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SEPSIS: UNDERSTANDING DIAGNOSTICS AND TREATMENTSTEPHANIE ELLENBERGER MSN, FNP2018

A little history…..

April 2003 the New England journal of Medicine published a large scale study consisting of approximately 750 million hospitalizations in the US over the span of 22 years. This data was collected via the National Hospital Discharge Survey using

the Uniform hospital Discharge Data set as a guideline.• Mortality rates for the entire cohort declined over the 22 years from 27.8 to 17.9 percent. However the incidences of sepsis increased actually tripling the number of in hospital deaths related to spies from 43,579 in 1979 to 120,491 in

2000.• The main causative organisms in these cases were predominantly Gram

negative organisms• In the 1980-1990s we saw insurgence from Gram negative to Gram positive infections and atypical infections like fungal disease. This shift was thought

to be related to increasing invasive procedures and the increase of immunosuppression (HIV, Steroids and immunetherapy, chemotherapy)

April 2003 the New England journal of Medicine published a large scale study consisting of approximately 750 million hospitalizations in the US over the span of 22 years. This data was collected via the National Hospital Discharge Survey using

the Uniform hospital Discharge Data set as a guideline.• Mortality rates for the entire cohort declined over the 22 years from 27.8 to 17.9 percent. However the incidences of sepsis increased actually tripling the number of in hospital deaths related to spies from 43,579 in 1979 to 120,491 in

2000.• The main causative organisms in these cases were predominantly Gram

negative organisms• In the 1980-1990s we saw insurgence from Gram negative to Gram positive infections and atypical infections like fungal disease. This shift was thought

to be related to increasing invasive procedures and the increase of immunosuppression (HIV, Steroids and immunetherapy, chemotherapy)

Epidemiology (adults)Epidemiology (adults)

• Median age 69

• Median LOS 9 days

• 35% diabetics

• 32% history cardiovascular disease

• Most common infections leading to sepsis

• Pneumonia 35%

• UTI 25%

• GI and Skin and soft tissue infections 11%

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Epidemiology (children)Epidemiology (children)

• 39% < age one

• 61% age 1-18

• At least one major comorbid factor present (78%)

• 38% with cerebral palsy or cognitive deficits

• 23% of infants had congenital heart disease

• 43% of cases are healthcare associated

Epidemiology: bacterial organismsEpidemiology: bacterial organisms

• Adults: Staphylococcus species, E Coli, Streptococcus (blood isolates)

• 31% had no identified pathogen

• Children: Enterococcus and Klebsiella (blood isolates)

• 38% had no identified pathogen

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SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES FOR SEPSIS

MANAGEMENT

In 2004 the first phase of the surviving sepsis campaign was published after its inception 2 years prior and through collaboration of multiple different international societies of medicine and nursing, with the goal to reduce

mortality from sepsis by 25% by:

1. Building awareness of sepsis2. Improving diagnosis3. Increasing use of appropriate treatment4. Educating healthcare professionals5. Developing guidelines of care6. Implementing a performance improvement program

In 2004 the first phase of the surviving sepsis campaign was published after its inception 2 years prior and through collaboration of multiple different international societies of medicine and nursing, with the goal to reduce

mortality from sepsis by 25% by:

1. Building awareness of sepsis2. Improving diagnosis3. Increasing use of appropriate treatment4. Educating healthcare professionals5. Developing guidelines of care6. Implementing a performance improvement program

-Surviving Sepsis Campaign 2016 update

SEPSIS:SEPSIS:SEPSIS IS DEFINED AS: A SYSTEMIC DYSREGULATION OF HOST RESPONSE TO INFECTION THAT HAS HIGH INCIDENCES OF MORBIDITY AND MORTALITY.

