• Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis

• “A little less conversation, a little more action please”

Infection• Infection is characterized by an

inflammatory response to microorganisms, or the invasion of normally sterile host tissue by those organisms

Bacteremia 

• Bacteremia is defined as the presence of viable bacteria in the blood.

Systemic inflammatory response syndrome (SIRS) 

SIRS refers to the consequences of a dysregulated host inflammatory response. It is clinically recognized by the presence of two or more of the following

• Temperature >38.5ºC or <35ºC • Heart rate >90 beats/min • Respiratory rate >20 breaths/min or PaCO2 <32 mmHg • WBC >12,000 cells/mm3, <4000 cells/mm3, or >10

percent immature (band) formsSIRS can result from a variety of conditions, such as

autoimmune disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery.

Sepsis 

• In sepsis, the clinical signs that define SIRS are present and are due to either a culture-proven infection or an infection identified by visual inspection .

Epidemiology

Martin, G. S., Mannino, D. M., Eaton, S., & Moss, M. (2003). The epidemiology of sepsis in the United States from 1979 through 2000. New England Journal of Medicine, 348(16), 1546–1554.

Harrison, D. A., Welch, C. A., & Eddleston, J. M. (2006). The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Critical Care, 10(2), R42.

Brun-Buisson, C., Meshaka, P., Pinton, P., Vallet, B., EPISEPSIS Study Group. (2004). EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Medicine, 30(4), 580–588.

[1993 - 2001]...a 17% reduction in mortality.

[1993-2001]...a 75% increase in... severe sepsis...

Incidenceof Sepsis

Mortalityof Sepsis

Population characteristics• The population at risk of developing sepsis is large. At any given

moment, approximately 50 percent of ICU patients have a nosocomial infection

Important risk factors include:• Bacteremia. Medical patients with bacteremia commonly have

hemodynamic consequences of infection including SIRS, sepsis, severe sepsis, or septic shock (95 percent)

• Advanced age (≥65 years).

• Impaired immune system function. Comorbidities that cause host-defense depression (neoplasms, renal or hepatic failure, AIDS) are common in septic patients.

• Community acquired pneumonia (CAP). Among patients with CAP, severe sepsis and septic shock will either develop or be present at admission in approximately 48 and 5 percent of patients, respectively

The most common manifestations of severe organ dysfunction were

• acute respiratory distress syndrome,

• acute renal failure,

• disseminated intravascular coagulation

Survival was reduced in patients with these complications

Prognostic effects of organ dysfunction in severe sepsis

Prevalence of hospital mortality associated with severe sepsis

CHARACTERISTICS THAT INFLUENCE OUTCOME

  Clinical characteristics that relate to the severity of sepsis include an

abnormal host response to infection

the site and type of infection

the timing and type of antimicrobial therapy

and the development of shock

• Initial management is aimed at securing the airway and correcting hypoxemia

• Intubation and mechanical ventilation may be required.

if Pseudomonas is an unlikely pathogen, we favor combining vancomycin with one of the following:

• Cephalosporin, 3rd or 4th generation (eg, ceftriaxone or cefotaxime), or

• Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or

• Carbapenem (eg, imipenem or meropenem).

Alternatively, if Pseudomonas is a possible pathogen, we combine vancomycin with two of the following

• Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or

• Antipseudomonal carbapenem (eg, imipenem, meropenem), or

• Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam,ticarcillin-clavulanate), or

• Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or

• Aminoglycoside (eg, gentamicin, amikacin), or • Monobactam (eg, aztreonam)

AntibioticsCultures / Antibiotics / Labs

Cultures PRIOR to Antibiotics ( 2 Sets, one peripheral and one from any line older than 48hrs)

IV Abx within 3 hrs in the ED, within 1 hr in the ICU Broad Spectrum, combination therapy for neutropenic and

patients with pseudomonas risk factorsVancomycin PLUS …….

Consider need for Source Control ! Drainage of abscess or cholangitis, removal of infected

catheters, debridement or amputation of osteomyelitis

• Once the patient's respiratory status has been stabilized, the adequacy of perfusion should be assessed.

• Hypotension is the most common indicator that perfusion is inadequate.

