Sepsis

Purvin Shah, DO, MS, FCCP, MBA 5/15/2014

15th Annual CV & Medicine Symposium

Outline

1. Introduction 2. Definitions 3. Epidemiology 4. Pathophysiology 5. Evaluation & Management 6. Prognosis 7. Conclusion

Introduction Why do we care so much about sepsis?

• Sepsis and its advanced forms (severe sepsis and septic shock): • Are major healthcare problems • Affect millions of people around the world each year • Kill 1 in 4 patients (and often more) • Are increasing in incidence

• Just like MI and Stroke, the outcome of patients with sepsis is highly dependent on the speed and appropriateness of therapy in the initial hours after sepsis develops.

Introduction

• As a non-ICU physician, how do YOU play a role in caring for patients with sepsis?

• Surviving Sepsis Campaign (SSC) Guidelines:

“…the committee believes that the greatest outcome improvement can be made through education and process change for those caring for severe sepsis patients in the non-ICU setting and across the spectrum of acute care.”

Critical Care Medicine, Feb. 2013, Vol. 41, No. 2, pp 577-637

Surviving Sepsis Campaign (SSC) Guidelines • 2004 – Initial SSC guidelines were published in 2004 and incorporated

evidence available through the end of 2003

• 2008 – Updated SSC guidelines in 2008 based on evidence available through the end of 2007

• 2012 – Revised SSC guidelines based on literature through Fall 2012

• Quality of evidence = high (A) to very low (D) • Strength of recommendations = strong (1) or weak (2)

Definitions

• Spectrum of severity of illness:

Sepsis/SIRS Severe Sepsis Septic ShockMODS

• 1991 – initially defined by ACCP and SCCM

• 2001 – reconsidered by ACCP, SCCM, ATS, ESICM, SIS (Surg. Inf. Soc.)

• 2012 – SCCM and ESICM (European Society of Inten. Care Medicine)

Definitions

• Infection – presence of bacteria in a normally sterile tissue • Bacteremia – presence of bacteria in blood • Sepsis – complicates severe infection • SIRS – complicates a non-infectious insult • Severe Sepsis – hypoperfusion or organ dysfunction • Septic Shock – sepsis-induced hypotension despite fluids • MODS – Multiple Organ Dysfunction Syndrome

Definitions • Sepsis

• Problem with regulating the body’s inflammatory response to an infection • Characterized by the cardinal signs of inflammation in tissues remote from the infection:

• Vasodilation • Leukocyte accumulation • Increased microvascular permeability

• SIRS – Systemic Inflammatory Response Syndrome • Identical to Sepsis BUT complicates a non-infectious insult:

• Pancreatitis, Surgery, Burns, Autoimmune D/O, Trauma, Thromboembolism, etc.

• Massive and uncontrolled release of pro-inflammatory mediators leads to widespread tissue injury and possibly MODS (high mortality)

Definitions

• Diagnostic Criteria for Sepsis = probable or documented infection PLUS some systemic manifestations of infection:

• General: • Temp. >38.3 C or <36 C • HR > 90/min. or >2 std. dev. above normal value for age • Resp. Rate > 20/min. • Altered mental status

• Inflammatory variables: • WBC > 20K or < 4K • Normal WBC with >10% immature forms (e.g. Bands) • Plasma Procalcitonin more than 2 std. dev. above normal value

Definitions

• Diagnostic Criteria for Sepsis (continued): • Hemodynamic variables:

• SBP < 90 mmHg • MAP < 70 mmHg • SBP decrease > 40 mmHg, or • SBP < 2 std. dev. Below normal for age

• Organ Dysfunction variables: • Hypoxemia (PaO2 / FiO2 < 300) • Oliguria (urine output < 0.5 mL/kg/hr for >2 hrs. despite fluids) • Platelets < 100K • Plasma total bilirubin > 4 mg/dL

Definitions

• Diagnostic Criteria for Severe Sepsis = sepsis-induced tissue hypoperfusion (low BP, high lactate or oliguria) or organ dysfunction (any of the following thought to be due to the infection):

• Sepsis-induced hypotension • Lactate > ULN (upper limits of normal) • U.O. < 0.5 mL/kg/hr. for >2 hrs. despite adequate fluid resuscitation • Acute lung injury (PaO2/FiO2<250) w/o pneumonia as infection source • Acute lung injury (PaO2/FiO2<200) with pneumonia as infection source • Creatinine > 2 mg/dL • Platelet count < 100 K • Coagulopathy: INR > 1.5

Definitions

• Septic Shock: sepsis-induced hypotension that persists despite adequate fluid resuscitation (30 mL/kg of crystalloids – some of this may be albumin)

• MODS: progressive organ dysfunction • The severe end of the illness spectrum • Primary MODS – organ dysfunction occurs early and directly from the insult

(e.g. renal failure due to rhabdomyolysis) • Secondary MODS – organ failure is NOT due to the insult itself but rather is a

consequence of host response (e.g. ARDS in patients with pancreatitis) • Includes: PaO2/FiO2 ratio, Platelet count, Bilirubin, Creatinine, Low BP, GCS

Epidemiology

• Incidence: More than 1,665,000 cases diagnosed in the U.S. annually.