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Systemic Inflammatory response syndromeSystemic Inflammatory response syndrome

• Two or more of the following:

• Body temperature >38 C or < 36 C (>100.4F or <96.8F)

• HR > 90

• RR >20 or PCO2 <32

• WBC > 12,000 or < 4000 OR >10% immature forms (bands)

SIRS: with or without organ dysfunctionSIRS: with or without organ dysfunction

DVT/PE

DKA

Pancreatitis

Malignancy

Rheumatologic disease

Trauma

Burns

CLINICALLY DEFINING SEPSIS

2 or more SIRS criteria + a suspected infection

(i.e. Leukocytosis, fever 101, RUL CAP)

2 or more SIRS criteria + a suspected infection

(i.e. Leukocytosis, fever 101, RUL CAP)

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Severe sepsisSevere sepsis

• SIRS criteria of 2 or more

• Infection present and determined to be the etiology of SIRS

• Sepsis Complicated with acute organ dysfunction

• (i.e. Leukocytosis, Fever 101, RUL CAP with renal and hepatic dysfunction)

Septic ShockSeptic Shock

• Sepsis induced hypotension after IV fluid resucitation.

• Requirement for vasopressors

A brief review of sepsis pathophysiology

A brief review of sepsis pathophysiology

• Cellular changes occur in the endothelial tissue potentiated by the cellular release of pro-inflammatory substances (cytokines) in response to the presence of infectious organisms.

• Endothelial damage and death of endothelial cells trigger coagulation which impedes blood flow, especially in the small vasculature causing tissue edema.

• Cytokines also cause vasodilation decreasing blood pressure

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–Johnny Appleseed

“Type a quote here.”

PathophysiologyPathophysiology

• Endothelial damage

• Inflammatory and pro-flammatory mediators trigger clotting cascade

• Clotting factors consumed…

CMSCore measure!!

(It’s all or nothing!!)

Core measure!!

(It’s all or nothing!!)

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Early, Goal directed therapy: best practice approach to sepsis

Early, Goal directed therapy: best practice approach to sepsis

• Sepsis bundles: help consistency throughout organization, also help to maintain CMS core measure criteria

• ER

• ICU

• Telemetry

WHY BUNDLES??(DO THEY REALLY WORK?)

• In the 2016 SCC update refers to a meta analysis of 50 studies comparing SSC bundle compliance internationally.

• These studies showed consistently that for every 3 months a hospital participated in SSC compliance there was a decreased in sepsis mortality by 0.7%

• There was also a decrease LOS by 4% for every 10% improvement in compliance.

1 hour sepsis bundle1 hour sepsis bundle

• Obtain cultures (prior to initiation of antibiotics)

• Delay antimicrobial therapy no more than 60 minutes to obtain appropriate diagnostics

• Administer broad spectrum antibiotics

• Measure lactate level, if > 2 will need repeated within 6 hours

• If hypotensive or lactate > 4 administer 30ml/kg crystalloid fluid bolus

• Persistent hypotension during of after fluid, start vasopressors

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“TIME Zero”“TIME Zero”TIME OF ER TRIAGE OR FROM THE EARLIEST DOCUMENTED CRITERIA MAKING THE PATIENT MEET SEPSIS/SEVERE SEPSIS/SEPTIC SHOCK

FLUIDS FLUIDS FLUIDS!!FLUIDS FLUIDS FLUIDS!!

The 2016 SSC update still recognizes fluid

resuscitation as the most important first step of sepsis

treatment to limit hypo perfusion of organs and

improve patient outcomes.

The 2016 SSC update still recognizes fluid

resuscitation as the most important first step of sepsis

treatment to limit hypo perfusion of organs and

improve patient outcomes.

Fluid ResucitationFluid Resucitation

• Initial fluid bolus: 30ml/kg of crystalloid fluid should be administered:

• 0.9% NACL or RL

• Albumin

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TARGET PRESSURE

MAP of 65mmHG

CVP: >8

Higher MAP targets (75-80mmhg)have been linked

to a significantly higher risk of arrhythmias and

without significant changes in mortality.

MAP of 65mmHG

CVP: >8

Higher MAP targets (75-80mmhg)have been linked

to a significantly higher risk of arrhythmias and

without significant changes in mortality.

That’s not where it ends…That’s not where it ends…

• Frequent assessment, VS, lactate

• Mean arterial pressure is the driver of tissue perfusion and therefore the target for fluid resuscitation and vasopressor titration. However central venous pressure monitoring can also be beneficial and used when available.

Vasopressor use in septic shock patientsVasopressor use in septic shock patients

1. Norepinephrine

2. Norepinephrine + vasopressin or epinephrine

3. Dopamine or neosynephrine

Low dosed (renal protective dopamine) is suggested

Dobutamine may be indicated for that who have ongoing hypoperfusion despite fluids and other vasopressor agents

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IV Corticosteroid Use in septic shock patients

IV Corticosteroid Use in septic shock patients

• Varying opinions on this subject: Multiple conflicting reports

• SCC recommends not using IV steroids unless patients are not responding to fluid bolus and vasopressors.

