SEPSIS UPDATE 2013David Willms MD FCCP FCCM

Sharp Memorial Hospital

Disclosures• Thermo Fisher• Clinical research support in sepsis trials from

• Spectral Diagnostics• Asahi Kahei

Objectives• Update knowledge on trends in incidence and outcomes

of severe sepsis• Review some of the changes in sepsis management

recommended in the latest Surviving Sepsis Campaign guidelines

• Discuss rationale behind current practice guidelines in sepsis diagnosis and management

Merinoff Symposium Sepsis Definition(“consumer and patient-friendly definition”)

“Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs”

Wall Street Journal October 20, 2010

Points to Consider• 1 – 3 million cases severe sepsis / year in U.S.• 500+ deaths / day• Incidence > CHF, breast CA, colon CA, AIDS

• EGDT: 16% absolute reduction mortality (NNT = 6)• Antibiotics < 1 hr: 13.7% reduction mortality (NNT = 7)• TPA for stroke: no impact on mortality• Emergent cath STEMI: NNT = 30

Gaieski Crit Care Med 2010; 38:1045NINDS Study Group N Engl J Med 1995; 333:1581Grines Am Heart J 2003; 145:47

Severe Sepsis Incidence

Gaieski Crit Care Med 2013; 41:1167

Sepsis Diagnostic Codes

Gaieski Crit Care Med 2013; 41:1167

Copyright © 2013 Critical Care Medicine. Published by Lippincott Williams & Wilkins.

Figure 1. Trends in septic shock incidence and septic shock hospital mortality, 1998–2009.

8

Utilization Patterns and Outcomes Associated With Central Venous Catheter in Septic Shock: A Population-Based Study*

Walkey, Allan J.; Wiener, Renda Soylemez; Lindenauer, Peter K.

Critical Care Medicine. 41(6):1450-1457, June 2013.

doi: 10.1097/CCM.0b013e31827caa89

What We Believe

• Early recognition and treatment of severe sepsis improves outcome

• Immediate initiation of antibiotic treatment once sepsis is identified is key to survival

• Early, vigorous resuscitation targeting appropriate physiological goals saves lives

• “Bundling” series of evidence-based management techniques works

• A team approach is necessary to optimize sepsis care

Continuum of Sepsis

Infection SIRS Organ Dysfunction Circulatory Failure/MODS

Sepsis Severe Sepsis Septic Shock

2012 Sepsis Bundles• To be completed within 3 hours

• Measure lactate level• Obtain blood cultures prior to administration of antibiotics• Administer broad spectrum antibiotics

• To be completed within 6 hours• Apply vasopressors (for hypotension not responding to initial fluid

resuscitation) to maintain MAP ≥ 65 mmHg• For persistent hypotension despite volume resuscitation (septic

shock) or initial lactate level ≥ 4 mmol/L:• Measure CVP• Measure ScvO2

• Remeasure lactate if initial lactate was elevated

Gao Crit Care 2005; 9(6):764

Compliance with early Sepsis Bundle and Mortality

Bundle Management of Early Severe Sepsis and Outcome

Nguyen Crit Care Med 2007: 35:1105

p < .0120.8%

39.5%

Multicenter Severe Sepsis and Septic Shock Bundle Implementation

Miller Am J Respir Crit Care Med 2013; 188:77

Updated Surviving Sepsis Guidelines

Crit Care Med 2013; 41:580–637

GRADE System

1. Strong (“we recommend”)

2. Weak (“we suggest”)

• Quality of Evidence

A. (high) RCTs

B. (moderate) downgraded RCTs or upgraded observational studies

C. (low) well-done observational studies with control RCTs

D. (very low) downgraded observational studies or expert opinion based on other evidence

UG ungraded, unable to quantitate

* Initial Resuscitation• Protocolized, quantitative resuscitation of patients with

sepsis-induced hypoperfusion (low BP after fluid resusc, or lactate ≥ 4 mmol/L). First 6 hr goals:• CVP 8-12 mmHg• MAP ≥ 65 mmHg• Urine output ≥ 0.5 mL/kg/hr• ScvO2 ≥ 70% (1C)

• If lactate elevated, target resusc to normalize lactate (2C)

Randomized Trials of EGDT

Treatment Rivers 2001 China 2010

Standard Therapy 49.2 42.5

Early Goal-Directed 33.3 24.8

28 day Mortality

Rivers N Engl J Med 2001;345:1368Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2010;22(6)331

Cryptic Shock

Patients with a baseline normal BP, Lactate > 4 mM/LControl n = 25 Treatment n = 23

Rivers N Engl J Med 2001; 345:1368

* Screening and Diagnosis, Source Control

• Routine screening of potentially infected seriously ill patients for severe sepsis (1C)

• Hospital-based performance improvement efforts (UG)• Cultures before antimicrobial therapy, if feasible without

undue delay (1C)• Prompt imaging studies to confirm source (UG)• Intervention for specific anatomic source control within

first 12 h of diagnosis if feasible (1C)• Intervention with least physiologic insult• Remove intravascular devices promptly if possible source