• An analysis reported increased rates from 13 to 78 cases per 100,000 between 1998 and 2009.

• Greatest in African-American males, during winter and patients > 65 yrs of age.

Epidemiology

• Pathogens: Gram-positive bacteria more than Gram-negative. Also, fungal sepsis has increased over the past decade. • Disease Severity: Increase in disease severity is noted – e.g., severe

sepsis increased from 26% to 44% over a 10-year period. Most common organ dysfunctions: ARDS, AKI, DIC. • Mortality: High mortality rate (12 to 50%). Increases stepwise: SIRS = 7%, Sepsis = 16%, Severe Sepsis = 20%, Septic Shock = 46% Mortality remains elevated at one-year among survivors of sepsis.

Risk Factors for Sepsis

• Bacteremia (study of 270 blood cultures: 95% of positive blood cultures were associated with sepsis, severe sepsis, or septic shock)

• Advanced age (>65 yrs) – age is an independent predictor of mortality • Immunosuppression – neoplasm, renal failure, hepatic failure, AIDS,

asplenism or immunosuppressant medications • Diabetes • Community-acquired pneumonia (CAP): severe sepsis develops in

48% of patients with CAP

Pathophysiology

• Normal Response to Infection: - Host immune cells (esp. macrophages)

recognize and bind to microbial components

- Activates an inflammatory response (release of proinflammatory cytokines TNF / IL-1, chemokines, NO, etc.)

- Polymorphonuclear leukocytes (PMN) become activated, migrate to injury site, release mediators causing inflammation (edema, erythema, warmth) and tissue repair & healing.

Pathophysiology

• Transition to Sepsis: - the normal inflammatory response

becomes uncontrolled and generalized because a large quantity of proinflammatory cytokines are released

- Complement cascade gets activated - Bacterial cell wall components and

bacterial products may enhance progression to sepsis

Pathophysiology

• Systemic effects:

- widespread cellular injury - derangements in metabolic auto-regulation - imbalances in coagulation and fibrinolytic systems - mitochondrial dysfunction - delayed apoptosis of activated macrophages and neutrophils

Pathophysiology

• Organ-specific effects:

- Hypotension (from diffuse vasodilation), myocardial depression - Pulmonary edema, V/Q mismatch, hypoxemia - Translocation of bacteria and endotoxin in the GI tract - Liver dysfunction - Acute renal failure - Encephalopathy

Evaluation & Management

• Early Management: First, stabilize airway & breathing – supplemental O2, monitor pulse ox, may need to intubate and place on mechanical ventilation. Check PCXR and ABG. Then, assess & restore perfusion – if low BP, then insert A-line catheter for accurate BP. EXAM: HR>90/min, obtundation / restless, oliguria / anuria, cool vasoconstricted skin. LABS: lactate > 4mmol/L Insert central venous catheter for infusion of meds & fluids / blood draws / measuring CVP and central venous O2 sat. (ScvO2).

Evaluation & Management

• Goals of initial resuscitation: (SSC Guidelines) within 1st 6 hours based on an EGDT trial of 263 patients (and a meta-analysis) with targeting of specific goals resulted in lower mortality (31% vs. 47%):

- ScvO2 > 70% - CVP = 8-12 mmHg - MAP > 65 mmHg - U.O. > 0.5 mL/kg/hour

Rivers E et al. “Early Goal-Directed Therapy in the treatment of severe sepsis and septic shock”; NEJM 2001; 345: 1368-1377

Evaluation & Management

• Lactate clearance – targeting a lactate clearance of >10% (versus targeting ScvO2 > 70%) gives same mortality benefit, hospital LOS, ventilator-free days, or incidence of multi-organ failure.

• Recommend targeting normalization of lactate level if initially elevated.

• Other targets (besides ScvO2, CVP, MAP, U.O.) – radial pulse pressure, aortic blood flow peak velocity, brachial artery blood flow velocity, passive leg raising, etc. can be used to guide fluid resuscitation.

