Sepsis in the Rural Setting: Early Recognition and Management

Mike Broyles, BSPharm, PD, PharmDDirector of Pharmacy and Laboratory ServicesFive Rivers Medical CenterPocahontas, AR

No Disclosures

ObjectivesUnderstand the definitions and differing clinical presentations of SIRS, Sepsis, Severe Sepsis and Septic shock as defined by SCCM/ACCP

Discuss the role of biomarkers, clinical presentation, and other laboratory tests used in the evaluation of patients with suspected Sepsis

Recognize how procalcitonin, other biomarkers, and clinical exam can assist in early recognition, risk stratification, and management of patients with suspected and confirmed Sepsis

Outline

Seriousness of sepsis

Difficulties with the

diagnosis of sepsis

Procalcitonin (PCT)• Biomarker• Kinetics

Comparison to other

biomarkers

Application of PCT into

sepsis managemen

t

• Strikes more than 750,000 people each year in the United States

• Mortality remains greater than 30% (1 person every 2.5 minutes)

• Mortality rate has not improved in the last 20 years• Newborn, pediatric, adults, aged• Morbidity• Surgical sepsis rate is increasing

• Clinical diagnosis remains challenging

Severe sepsis is costly and life-threatening

Determinants of mortality from sepsis

• Early intervention is critical• Appropriate antibiotic therapy within

one hour of hypotension• Resuscitation / re-establish perfusion

within six hours

Duration of hypotension before initiation of appropriate ABX therapy is the critical determinant of survival in septic shock

Why do we struggle with the diagnosis of sepsis?

Relationship of SIRS, Sepsis, and Infection

SIRS Criteria: Two or more of the following

• Temperature > 100.4F (38C) or < 96.8F (36C)• Heart rate > 90 beats/minute• Respiratory rate > 20 breaths/minute or

PaCO2 < 32 mm Hg• WBC

o > 12,000/mm3 o < 4000/mm3 o > 10% immature (band) forms

• Tachycardia – 718 possibilities• Tachypnea - 371 possibilities • Increased/Decreased Temperature – 1380

possibilities• Increased/Decreased WBC – 350

possibilities

Making the Diagnosis

www.diagnosispro.com

541 possible diagnoses with 2 or more of the criteria

Sepsis: ACCP/SCCM Definitions•Sepsis is SIRS plus a known or suspected infection.•Severe Sepsis is sepsis associated with organ dysfunction, hypoperfusion, or hypotension.• Septic Shock is sepsis-induced hypotension despite adequate

fluid resuscitation along with the presence of perfusion abnormalities.

• May include• Lactic acidosis• Oliguria• An Acute alteration in mental status• Others…

Bone RC, et al. Chest 1992 Jun;101(6):1644-55.

SIRSSepsis

Severe SepsisSeptic Shock

100% 100% 100%

0% 0% 0%Pretest situation: only clinical assessment is available

Assessment of individual features and addition of PCT

Post-test situation: Individually adjusted risk assessment

Probability of a Sepsis Diagnosis

   

40%

PCT 2.0

PCT 0.3

> 90%

< 10%

Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis

What is Procalcitonin and its role in sepsis management?

Procalcitonin• PCT is an immunologically active protein• PCT is induced in systemic inflammatory reactions • Bacterial infections induce PCT• PCT induction is generally in direction proportion to

the bacterial insult to the body• Viral infections, autoimmune diseases, transplant

rejections, and allergic reactions generally do not induce PCT

• PCT is therefore an “indirect marker” of a bacterial infection: PCT a measurement of the body’s inflammatory response to the bacteria

Calcitonin: Source of

production in healthy

people

Müller B. et al., JCEM 2001

In relevant bacterial infection, PCT is produced and released into circulation from the entire body

Highly specific induction – Produced all tissue

Healthy Sepsis

PCT:Source of Productionin Septic Patients

PCT Kinetics

• Rapid kinetics: detectable 3 hours after infection has begun, with a peak after 12 to 24 hours

• Peak values up to 1000 ng/ml• Half-life: ~ to 24 hours

17Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892

Time (Hours)