• Adrenal insufficiency (adrenocorticotropic hormone <9) may benefit

• History of steroid use or AI

Lactic AcidLactic Acid

• Multiple RCTs that have shown on large scale studies statistically significant mortality reduction when lactate guided resuscitation used. Mean LOS of ICU stay is not significantly changed.

Lactic acid trending in the septic patientLactic acid trending in the septic patient

• In tissue hypoxemia, lactate is overproduces by anaerobic glycolysis

• Serum lactate levels are a beneficial biomarker to use during initial sepsis workup and during treatment.

• Elevated serum lactate levels can be directly correlated with increased risk mortality rates

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Acute hospital mortality according to serum lactate level in patients requiring vasopressors

Acute hospital mortality according to serum lactate level in patients requiring vasopressors

2016 analysis published by the

journal of thoracic disease analyzing 86 septic shock patients with lactic acidosis

2016 analysis published by the

journal of thoracic disease analyzing 86 septic shock patients with lactic acidosis

Hospital mortality

Lactate <4

Lactate 4-8

Lactate >8

P value

24 hour Mortality

10% 35% 52.8% 0.011

48 hour Mortality

30% 65% 72.2% 0.033

Lactate > 4Lactate > 4

30ML/KG CRYSTALLOID BOLUS: REGARDLESS OF HYPOTENSION

ProcalcitoninProcalcitonin

• Procalcitonin is a biomarker that can be used as an indicator to de-escalate antibiotics.

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DIURECTICSDIURECTICS

JUST SAY NO!!!

(EMBRACE THE USE OF ALBUMIN)

Identify a source!Identify a source!

• What brought the patient through the door of your ER?

• A thorough HPI can make all the difference in your patient’s outcome.

• Focus antibiotics on the suspected source (not everyone needs Vanco and zosyn as empiric therapy)

• “Panculturing” a patient should be a last resort.

Molecular diagnostics of blood culturesMolecular diagnostics of blood cultures

• Rapid microbial detection with ID of organism through PCR, providing a quicker sensitivity and therefore able to provide better early goal directed therapy.

• Can often help decrease LOS

• Blood, respiratory, urine, wounds

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Please look for central lines, PICC lines, mediports, tunneled HD catheters, etc. and consider these as possible infectious

sources on admission.

If a venous access device IS the source of the patient’s sepsis, then in order to properly treat the source needs

controlled/removed.

If they are not proven noninfected on admission the patient may face unnecessary removal of a noninfected device or we

may be missing the source of a bacteremia.

Please look for central lines, PICC lines, mediports, tunneled HD catheters, etc. and consider these as possible infectious

sources on admission.

If a venous access device IS the source of the patient’s sepsis, then in order to properly treat the source needs

controlled/removed.

If they are not proven noninfected on admission the patient may face unnecessary removal of a noninfected device or we

may be missing the source of a bacteremia.

FOLEY CATHETERS/ INDWELLING

URINARY CATHETERS

**IF THIS IS THE SUSPECTED SOURCE OF THE PATIENT’S INFECTION THE CATHETER SHOULD BE EXCHANGED IF NOT DONE SO IN THE LAST 48 HOURS PRIOR TO COLLECTING A UA/URINE CULTURE**

Antimicrobial therapy

Antimicrobial therapy

“IN THE PRESENCE OF SEPSIS OR SEPTIC SHOCK, EACH HOUR DELAY IN ADMINISTRATION OF APPROPRIATE ANTIMICROBIALS AND ASSOCIATED WITH A MEASURABLE INCREASE IN MORTALITY”.