Time Sensitive Diseases

< 5%

Trauma

< 8%

Stroke

< 10%

AMI

20 - 46%Sepsis

SCREENING FOR SEPSIS

Sample Data from an Emergency Department Using SIRS Criteria as an indicator

Evaluation Criteria

• Hyperthermia: > 101.0 F• Hypothermia: < 96.8 F• Tachycardia: > 90 bpm• Tachypnea: > 20 bpm (resp. rate)• SBP < 90 mmHg or MAP < 65 mmHg

Sample ED Data From Local Hospital

Assessment in ED* # ED Patients Disch Dx Sepsis %

Met Less Than Two Evaluation Criteria in ED

34,901 (82%) 179 0.5%

Met Two or More Evaluation Criteria in ED

7,610 (18%) 239 3.1%

Total Patients 42,511 418 1.0%

* Assessment against Evaluation Criteria based on the patient’s first vital signs taken

* Antimicrobial Therapy• Effective IV antimicrobials within 1 hour recognition of

severe sepsis (1C) and septic shock (1B)• One or more drugs active against all likely pathogens, with

adequate tissue penetration (1B)• Combination empiric therapy for neutropenic severe sepsis,

MDRO, Pseudomonas bacteremia (2B)• Reassess daily for potential antibiotic deescalation (1B)

• Empiric combination therapy not more than 3-5 days (2B)• Duration therapy typically 7-10 days, some exceptions (2C)• Do not use antimicrobials in patients with severe inflammatory states

determined to be of noninfectious cause (UG)• Use low procalcitonin levels or similar biomarkers to assist in

discontinuation of empiric antibiotics, if no subsequent evidence infection (2C)

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Kumar Crit Care Med 2006; 34:1589

Procalcitonin• Procalcitonin (PCT):

• Biomarker for assessing the risk of sepsis.1

• Gained acceptance in the last 10 years.1

• Precursor of calcitonin.2

• Modulates immune processes.1

• Levels correlate with severity of bacterial infection.2

PCT

1 Meisner M “Procalcitonin – Biochemistry and Clinical Diagnosis” 2010 UNI-MED Verlag AG Bremen – London – Boston.2 Muller B, et al. J Clin Endocrinol Metab 2001 Jan;86(1):396-404.

FDA clearance

For use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission, for progression to severe sepsis

and septic shock.

PCT

BRAHMS PCT LIA FDA clearance letter Jan 2005.Vidas® BRAHMS PCT Assay FDA clearance letter Oct 2007.BRAHMS PCT sensitive Kryptor ® FDA clearance letter Mar 2008.

Pharmacokinetics • PCT:

• PCT levels:

• Meisner concluded that falling levels approaching normal range are generally signs of a good prognosis.1

• Very stable protein.1

• Half-life about 24 hours. 1

• Reliable tool for early assessment of severe bacterial infection.2

• Rises rapidly, and to a high degree, in response to infection.2 • Long plasma half-life.2 • Halves daily when infection is controlled by host immune system and

antibiotic therapy.3

PCT

1 Meisner M “Procalcitonin – Biochemistry and Clinical Diagnosis” 2010 UNI-MED Verlag AG Bremen – London – Boston.2 Gendrel D, et al. Clin Infect Dis 1997 Jun;24(6):1240-2.3 Schuetz P, et al. Expert Rev Anti Infect Ther 2010 May;8(5):575-87.

PCT in the Intensive Care Unit• ProHosp:1

• PRORATA:2

• 1359 patients with lower respiratory tract infections.• Standard guidelines group and PCT algorithm group.• Overall adverse rate similar between groups.• Mean duration of antibiotics exposure in PCT group was lower (5.7 vs. 8.7 days)

as was frequency of antibiotic-associated adverse effects (19.8% vs. 28.1%).

• 621 ICU patients with suspected bacterial infections.• Standard guidelines group and PCT algorithm group.• Mortality of the two groups were similar (21.2% vs. 20.4%).• PCT group had significantly more days without antibiotics.

• 14.3 vs. 11.6 days (p < 0.0001).

1 Schuetz P, et al. JAMA 2009 Sep 9;302(10):1059-66.2 Bouadma L, et al. Lancet 2010 Feb 6;375(9713):463-74.

Non-Bacterial Stimuli• PCT levels also increase during other conditions:

• 1st days after trauma.• Surgical trauma including extracorporeal circulation.• Burns.• Neonates.• Molecular treatment with:

• OKT3 antibodies.• Interleukins.• TNF- .a

• Medullary C-cell carcinoma / small cell lung carcinoma / bronchial carcinoid.• Severe organ perfusion anomalies.

PCT

BRAHMS PCT sensitive Kryptor® Thermo Fisher Scientific BRAHMS LLC 2010

• Objective:

• 94 consecutive patients ≥ 16 years old admitted to the ICU with a stay of at least 24 hours.

PCT in the Intensive Care Unit

Castelli GP, et al. Crit Care Med 2009 Jun;37(6):1845-9.

• To investigate the diagnostic value of PCT and CRP in septic complications after major trauma.