Plas

ma

Conc

entr

ation

1 2 6 12 24 48 72

PCT

• In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection

• Integrating PCT in sepsis management can lead to improved patient outcomes

PCT values correlate directly with severity of bacterial load

Healthy Individuals

Local Infections

Systemic Infections (Sepsis)

Severe Sepsis

Septic Shock

0.05 ng/ml

0.5 ng/ml

2 ng/ml

PCT as a response to bacterial challenge

Elevated or rising PCT values• Systemic response to bacterial infection

oProgressing infectiono Immune system is overwhelmed

• Risk of significant disease progression

Low PCT values in presence of clinical presentation• Self-limiting infection• Non-bacterial etiology• Early phase of infection

• Primary inflammation syndrome following trauma: multiple trauma, extensive burns, major surgery (abdominal and transplant)

• Severe pancreatitis or severe liver damage (1)• Prolonged circulatory failure: IE severe multiple organ

dysfunction syndrome (MODS) (1.4)• Medullary C-cell cancers of the thyroid, pulmonary small-

cell carcinoma and bronchial carcinoma• Newborn < 48hr - increased PCT values (physiological

peak)

Procalcitonin release in the absence of infection

Newborns less than 48 hours PCT measurements

Age (hours) PCT (ng/ml)0 – 6 hours ≤ 2

6 – 12 hours ≤ 812 – 18 hours ≤1518 – 30 hours ≤ 2130 – 36 hours ≤ 1536 – 42 hours ≤ 842 – 48 hours ≤ 2

Chiesa et al., Council & Institute of Ped (1998) 45: 89-97

C-Reactive Protein (CRP)• Acute Phase Reactant synthesized by

the liver• Secretion triggered by cytokine (IL-6, IL-1, TNF-

α)

• Produced in response to acute & chronic inflammation • Bacterial, Viral, Fungal• Rheumatic• Inflammatory diseases• Malignancy• Tissue Injury, Necrosis• Steroid Treatment• Liver Failure• Obesity

• Advantages: o Rises in 4 to 6 hours

• Disadvantages: o Non-specifico No correlation to SOFA Scores, o Slow Kinetics (peak 36-50h)

Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79

Interleukin-6 (IL-6)• Pro-inflammatory cytokine (messenger protein)• Blood, monocytes, and endothelial cells• Advantage

o Quick rise – one houro Decreases rapidly

• Disadvantageo Any inflammatory process can increase IL-6o Affected in immune-compromised patientso Sample must be cooled and spun immediatelyo Containers must be free of endotoxins since IL-6 can be formed by

decomposed leukocytes in the blood sample

Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79

LactateLactate (lactic acid) is produced due to inadequate tissue perfusion – a defining parameter of late sepsis.• Advantage

• Rapid turn-around• Readily available• Reliable marker of perfusion and prognosis

• Disadvantage• Late elevation in course of sepsis• Non-specific

Reduction of lactate is advocated as a target for therapeutic interventions (2C)

Blomkalns AL www.emcreg.org 2007Poeze M, et al. Crit Care Med 2005 Nov;33(11):2494-500Muller B, et al. Crit Care Med 2000 Apr;28(4):977-83

Diagnostic accuracy of PCT compared to other biomarkers used in sepsis

Day 1

@ ...

Day 2

@ ...

Day 2

@ ...

Day 2

@ ...0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

0.05 0.05 0.05

2.7

4.3

1.51

PCT LactateTro-ponin

BP 142/82 90/58 98/60

“BE”: UTI Case: Lactate Specificity

ABX Ceftriaxone Zosyn-Tobramycin Vancomycin

Case PresentationsApplication of PCT use for Sepsis and Antibiotic Management

HW

CC/Hx/

Presentation

73 Y/O femaleCC: dysuria, mental status changes, fever, nausea/vomitingS/P laparoscopic cholecystectomy: 4 days post procedural complication r/oTemp 103.4RR 19BP 86/52HR 95WBC 28.4 w/4 bandsSrCr 1.6 w/ BUN 38Mini-cath UA• Nitr

ite positive

• 4+ bacteria

Medications

Amlodipine 10mg dailyBenazepril 20mg dailyPropranolol LA 160mg dailyHCTZ 25mg dailyAspirin 81 mg dailyFurosemide 40mg prn daily for leg edemaOxybutynin 5mg bid Alprazolam 0.5mg tid Dicyclomine 10mg prn tid for irritable bowelMeloxicam 15mg dailyZolpidem 5mg hs

