lancet 2001; 357:911-916.Sakr Y. Br J Anaesth 2007; 98:216-224.Brunkhorst FM. N Engl J Med 2008; 358: 125-139.Perner A. N Engl J Med 2012; 367:124-134.
Risk and no benefit, HES should not be used!!!
Grade 1B
Fluid Volume
30 mL/Kg crystalloid – A portion may be an albumin equivalent– More rapid administration or larger amounts
may be needed
Continue fluid administration as long as there appears to be hemodynamic improvement
Grade 1C
Grade UG
Volume ResponsivenessCVP > 8 cmH2O– > 12 cmH2O on the vent
Swan-Ganz Catheter– PCWP– Cardiac output
Non-invasive Monitors– PiCCO Catheter– FloTrac– Pulse Pressure Variation
IVC via EchoMAP and Heart Rate
Grade 1D
Grade 1C
CVP
Spontaneous Breathing > 8 cmH2O
Ventilatory Breathing > 12 cmH2O
Primarily based on expert opinion– Dellinger RP. Crit Care Med 2004; 32:858–873– Rivers E. N Engl J Med 2001; 345:1368–1377– Practice parameters for hemodynamic support of
sepsis in adult patients with sepsis. Crit Care Med 1999; 27:639–660
Pulmonary Capillary Wedge Pressure
PCWP < 12 mmHg predicts a fluid bolus with increase cardiac output with a PPV of only 54%
However the “Gold Standard” for “volume responsiveness” may be a increase in cardiac output of > 15% after a fluid challenge
Osman D. Crit Care Med 2007; 35:64–68
Non-invasive Monitoring
PPV
CVP
PCWP
PPV PPV
Echocardiography
Does volume overload contribute to morbidity and mortality?
1. True2. False
Does volume overload contribute to morbidity and mortality?
1. True2. False
Avoid Volume Overload
Tolerated as long as volume responsive– Fluid challenges usually required for the initial
24-48 hoursFinfer S. N Engl J Med 2004; 350:2247–2256
Decrease the rate when no longer volume responsive
Grade 1D
Volume Overload, Cont’dIndependent predictor of mortality – Boyd JH. Crit Care Med 2011; 39(2):259-265– Vincent JL. Crit Care Med 2006; 34:344–353– Uchino S. Crit Care Med 2006; 10:R174
Prolonged mechanical ventilation – Upadya A. Intensive Care Med 2005; 31:1643–1647
ARDS – Humphrey H. Chest 1990; 97:1176–1180– Simmons RS. Am Rev Respir Dis 1987; 135:924–929– Mitchell JP. Am Rev Respir Dis 1992; 145:990–998– Wiedemann HP. N Engl J Med 2006; 354:2564–2575
Sepsis – Alsous F. Chest 2000; 117:1749–1754– Rivers E. N Engl J Med 2001; 345:1368–1377
Abdominal compartment syndrome– Malbrain ML. Crit Care Med 2005; 33:315–322– McNelis J. Arch Surg 2002;137:133–136
Cerebral edema and herniation– Uchino S. Crit Care 2006; 10:R174
MAPMAP
Urinary output (mL) 49 +18 56 +21 43 +13 .60/.71
Capillary blood flow (mL/min/100 g) 6.0 +1.6 5.8 +11 5.3 +0.9 .59/.55
Red Cell Velocity (au) 0.42 +0.06 0.44 +016 0.42 +0.06 .74/.97
Pico2 (mm Hg) 41 +2 47 +2 46 +2 .11/.12
Pa-Pico2 (mm Hg) 13 +3 17 +3 16 +3 .27/.40
75 mm Hg65 mm Hg 85 mm Hg F/LT
Adapted from Table 4, page 2731, with permission from LeDoux, Astiz ME, Carpati CM, Rackow ED. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med2000; 28:2729-2732
Grade 1C
What is the pressor of choice for a patient in septic shock?