AS WELL AS INCREASING ORGAN DYSFUNCTION

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Antimicrobial therapyAntimicrobial therapy

• Gram positive coverage:

• Betalactams (PCN, 1st/2nd generation cephalosporins, vancomycin, linezolid)

• Soft tissue infections, SSI

• CAP, post viral pneumonia

VANCOMYCIN

• Lipophilic (must saturate adipose tissue)• Bacteriostatic• Must achieve therapeutic drug level to be effective• Renally cleared, dose dependent on accurate creat

clearance and body weight

*If high clinical suspicion of a Gram positive source of sepsis consider pairing with betalactam while awaiting ID and sensitivities**

• Lipophilic (must saturate adipose tissue)• Bacteriostatic• Must achieve therapeutic drug level to be effective• Renally cleared, dose dependent on accurate creat

clearance and body weight

*If high clinical suspicion of a Gram positive source of sepsis consider pairing with betalactam while awaiting ID and sensitivities**

GRAM NEGATIVE COVERAGE

-UTIs, intraabdominal abscesses, chronic wounds, biliary infections, HCAP or aspiration pneumonias:

Betalactams with betalactamase inhibitors (Unaysn, Zosyn, Zerbaxa, Avycaz), later generation cephaloporins (3rd/4th) Carbapenums, Floroquinolones, aminoglycosides.

-UTIs, intraabdominal abscesses, chronic wounds, biliary infections, HCAP or aspiration pneumonias:

Betalactams with betalactamase inhibitors (Unaysn, Zosyn, Zerbaxa, Avycaz), later generation cephaloporins (3rd/4th) Carbapenums, Floroquinolones, aminoglycosides.

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Drug resistant Gram Negative organismsDrug resistant Gram Negative organisms

-GRAM NEGATIVE BACTERIA PRODUCING ENZYMES THAT CLEAVE THE BETALACTAM RING RENDERING THEM INFECTIVE.

ESBL: RESISTANT TO PCN AND CEPHALOSPORINS (CARBAPENUMS CAN RETAIN EFFICACY)

CRE & KPC: RESISTANT TO ALL BETALACTAMS (INCLUDING CARBAPENUMS)

Gram Negative Coverage continuedGram Negative Coverage continued

• In severe cases, if strong suspicion of Gram negative etiology:

• Consider dual gram negative coverage:

• PCN w/betalactamase inhibitor, 3rd/4th generation cephalosporin, or carbapenum + floroquinolone or aminoglycoside

Combination antimicrobial therapyCombination antimicrobial therapy

• Combination therapy is the addition of dual antibiotics for synergistic effect on a single pathogen.

• Sometimes used in severe sepsis/shock or the treatment of neutropenic sepsis.

• SSC recommends that if combination therapy is used initially for septic shock that discontinuation of this therapy occur once patient has had clinical improvement.

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Fungal coverage: when to considerFungal coverage: when to consider

• Neutropenic patients

• HIV/AIDS

• Transplant recipients

• Prolonged vascular access devices (HD catheters, CVC)

• PD catheter related infections

• Prolonged antibiotic use

• Current TPN use

Helpful fungal serologies to remember for workup of invasive fungal disease

Helpful fungal serologies to remember for workup of invasive fungal disease

• Beta 1 3d glucan

• Fungal antibodies by CF and ID

• Aspergillus Galactomanan

• Urine histoplasmosis AG

• Serum Cryptococcus AG

Viral IllnessesViral Illnesses

• Influenza

• Humanmetapneumovirus

• RSV

• Parainfluenza

• Rhinovirus

• Rotavirus

• Norovirus

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Blood ProductsBlood Products

• SSC reviewed trials evaluating blood transfusions in septic patients.

• Protocol Based Care for Early Septic Shock (ProCESS) trial

• Transfuse Hgb < 7.0

• Transfuse plt < 10 prophylactically

Disseminated intravascular Coagulation: A major complication

Disseminated intravascular Coagulation: A major complication

• Decreased platelets

• Prolonged PT/PTT times

• Elevated D Dimer

• Decreased fibrinogen

ANTICOGULANTSANTICOGULANTS

• Antithrombin (AT) and Thrombomodulin (TM

• Not statistically beneficial in treatment of sepsis prior to DIC

• Associated with increased risk of bleeding

• Septic patients with DIC may have some benefit

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THE FUTURE OF SEPSIS:

New definitions of sepsis

New definitions of sepsis

2016THE THIRD INTERNATIONAL CONSENSUS DEFINITIONS FOR SEPSIS AND SEPTIC SHOCK

• The society of Critical care medicine + the European society of Intensive care medicine.

• Critical care, ID, surgical, and pulmonology

WHY???WHY???