Evaluation & Management

• Screening – recommend routine screening for Sepsis in potentially infected seriously ill patients (so treatment can be started early)

• Diagnosis – 2 sets of blood cultures BEFORE Abx Tx is started (as long as there is no significant delay >45 min. in starting Abx).

• - blood cultures (peripheral and through each vascular access device) • - sputum cultures • - urine cultures • - wound cultures • - rapid influenza antigen testing (during the flu season) • - appropriate imaging studies (to identify abscess for I&D, etc.)

Evaluation & Management

• Antibiotics – administer effective IV Abx within the 1st hour of recognizing septic shock and severe sepsis.

• Each hour delay is associated with increase in mortality • Initial empiric Abx Tx should have activity against all likely pathogens

(bacterial, viral, fungal) and penetrate in adequate concentrations into the tissues that are thought to be infected.

• Hospitalized patients – Gram-positives are most common, then Gram-negatives • Neutropenic patients – wide range of potential pathogens, esp. Gram-negatives • Avoid recently used anti-infective agents • Add fluconazole or an echinocandin if candidemia is a concern

• (e.g., neutropenia, immunosuppressed, prior broad-spectrum abx tx, etc.)

Evaluation & Management

• Antibiotics – • Studies have shown combination therapy produces better clinical outcomes

in severely ill, septic patients with a high risk of death. • Duration = 7-10 days based on clinical judgment

• Longer if: • slow clinical response • undrainable focus of infection • bacteremia with S. aureus • some fungal and viral infections

• Re-assess patients daily for de-escalation of abx tx once pathogen is known. • Start anti-viral tx early if a viral infection is suspected (e.g., influenza).

Evaluation & Management

• Source Control – • Look for specific anatomical diagnosis of infection and intervene w/in 12 hrs.

• Necrotizing soft tissue infection debridement • Abscess drainage • peritonitis, cholangitis, intestinal infarction surgical intervention

• Use the intervention with the least physiologic insult • e.g. percutaneous rather than surgical drainage of an abscess

• Remove any potentially infected intravascular access devices

Evaluation & Management

• IV Fluids – rapid, large volumes are indicated (e.g., 5 liters in 6 hours) unless CHF is present. Repeat IV fluid boluses until:

- BP is acceptable - tissue perfusion is acceptable - CHF develops - perfusion fails to improve with IV fluids

• Crystalloids – initial fluid of choice (e.g., NS, LR) = 30 mL/kg bolus

• Albumin (more costly) – should be used if amount of crystalloids will be too much.

• DO NOT USE hydroxyethyl starch (Hespan) b/c of increased mortality (51% vs. 43%). SAFE trial, 6S trial, VISEP trial

Evaluation & Management

• Vasopressors – used in patients that remain hypotensive despite adequate fluid resuscitation (or that develop pulmonary edema from IV fluids).

• Target – MAP > 65 mmHg • Norepinephrine is preferred 1st choice (more potent, more effective for BP) • Epinephrine – 2nd choice • Vasopressin – can also be added at low-dose • Dopamine – only for highly selected pts (low risk of arrhythmias, low EF)

• Do NOT use low-dose dopamine for renal protection does not work. • Phenylephrine – use if norepinephrine causes arrhythmias, high CO with low

BP or add as combination therapy to other vasopressor/inotrope drugs

Evaluation & Management

• Inotropic Therapy –

• Dobutamine – • Upto 20 mcg/kg/min added to vasopressors

• Use if: • Persistent Hypoperfusion

• ScvO2 remains < 70% (despite adequate intravascular volume and adequate MAP)

• Myocardial Dysfunction (low CO) is present

• Recommend against using it to increase cardiac index to a predetermined supranormal levels – no benefit shown with this strategy

Evaluation & Management

• Corticosteroids – • Use only if BP is still low despite adequate fluid resuscitation and vasopressor

therapy • Dose of 200 mg / day in divided doses (e.g., 100 mg Hydrocortisone Q12 hrs) • Do not use the ACTH stimulation test to identity pts to give steroids

• Random cortisol levels have not been demonstrated to be useful. • Taper steroids when pt is off vasopressors • No recommendation for optimal duration

• No difference in outcome was noted in 3 vs. 7 days of treatment • Do not use as “preventive” therapy if shock is not present

Evaluation & Management

• Packed Red Blood Cell (PRBC) Transfusions – • Give PRBCs when Hb < 7.0 g/dL

• If no MI, ischemic CAD, severe hypoxemia or acute hemorrhage • Optimal Hb level is not known but Hb b/t 7-9 vs. 10-12 g/dL was NOT

associated with increased mortality in critically ill pts. • Do not use erythropoietin as a tx of anemia in severe sepsis

• No specific info. is available regarding its use in septic pts.