• However, critical hypoperfusion can also occur in the absence of hypotension, especially during early sepsis.

• Common signs of hypoperfusion include cool, vasoconstricted skin due to redirection of blood flow to core organs (although warm, flushed skin may be present in the early phases of sepsis), obtundation or restlessness, oliguria or anuria, and lactic acidosis.

Once it has been established that hypoperfusion exists, early restoration of perfusion is necessary to prevent or limit multiple organ dysfunction, as well as reduce mortality

• Tissue perfusion should be promptly restored using intravenous fluids, vasopressors, red blood cell transfusions, and inotropes

• We recommend patients be managed with therapy aimed at achieving a central (or mixed) venous oxygen saturation ≥70 percent within six hours of presentation

• It is reasonable to simultaneously aim for a central venous pressure 8 to 12 mmHg,

• mean arterial pressure (MAP) ≥65 mmHg, • urine output ≥0.5 mL per kg per hour.

• We recommend boluses of intravenous fluids as first-line therapy in patients who demonstrate impaired perfusion

• Fluid boluses are repeated until blood pressure and tissue perfusion are acceptable, pulmonary edema ensues, or there is no further response. These parameters should be assessed before and after each fluid bolus. There are no data to support preferential administration of crystalloid or colloid.

• We recommend vasopressors for patients who remain hypotensive following intravascular volume repletion (Grade 1B). Although there is no definitive evidence of the superiority of one vasopressor over another, we suggest beginning with norepinephrine (Grade 2C).

• For patients whose ScvO2 remains <70 percent after intravenous fluid and vasopressor therapy, it is reasonable to administer additional therapies, including blood transfusions or inotropic therapy.

• Prompt identification and treatment of the site of infection are essential. Sputum and urine should be collected for gram stain and culture. Intra-abdominal fluid collections should be percutaneously sampled. Blood should be taken from two distinct venipuncture sites and from indwelling vascular access devices and cultured aerobically and anaerobically.

• Antibiotics should be administered immediately after appropriate cultures have been obtained. We recommend empiric broad spectrum antibiotics when a definite source of infection can not be identified (Grade 1B).

• Potentially infected vascular access devices should be removed (if possible), abscesses should be drained, and extensive soft tissue infections should be debrided or amputated

• In patients with septic shock or severe sepsis with a high risk of death, defined as an APACHE II score >25, multiple organ dysfunction, or sepsis-induced acute respiratory distress syndrome, we suggest that recombinant human activated protein C be administered if contraindications do not exist (Grade 2B). Effort should be made to initiate the infusion within 24 hours from the first-sepsis induced organ dysfunction.

• Glucocorticoid therapy, nutritional support, and glucose control are additional issues that are important in the management of patients with severe sepsis or septic shock. Each is discussed in detail in separate topic reviews.

Comparison With Other Major Diseases

†National Center for Health Statistics, 2001. §American Cancer Society, 2001. *American Heart Association.

2000. ‡Angus DC et al. Crit Care Med. 2001;29(7):1303-1310;29(7):1303-1310.

AIDS* Colon BreastCancer§

CHF† Severe Sepsis‡

Cas

es/1

00,0

00

0

50

100

150

200

250

300

Incidence of Severe Sepsis Mortality of Severe Sepsis

0

50.000

100.000

150.000

200.000

250.000

De

ath

s/Y

ea

r

AIDS* SevereSepsis‡

AMI†Breast Cancer§

Emergency Department Critical Care Volume Increases

1. National Center for Health Statistics; 2001

2. Ann Emerg Med 2002;39:389-963. Curr Opin Crit Care Dec.2002

-10

10

30

50

70

Vis

its /

ED

(%

Ch

an

ge)

Visits/ED

Total visits/ED

Critical Care

Urgent

Nonurgent

P < 0.001 for all groups

• 102 million National ED visits in 1999•17% (17.5 million) “immediately life threatening”1

• 57 California Emergency Departments (1990-1999)2

• 50% (387,616) Severe Sepsis Cases Initially Present ED

6 Hour Resuscitation Bundle

• Early Identification• Early Antibiotics and

Cultures• Early Goal Directed

Therapy

6 - hour Severe Sepsis/Septic Shock Bundle

• Early Detection:– Obtain serum lactate

level.