1. Dopamine2. Norepinephrine
(Levophed) 3. Vasopressin4. Phenylephrine
(Neosynephrine)5. All the above
What is the pressor of choice for a patient in septic shock?
1. Dopamine2. Norepinephrine
(Levophed) 3. Vasopressin4. Phenylephrine
(Neosynephrine)5. All the above
VasopressorsNorepinephrine
Dopamine
Vasopressin
Epinephrine
Phenylephrine
Norepinephrine vs Dopamine
No significant difference in mortality (p = 0.10)– Trend for less death in the ICU (p = 0.07)– No difference at hospital discharge or 1 yr
Increased rate of adverse events with Dopamine– Arrhythmias (p = < 0.001)
Atrial FibrillationVentricular TachycardiaVentricular Fibrillation
– Skin Ischemia (trend; p = 0.09)
DeBacker D. N Engl J Med 2010; 362:779-789
Norepinephrine vs Dopamine,Cont’d
Norepinephrine should be the first line vasopressor
Dopamine is an alternative to Norepinephrine – Only in highly selected patients with low risk
of:TachyarrhythmiasAbsolute or relative bradycardia
Grade 1B
Grade 2C
Vasopressin
Adding Vasopressin to Norepinephrine showed no mortality benefit compared to Norepinephrine alone (p = 0.26)– Did lower Norepinephrine requirements– May have other potential physiologic benefits
Should not be used as a single agent
Russel JA. N Engl J Med 2008; 358:877-887Grade UG
Epinephrine
First line in pts poorly responsive to Norepinephrine and Dopamine– No evidence of worse outcomes
Increased risk of:– Tachycardia– Elevated lactate– Decreased splanchnic circulation
Add to or instead of Norepinephrine
Grade 2B
Phenylephrine
Not recommended!!!– Except:
Norepinephrine induced arrhythmiasCardiac output is highPersistently low BPSalvage therapy
Decreases cardiac output
Grade 1C
Hemodynamic Equations
DaO2 = CO x Hgb x SaO2 – Oxygen delivery
VO2 = CO x Hgb x (SaO2 - SvO2)– Oxygen consumption
O2 ER= VO2/DaO2 – Oxygen extraction ratio
~ 0.2 to 0.3VO2 > DaO2 OR DaO2 < VO2 = Dysoxia
– Dysoxia = lactic acidosis = organ failure = death
Venous Oxygen Saturation
Physiology
Adapted from:http://ht.edwards.com/resourcegallery/products/swanganz/pdfs/svo2edbook.pdf
ScvO2/SvO2 Goal
> 70%/65% respectively– Normal or shunt physiology
< 70%/65% respectively– Transfuse to a Hgb > 10
OR– Start Dobutamine
No specific cardiac output/index
Grade 1C ScvO2 = subclavian veinSvO2 = pulmonary artery
Ionotropic Therapy
Dobutamine: – Max dose 20 mcg/Kg/min
Titrate to NO pre-defined CO
– Used in states with:Elevated cardiac filling pressuresLow cardiac outputScvO2 < 70% OR SvO2 < 65%
Grade 1B
Grade 1C
RBC Transfusion Therapy
Only if the Hgb < 10 with EGDTOnly if the Hgb < 7.0 g/dL in other ICU patients – Target 7 to 9 g/dL– Consider earlier for myocardial
ischemia/ischemic coronary disease, severe hypoxemia, acute hemorrhage, cyanotic heart disease or lactic acidosis
No EPO
Grade 1B
Napolitano LM. Crit Care Med 2009; 37(12): 3124-3157
Grade 1B
FFP Transfusion Therapy
No FFP to reverse coagulopathy in the absence of bleeding or invasive procedures
No high-dose Antithrombin– Studies had revealed that a subgroup with
severe sepsis and high risk of death = better survival
Grade 2D
Grade 1B
Platelet Transfusion Therapy
< 10,000 – prophylactically in absence of bleeding
< 20,000 - significant risk of bleeding
> 50,000 – active bleeding, surgery or invasive procedures
Grade 2D
Other Investigation Therapy