• Fresh Frozen Plasma (FFP) – • Do not use to correct clotting abnormalities unless bleeding is present or

invasive procedures are planned

Evaluation & Management

• Platelets – • Sepsis is thought to be associated with

• Limitation of platelet production • Increased platelet consumption

• Transfuse when: • Plts < 10K if no bleeding is present • Plts < 20K if pt has a significant risk of bleeding

• Higher platelet levels (> 50K) are advised if: • Active bleeding • Surgery • Invasive procedures

Evaluation & Management

• Recombinant Activated Protein C (rhAPC, Xigris) –

• Approved in 2001 after PROWESS trial showed a significant reduction in mortality (24.7% vs. 30.8% with placebo)

• Shown to be ineffective in later studies (e.g., PROWESS SHOCK trial in 2011) so the drug was withdrawn from the market by Eli Lilly.

Evaluation & Management

• Glucose Control –

• Recommend a protocolized approach to be used when 2 consecutive blood glucose levels are > 180 mg/dL.

• Target blood glucose level < 180 mg/dL.

• Monitor blood glucose levels every 1-2 hours.

• Other – • DVT / PUD Px, Enteral feedings, vent. support

Surviving Sepsis Campaign Bundles

• Within 3 hours:

• Measure lactate level (to assess perfusion)

• Obtain blood cultures before giving antibiotics

• Administer broad-spectrum antibiotics

• Administer 30 mL/kg crystalloid if: • Hypotension • Lactate > 4 mmol/L

Surviving Sepsis Campaign Bundles

• Within 6 hours:

• Start vasopressors if hypotension persists despite initial fluid resuscitation • Maintain MAP > 65 mmHg

• If hypotension persists despite volume resuscitation OR initial lactate > 4 mmol/L, then:

• Measure CVP (central venous pressure) – target CVP > 8 mmHg • Measure ScvO2 – target ScvO2 > 70%

• Remeasure lactate if initial lactate was elevated • Target lactate – normal value (< 2.2 mmol/L)

ProCESS Trial

• Protocolized Care for Early Septic Shock – 31 hospitals in the U.S. • 1341 patients in 3 groups: protocol-based EGDT (439 pts), protocol-based

standard therapy (446 pts), or usual care (456 pts) • Results: 60-day mortality rates were similar (21.0%, 18.2%, 18.9%). No

significant differences in 90-day or 1-year mortality. • SSC Response: usual care mortality (18.9%) is already low (b/c of overall

improvement in our care of these sick pts – 70% of hospitals use a “sepsis protocol”) vs. 46.5% in 2001 EGDT trial. Also, this study does not address pts with severe sepsis without septic shock – aggressive mgt of these pts has likely lowered mortality rates.

“A Randomized Trial of Protocol-Based Care for Early Septic Shock”. NEJM May 1, 2014, Vol. 370, No.18, pp. 1683-1693

Other Recent Trials

• High vs. Low Blood-Pressure Target in Patients with Septic Shock (NEJM 4/24/14, vol. 370, no. 17, pp. 1583-1593) – 776 pts

• No significant difference in mortality (28-day or 90-day) with MAP of 65-70 mmHg vs. 80-85 mmHg

• Albumin Replacement in Patients with Severe Sepsis or Septic Shock (NEJM 4/10/14, vol. 370, no. 15, pp. 1412-1421) – 1818 pts

• Use of Albumin in addition to crystalloids did not improve survival at 28 and 90 days.

Prognostic Factors

• Host Response – Leukopenia or Failure to develop a fever = poor prognosis • Co-Morbidities – new-onset a. fib., age > 40 yrs, AIDS, liver disease, cancer,

EtOH abuse, immunosuppression = poor prognosis • Site of infection – UTI = lowest mortality rate BUT GI or pulmonary source

= higher mortality • Type of infection – nosocomial infection = higher mortality (compared to

community-acquired pathogens) • Abx Tx – Appropriate Abx Tx = lower mortality. BUT, prior Abx Tx = higher

mortality • Failure to restore perfusion early = higher mortality

Conclusion

• Sepsis – • Is a major healthcare problem with • an increasing incidence and • a high mortality rate • affecting millions of people around the world every year.

• Its outcome depends on the speed and appropriateness of therapy early after recognizing its presence.

• There are evidence-based guidelines published to guide its management with updates every 4 years.