• Early Blood Cx/Antibiotics:– within 3 hours of

presentation.

• Early EGDT: • Hypotension (SBP < 90,

MAP < 65) or lactate > 4 mmol/L:– initial fluid bolus 20-40 ml of

crystalloid (or colloid equivalent) per kg of body weight.

• Vasopressors:– Hypotension not responding to

fluid– Titrate to MAP > 65 mmHg.

• Septic shock or lactate > 4 mmol/L:– CVP and ScvO2 measured.– CVP maintained >8 mmHg.– MAP maintain > 65 mmHg.

• ScvO2<70%with CVP > 8 mmHg, MAP > 65 mmHg:– PRBCs if hematocrit < 30%. – Inotropes.

Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis

Thiel, S. W., Asghar, M. F., Micek, S. T., Reichley, R. M., Doherty, J. A., & Kollef, M. H. (2009). Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis*. Critical Care Medicine, 37(3), 819–824. doi:10.1097/CCM.0b013e318196206b

After

Before

Time from Entering ED to Transfer to

MICU

Reduced by 51%

Time from Entering ED to Catheter

Insertion

Reduced by 60%

Time from Entering ED to Receiving Antibiotics

Reduced by 42%

Rhode Island Hospital EGDT Data

24 - hour Severe Sepsis and Septic Shock Bundle

• Glucose control:– maintained on average <150 mg/dL (8.3 mmol/L)

• Drotrecogin alfa (activated):– administered in accordance with hospital guidelines

• Steroids:– for septic shock requiring continued use of

vasopressors for equal to or greater than 6 hours.• Lung protective strategy:

– Maintain plateau pressures < 30 cm H2O for mechanically ventilated patients

Fluid therapy

• Central Line Access (Fluid hydration +/- pressor)

• 1st line therapy – fluids, fluids, fluids!

• Crystalloid equivalent to colloid

• Initial 1-2 Liters (20mg /kg) crystalloid or 500 ml colloid

• Careful in CHF patients !!

Fluid Challenge

What is the difference between an infusion and a challenge?

250 to 500 ml colloid (or blood products)500 to 1000ml Hartmann’s [NOT 5% dextrose]As fast a possible (with pressure bag)You at the bedside

Pressors

• See separate lecture on vasopressors– Start with Levophed (norepinephrine) as first

line therapy +/- Vasopressin– Consider Dopamine peripherally on floor

• ** This is available in crash cart ** If not responding to fluids, don’t want for pharmacy to send levophed.

Corticosteroids

• Use in Septic Shock, if NO response to vasopressors and fluids– HYDROCORTISONE 200mg -300mg / day

Divided doses (Q6hrs)• Initial Dose 100mg IV x1• Consider for patients who received etomidate• No need for cosyntropin stim test• Wean Steroids QUICKLY once off pressors

Markers of perfusion

What are they?

• Clinical signs– Warm skin, conscious level, u/o

• Haemodynamic variables– CVP

• Bloods– Serum Lactate– ScvO2

CVP

What does it mean?

Starling’s Law

Estimate of LVEDV (i.e. preload)

Not always a good correlation with volume-responsiveness

However if low strongly suggestive of hypovolaemia

Lactate

What does it mean?

• Increased production (anaerobic glycolysis)– Tissue hypoperfusion– Tissue dysoxia

• Reduced metabolism– Hepatic– Renal

• <1 is normal, 1-2 is a concern, >2 is bad, >4 is very bad

ScvO2

What does it mean?

• Balance between oxygen delivery and consumption (VO2)

• Fick principle

• ScvO2 = SaO2 - VO2

CO

• Target > 70%

ScvO2

What can I do if it’s low?

Delivery = [Hb] x SpO2 x 1.34 x HR x SV

Fluid optimise

Transfuse packet cells

HCt > 30%

Inotropes

xSurviving Sepsis targets of fluid resuscitation

What are they?

• SBP > 90• MAP > 65• CVP 8 - 12• U/o > 0.5 ml/kg/hr • Lactate < 1• ScvO2 >70• HCt > 30

Further Management

What else can be done?