Immunoglobulins– No use
Selenium – Antioxidant– No use
Grade 2B
Grade 2C
Diagnostic TestingLactate level– Within 3 hours
Cultures– Prior to antibiotic administration
Do not delay resuscitation for antibiotic administration> 50% of cases of severe sepsis and septic shock will be culture negative
– Minimum 2 blood culturesOne peripheral and one from each vascular access device
Imaging– If not too unstable
Grade 1C
Grade 1D
Diagnostic Testing, Cont’d
Serologies:– Strep pneumo and Legionella Urine Ag– Mycoplasma IgM– 1,3 B-D-glucan– Mannan and anti-mannan Ab’s
Procalcitonin– Use low levels to assist with Abx D/C
Grade 2B
Grade 2C
Antibiotic Therapy
IV route within the 1st hour– Septic Shock– Severe Sepsis
One or more drugs with activity against the likely pathogens– Double cover if MDR pathogens– Combo therapy for neutropenic fever– Beta-lactam and macrolide for Strep pneumonia
Grade 1B
Grade 1C
Grade 1B
Grade 2B
Grade 2B
Grade 2B
ABX, Cont’d
Reassess routinely
De-escalate after >3-5 days
Duration of treatment ~7-10 days
Stop therapy if the syndrome is not infectious
Grade 1B
Grade 2B
Grade 2C
Grade 1D
Source ControlSeek, diagnose or exclude potential anatomical infections and treat expectantly– Within the first 12 hrs
Delay definitive treatment of peripancreatic necrosis until demarcation of tissue has occurred
Attempt percutaneous over surgical intervention if possible
Remove vascular access suspected after other access has been placed
Grade 1C
Grade 2B
Grade UG
Grade UG
Corticosteroids
Hydrocortisone – 200 mg/day– Only with persistent hypotension/poorly
responsive to vasopressor therapy– Consider a continuous infusion– Do not do an ACTH stimulation test
No DexamethasoneFludrocortisone if other steroid than HCTWean steroids when off pressors
Grade 2B
Grade 2C
Grade 2B
Grade 2C
Grade 2D
Grade 2D
Corticosteroids, Cont’d
Annane D. JAMA 2002; 288:862–871– Cosyntropin Stim Test delta < 9 = non-responders– 10% decrease in mortality if treated with steroids– 17% decrease in pressor requirements
Sprung CL. N Engl J Med 2008; 358:111-124– No significant difference in mortality – Shock was reversed more quickly – More episodes of superinfection, including new sepsis
and septic shock but not statistically significant
CIRCI(Critical Illness Related Corticosteroid Insufficiency)
Marik PE. Crit Care Med 2008 Vol. 36 (6): 1937-1949
CIRCI, Cont’d
Recombinant Human Activated Protein C(Xigris)
Withdrawn from the market 2011– No benefit
Mechanical Ventilation
Target tidal volume = 6 mL/KgPlateau pressure goal < 30 cmH2OAllow permissive hypercapniaUse PEEP to decrease FiO2
– Higher PEEP vs lowerRecruitment maneuvers
Grade 1A
Grade 1C
Grade 1B
Grade 1B
Grade 2C
Grade 2C
ARDS
ARMA Trial– The Acute Respiratory Distress Syndrome
Network. N Engl J Med 2000;342:1301-08.Alveoli Trial– Brower RG. N Engl J Med 2004;351:327-36
Mechanical Ventilation, Cont’d
Consider prone positioning– P:F ration <100
HOB elevated– Goal > 30-45
NIPPV considered in mild ALI/ARDS– Low threshold for intubation
Grade 1B
Grade 1B
Grade 2B
Grade 2C
Mechanical Ventilation, Cont’d
Weaning protocolsSelective Oral/Digestive Decontamination– Oral chlorhexidine gluconate– Decreases VAP
Avoid pulmonary artery cathetersConservative fluid management (FACTT)– Wiedemann et al. N Engl J Med 2006;
354:2564-2575.