HW

ED Treatment Plan: Dx of Sepsis due to UTI

• Admit to ICU • Meropenem • Tobramycin• Cystalloids and dopamine

HW• Hospitalist orders PCT in ICU after admission• PCT 0.25 ng/ml • Fluid bolus and continued rehydration• DC dopamine• DC merpenem• DC tobramycin• Start piperacillin/tazobactam • Moved to Med-Surg• Cx: Proteus mirabilis sensitive to 1st generation

cephalosporins and resistant to quinolones (day2)• Changed to cephalexin

HW Clinical Perles• Patient met SIRS criteria• SIRS criteria complicated by medications?• SIRS criteria clouded by volume depletion?• Baseline PCT • Process to ensure PCT draw• Establish a process - Order sets

Considerations

• Assumed sepsis prompting aggressive response• ICU admission?• Vasopressor?

Labs/X-

Ray/Plan

Temp 99.2Pulse 80-90WBC 13.1SrCr 2.1PCT 21Plain FilmUS: Subcutaneous edema suggesting cellulitis, but no localized collectionsMRI: Myositis involving vastus lateralis muscle with overlying cellulitis. Most likely etiologies from infection or traumaSurgery consultAntibiotics

CC/Hx/

Presentation

48 Y/O maleOccupation: LinemanCC: Worsening right thigh and knee painFive scratches on leg, 2 -3 cm in length from thorns/briarsPain is not proportional to visual presentationStarted 24 hours agoComplains area is “pulsing”Patient states: “Some swelling in last 18 hours”

WR

WR

ED orders

• Clindamycin 300 IV once • Doxycycline 100 mg IV once

Initial Admission orders

• Clindamycin 300 mg IV every 6 hours• Doxycycline 100 mg IV every 12 hours

WR

Revised admission orders

• DC Doxycycline• Clindamycin 800 mg IV every 8 hours• Piperacillin/tazobactam 3.375 grams IV

every 6 hours

WR

ED @ 1130 Day 1 @ 0800 Day 1 @ 12000

1

2

3

4

5

6

Lactic Acid

ED @ 1130 Day 1 @ 0530 Day 1 @ 0800 Day 1 @ 12000

100

200

300

400

500

600

PCT

ED @ 1120 Day 1 @ 0530 Day 1 @ 08000

2

4

6

8

10

12

14

16

WBC

ED @ 1130 Day 1 @ 0530 Day 1 @ 12000

1

2

3

4

5

6

7

SrCr

WR – MRI Leg

WR – MRI Leg

WR Clinical Perles: Continued Procalcitonin escalation despite suspected adequate Abx

• Clinical presentation mismatch to seriousness of illness

• A significant elevation in PCT is always a cause for concern

• Resistant organism• Abscess• Need for surgical intervention • Other source/site of infection

STMedications

Glargine insulin 32 units dailyRegular insulin Sliding ScaleSitagliptin 100mg dailyLisinopril 20mg bidFurosemide 20mg bidCarvedilol 25mg bid Gabapentin 400mg tidPregabalin 150mg bid Alprazolam 0.5mg prn tid“Aleve” 440mg prn bid on “most days” Hydrocodone/Acet 5mg/325mg prn q 4h for pain

CC/Hx/

Presentation

66 Y/O female CC: pain, tenderness, and fever with recurrent cellulitis of left great toe and shin just superior to ankleSecond day of recurrent infection that had “resolved” two weeks agoAdult onset insulin dependent diabeticNeuropathy in legs/feetMild CHFHTN

ST clinical course

Admission – AM

• Plain film • Scheduled MRI• WBC 12.8• PCT 0.6• SrCr 1.8• Piperacillin/Tazobactam • Vancomycin

ST clinical course

Day 1 - AM

• WBC 14.4• PCT 16• Lactate 2.1• SrCr 1.7• Replace Piperacillin/Tazobactam with Meropenem

