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 ??