• Advances in understanding the pathobiology and treatment of sepsis.

• Propose that sepsis is not just inflammatory mediated rather multifactorial:

• SIRS criteria does not equal dysregulated host response

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OUTCOMES:

SEVERE SEPSIS IS A REDUNDANT TERM

ORGAN DYSFUNCTION IS A MEASURE OF SEVERITY OF SEPSIS SYNDROME

MEASURE ORGAN DYSFUNCTION

SepsisSepsis

• Life threatening organ dysfunction caused by a dysregulated host response to infection

• Organ dysfunction: Acute change in SOFA score >2 points.

• Baseline SOFA of 0 is assumed in patients without known preexisting dysfunction

Proposed New Septic Shock Definition Proposed New Septic Shock Definition

• Large variable interpretation of septic shock incidence and outcomes

• Goal: New definition of Septic shock

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SOFA

qSOFAqSOFA

• Bedside criteria to identify adult patients at greater risk of poor outcomes.

• Recommended to be used as a prompt to investigate further for organ dysfunction and even escalate care.

• RR > 22

• Altered mentation (GCS <13)

• Systolic BP < 100mmhg

–Third international consensus definitions for sepsis and septic shock 2016

“Septic Shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of

mortality than sepsis alone”

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Septic ShockSeptic Shock

• Hypotension requiring vasopressor use to maintain MAP >65

• Serum lactate > 2 AFTER adequate fluid resucitation

Surviving sepsis campaign response:Surviving sepsis campaign response:

• Initial treatment should remain the same

• Organ dysfunction needs identified

• qSOFA is an appropriate tool to assess for deterioration of the septic patient.

• Clarified qSOFA is NOT a definer of sepsis but rather an indicator of increased mortality risk or prolonged ICU stay

REMEMBER…..

THE FOCUS IS ON EARLY IDENTIFICATION AND PROMPT INTERVENTION!!

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Gotts, J. E., & Matthay, M. A. (2016). Sepsis: Pathophysiology and clinical management. Bmj, I1585. doi:10.1136/bmj.i1585

Lee, S. M., & An, W. S. (2016). New clinical criteria for septic shock: Serum lactate level as new emerging vital sign. Journal of Thoracic Disease, 8(7), 1388-1390. doi:10.21037/jtd.2016.05.55

Martin, G. S., MD, Mannino, D. M., MD, Eaton, S., MD, & M. M., MD. (2003, April 17). The Epidemiology of Sepsis in the United States from 1979 through 2000 | NEJM. Retrieved July 20, 2018, from https://www.nejm.org/doi/full/10.1056/nejmoa022139

Mira, J. C., Gentile, L. F., Mathias, B. J., Efron, P. A., Brakenridge, S. C., Mohr, A. M., . . . Moldawer, L. L. (2017). SepsisPathophysiology, Chronic Critical Illness, and Persistent Inflammation-Immunosuppression and Catabolism Syndrome. Critical Care Medicine, 45(2), 253-262. doi:10.1097/ccm.0000000000002074

National Center for Health Statistics. (2018, September 10). Retrieved September 20, 2018, from https://www.cdc.gov/nchs/nvss/index.htm

Okamoto, K., Tamura, T., & Sawatsubashi, Y. (2016). Sepsis and disseminated intravascular coagulation. Journal of Intensive Care, 4(1). doi:10.1186/s40560-016-0149-0

Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., . . . Angus, D. C. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama, 315(8), 801. doi:10.1001/jama.2016.0287

Surviving Sepsis Campaign Responds to Sepsis-3. (2016, March). Retrieved September 11, 2018, from http://survivingsepsis.org/SiteCollectionDocuments/SSC-Statements-Sepsis-Definitions-3-2016.pdf

Vijayan, A. L., V., Ravindran, S., Saikant, R., Lakshmi, S., Kartik, R., & G, M. (2017). Procalcitonin: A promising diagnostic marker for sepsis and antibiotic therapy. Journal of Intensive Care, 5(1). doi:10.1186/s40560-017-0246-8

Vital Signs: Epidemiology of Sepsis: Prevalence of Health Care Factors and Opportunities for Prevention. (2017). Annals of Emergency Medicine, 69(1), 131-135. doi:10.1016/j.annemergmed.2016.10.016