• Low tidal volume ventilation• Steroids in septic shock• Activated Protein C• Glycaemic control• Stress ulcer prophylaxis• Thromboprophylaxis• Sedation scoring / holds etc.

System-based Approaches to sepsis

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.

xSystem-based Approaches to sepsis

Early-Goal Directed TherapyINCLUSION = SEPSIS AND [BP < 90 after fluid OR Lactate > 4]

CVP 8-12 Fluids CVP 8-12

MAP > 65 Vasopressors MAP > 65

TransfusionsDobutamine

ScvO2 > 70%

49% mortality 33% mortality

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.

Control Intervention EGDT

System-based Approaches to sepsis

Rivers, E., Nguyen, B., Havstad, S., Ressler, J., Muzzin, A., Knoblich, B., Peterson, E., et al. (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine, 345(19), 1368–1377.

Used to promote:1. CVP > 8 as an initial target2. Use of Svo2 monitoring and use of blood/dobutamine

A Multidisciplinary Community Hospital Program for Early and Rapid Resuscitation of Shock in Nontrauma Patients

Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest, 127(5), 1729–1743.

A Multidisciplinary Community Hospital Program for Early and Rapid Resuscitation of Shock in Nontrauma Patients

Sebat, F., Johnson, D., Musthafa, A. A., Watnik, M., Moore, S., Henry, K., & Saari, M. (2005). A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest, 127(5), 1729–1743.

Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis

Thiel, S. W., Asghar, M. F., Micek, S. T., Reichley, R. M., Doherty, J. A., & Kollef, M. H. (2009). Hospital-wide impact of a standardized order set for the management of bacteremic severe sepsis*. Critical Care Medicine, 37(3), 819–824. doi:10.1097/CCM.0b013e318196206b

All physicians, nurses, and patient care technicians in the emergency department and intensive care units received formal order set clinical education. Additionally, all hospital floor clinical nurse specialists and advance practice nurses, along with the house staff physicians in these areas, were in-serviced on the order sets....These educational endeavors included training in sepsis pathophysiology, monitoring of central venous pressures, assessment of central venous blood oxygen saturation, and the pharmacotherapy of sepsis

1. EDUCATION2. ORDER SET with recommendations and goals for sepsis treatment.

BEFORE

Do whatever it is that you normally do. We will be watching.

AFTER

Lactate

Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2010;182(6):752–61.

Evidence is clear that Lactate levels are predictive of death and MODS

Clearance of lactate is associated with improved survival

Algorithms of care based on lactate clearance appear to work as well or better than other approaches.

Jones AE, Shapiro NI, Trzeciak S, et al. Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy: A Randomized Clinical Trial. JAMA: The Journal of the American Medical Association 2010;303(8):739–46.

Goals in resuscitation

Early, quantitative resuscitation goals vs. standard care have resulted in improved mortality

The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis *. Jones, Alan E. MD; Brown, Michael D. MD, MSc; Trzeciak, Stephen MD, MPH; Shapiro, Nathan I. MD, MPH; Garrett, John S. MD; Heffner, Alan C. MD; Kline, Jeffrey A. MD; on behalf of the Emergency Medicine Shock Research Network investigators Critical Care Medicine. 36(10):2734-2739, October 2008.

Goals in resuscitation

Initial fluid resuscitation:

CVP 8-12, MAP > 65, UOP 0.5 mL/kg/hr, ScVO2 70% and Lactate Clearance.

Give enough volume to maximize stroke volume. Start with 20cc/kg in most patients. Goal?

Give vasopressors to raise the MAP enough to maintain adequate end-organ perfusion.

Assessment of Cardiac Function

UOP and Lactate Clearance are nice global indicators of success.

Evidence-Based Sepsis Evidence-Based Sepsis GuidelinesGuidelines

• Components:• Early Recognition

• Early Goal-Directed Therapy– Monitoring– Resuscitation– Pressor / Inotropic Support

• Steroid Replacement

• Recombinant Activated Protein C

• Source Control

• Glycemic Control

• Nutritional Support

• Adjuncts: Stress Ulcer Prophylaxis, DVT Prophylaxis, Transfusion, Sedation, Analgesia, Organ Replacement

Evidence-Based Sepsis Evidence-Based Sepsis GuidelinesGuidelines