* Fluid Therapy of Severe Sepsis• Initial fluid challenge of 30 mL/kg crystalloid (or

equivalent) in sepsis with tissue hypoperfusion (1C)• Crystalloid initial fluid of choice in sepsis resusc (1B)

• Albumin if substantial amount of fluids required (2C)• Not use hydroxyethyl starches for resusc fluid (1B)

• Apply fluid challenge technique – continue challenges as long as hemodynamic improvement based on dynamic or static variables (UG)

* Vasopressors• Target mean arterial pressure (MAP) 65 mmHg (1C)• Norepinephrine first choice pressor (1B)• Add epinephrine (or substitute) when additional agent needed to

maintain MAP (2B)• Vasopressin (0.03 units/min) can be added to NE to raise MAP or

decrease NE dose (UG)• Not as initial vasopressor• Doses > 0.03-0.04 units/min only as salvage therapy

• Dopamine only in highly selected patients• Low risk of tachyarrhythmias and relative bradycardia (2C)

• Phenylephrine not recommended (1C) except:• If NE use is associated with serious arrhythmias• CO known to be high, and BP persistently low• Or salvage when combined other pressors fail to meet MAP goal

• Arterial catheter recommended if feasible (UG)

* Inotropic Therapy• Dobutamine trial up to 20 mcg/min IV infusion (1C) if:

• Myocardial dysfunction with elevated filling pressures and low CO• Signs of hypoperfusion, despite volume resusc and adequate MAP

• Not use strategy to increase cardiac index to arbitrary supranormal levels (1B)

* Corticosteroids in Severe Sepsis• Not use steroids in sepsis in absence of shock (1D)• Not use steroids if fluid resusc and vasopressors restore

hemodynamic stability• If persistent hemodynamic instability despite fluids and

pressors, use IV hydrocortisone alone at 200 mg/d (2C)• Do not use ACTH stim test to determine who should receive

hydrocortisone (2B)• Taper hydrocortisone when pressors no longer required (2D)• When hydrocortisone used, administer continuous IV drip (2D)

Steroid Trials

French Trial Corticus Trial

Severity of Illness ++++ ++

Duration of Shock ≤ 8 hr ≤ 72 hr

Degree Hypotension ++++ ++

Potential Selection Bias Unlikely Yes

Annane JAMA 2002;288:862Sprung N Engl J Med 2008;358:111

* Some Miscellaneous ‘No’s• Low-dose dopamine for renal protection (1A)• Erythropoietin as specific anemia treatment (1B)• FFP to correct lab abnormality absent bleeding (2D)• Antithrombin for severe sepsis (1B)• Intravenous immunoglobulins in severe sepsis, shock (2B)• Intravenous selenium for severe sepsis (2C)• rhAPC (no longer available)• Sodium bicarbonate for improving hemodynamics in

lactic-acidemia with pH ≥ 7.15 (2B)

N Engl J Med 2012; 366:2055

Why Sepsis Trials Failed• Drug not biologically active• Mediator milieu too complex/redundant for a single-point attack to

alter the disease• Animal models not relevant to human sepsis• Effective, but-

• Too little• Too late

• Effective in ameliorating morbidity, but patient would have lived or died anyway

• Patients too heterogeneous• Investigators not focused on enrolling patients meeting both entry

criteria and spirit of protocol• Clinical enrollment criteria, for intervention that is biologically based

Some Ongoing Therapeutic Trials• Polymixin B Hemoperfusion (EUPHRATES)• Thrombomodulin (ART 123)• Trials of components of EGDT

* Other Addressed Issues in Sepsis• Blood product administration• Mechanical ventilation, ARDS• Sedation, analgesia, NMB• Glucose control• Renal replacement therapy• DVT prophylaxis• Stress ulcer prophylaxis• Nutrition• Setting goals of care• Pediatric special considerations

* Mechanical Ventilation in Sepsis-Induced ARDS

• Target tidal volume of 6 mL/kg PBW (1A)• Pplat be measured and kept ≤ 30 cmH2O (1B)

• PEEP to avoid alveolar collapse at end expiration (1B)• Higher rather than lower PEEP levels in moderate to severe sepsis-induced

ARDS (2C)• Recruitment maneuvers in severe refractory hypoxemia (2C)• Prone positioning if PaO2/FiO2 ≤ 100 if experienced site (2B)• Maintain HOB elevated 30-45 deg to prevent VAP (1B)• NIV in selected ARDS patients if benefits thought to outweigh risks (2B)• Weaning protocols including daily screens, SBTs (1A)• No routine use of PA catheter for sepsis induced ARDS (1A)• Conservative rather than liberal fluid strategy in established ARDS (1C)• Not use beta-2 agonists in absence of bronchospasm (1B)

Prone Positioning in Severe ARDSlan–Meier Plot

of the Probability of Survival from Randomization to Day 90.

Guérin C et al. N Engl J Med 2013;368:2159-2168

Guerin N Engl J Med 2013; 368:2159

28-day Mortality

Prone 16%Supine 32.8%

Higher PEEP for ARDS

N Engl J Med 2004; 351:327

Thank you, and good luck!