Grade 1A
Grade 1A
Grade 1C
Grade 2B
Beta-Agonists
No recommended for routine use – Nebulized (Ok if concern for bronchospasm)
Trend for less vent daysSlightly faster heart rates at day #2Trend for increased mortality
– Intravenous (Salbutamol)Increased mortality
Grade 1B
Sedation, Analgesia and NMB
Use Sedation protocol– Minimize intermittent and continuous
treatmentsUse Sedation scales
Avoid NMB – Without ARDS– With ARDS (Sepsis-induced and P:F <150)
< 48 hours
Grade 1B
Grade 1B
Grade 1C
Grade 2C
Glucose Control
Use intravenous insulin to control blood sugars– If 2 consecutive BS’s > 180
Goal < 180– ? Target range 110-180 mg/dL
Avoid hypoglycemia
Grade 1B
Grade ? 1A
Grade 2C
Renal Replacement Therapy
CRRT and Intermittent HD are equivalents
CRRT should be used if hemodynamically unstable
Grade 2B
Grade 2D
Bicarbonate Therapy
Avoid NaHCO3 in patients with a pH > 7.15 and lactic acidemia for the purpose of improving hemodynamics or to reduce vasopressor requirementsGrade 2B
Thromboembolism Prophylaxis
LMWH daily vs Low dose UFH BID LMWH daily vs Low dose UFH TIDDalteparin if creat clearance < 30 mL/min– LMWH or UFH
Mechanical prophylaxis if contraindications to heparin products Combo therapy in patients who are high risk– Severe sepsis, history of DVT, or orthopedic surgery
Grade 1B
Grade 2C
Grade 2C
Grade 2C
Grade 1AGrade 2C Grade 1A
Stress Ulcer Prophylaxis
If risk of bleeding– H2 blocker
– Proton Pump Inhibitor
– PPI over H2
No risk of bleeding = no PPI
Grade 1B
Grade 1B
Grade 2C
Grade 2B
Nutrition
Oral or enteral nutrition in the 1st 48 hrs vs complete fasting or just glucoseAvoid full caloric feeding for the 1st full week– Low dose feeding up to 500 Kcal/day and
advance as tolerated (60-70%)IV glucose and EN vs TPN alone or TPN and EN in the 1st weekNo specific immunomodulating form
Grade 2C
Grade 2B
Grade 2B
Grade 2C
Surviving Sepsis Bundles
Bundles
Point/Counterpoint Editorials– Are the best patient outcomes achieved when
ICU bundles are rigorously adhered to?Pros: Dr. Delinger
– Not perfect/have flaws, but are based on the best available evidence.
Cons: Dr. Marik– Not completely “evidence based” and “cook book”
medicine can harm the patient.
CHEST 2013; 144(2):372-380
Is there byass/conflict of interest when it comes to the Surviving Sepsis Campaign Guidelines and Early Goal
Directed Therapy?
1. Yes2. No
Is there byass/conflict of interest when it comes to the Surviving Sepsis Campaign Guidelines and Early Goal
Directed Therapy?
1. Yes2. No
Benefits of theSurviving Sepsis Campaign
Surviving Sepsis Campaign Improvement Program– Resuscitation Bundle - First 6 hours
Compliance increase linearly from 10.9% to 31.3% over two years ( p = 0.0001)
– Management Bundle - First 24 hoursCompliance increase linearly from 18.4% to 36.1% over two years ( p = 0.008)
– Unadjusted odds ratio for hospital mortality decreased from 37% to 30.8% over two years (p = 0.001)
THE END
?? QUESTIONS ??