Day 1 - PM

• WBC 16.8• PCT 26• Lactate 2.1• Replaced Vancomycin with Linezolid

ST clinical course

Day 2 - AM

• WBC 24.8• PCT 77• Lactate 4.4 • SrCr 2.4• Worsened hemo-dynamically: increased LVP rate• Added Tobramycin 7mg/kg

Day 2 - PM

• PCT 64• Lactate 2.2

ST clinical course

Day 3 - AM

• WBC 22.0• PCT 39• Lactate 1.9• Blood Cx: gram stain gram negative rods

Day 3 - PM

• First blood Cx and sensitivity completed• Escherichia coli: CRE

Culture Report Organism 01 Escherichia coli (esccol) Antibiotics Ampicillin RAmpicillin/Sulbactam RCeftizoxime RGentamicin RESBL POSCefoxitin RCeftazidime RCeftriaxone RCefepime RImipenem RMeropenem RAmikacin STobramycin SPiperacillin/Tazobactam RLevofloxacin RTrimethoprim/Sulfamethox R

ST Blood Culture #1

Ad-mis-sion

Day 1 AM

Day 1 PM

Day 2 AM

Day 3 AM

Day 4 AM

Day 5 AM

0

5

10

15

20

25

30

WBC

Ad-mis-sion

Day 1 AM

Day 1 PM

Day 2 AM

Day 2 PM

Day 3 AM

Day 4 AM

Day 5 AM

0102030405060708090

PCT

Ad-mis-sion

Day 1 AM

Day 2 AM

Day 3 AM

Day 4 AM

Day 5 AM

0

0.5

1

1.5

2

2.5

3SrCr

Day 1 PM Day 2 AM Day 2 PM Day 3 AM Day 4 AM Day 5 AM0

0.51

1.52

2.53

3.54

4.55

Lactic Acid

ST Clinical Perles

• Understanding PCT principles will allow effective monitoring and shorten time to intervene > requires through education efforts

• Reducing intervention time can preempt more serious disease progression

• PCT is effective in monitoring and managing antibiotic therapy

GMCC/Hx83 Y/O

femaleNursing home residentCC: SOBWorsening over 4 daysCOPD (Gold Stage III)Recent pneumonia hospitalizationCHFHTNFibromyalgiaGERDAAA Repair2 stents in 2012Spine surgery X4

Presentation

Pulse Ox 82%RR 24Prolonged expirationRhonchi bilaterally A/PChest filmWBC 3.2Platelets 99,000PCT 0.06Temp 102.4BP 143/87Pulse 77BNP 489

GMMedications

Ticagrelor 90mg bidAspirin 81mg daily (was 325mg)Pregabalin 75mg bidCarvedilol 6.25mg bid Atorvastatin 40mg dailyAmiodarone 100mg dailyEnalapril 20mg bid Mirtazapine 15mg hsFurosemide 40mg daily (doubled last 4 days)Hydrocodone/APAP 10mg qid Duloxetine 60mg dailyIpratropium/Albuterol qidAlbuterol prn q 2 hours“Prednisone taper”

Assessment/

Plan

Pneumonia• Infilt

rates

• Productive cough

• Signs of infection/inflammation

COPD exacerbationCHF exacerbationCefepimeVancomycinMethylpresnisoloneFurosemidePeripheral smear

GM

Admission

• Cefepime 1gm q 8 hours• Vancomycin dose adjusted• Furosemide 40mg IV q 12 hours• Methylprednisolone 60mg IV q 6 hours

Day 1 AM

• All meds same except:• DC Furosemide: BP 90/60’s & HR > 110

Admit Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Methylprednisolone60mg q 6h 60mg q 6h 40mg q 6h 40mg q 8h 40mg q 8h 40mg q12h 40mg daily

Admission Day 1 Day 2 Day 3 Day 4 Day 5 Day 60

5

10

15

20

25

30

3.2

18.122.8

28.224.6

16.3

10.8

WBC

Admission Day 1 Day 2 Day 3 Day 4 Day 5 Day 60

2

4

6

8

10

12

14

5.6

12.8

5.9

3.1

1.40.8 0.4

PCT

Admission Day 1 Day 2 Day 3 Day 4 Day 5 Day 60

2

4

6

8

10

12

14

5.6

12.8

5.9

3.1

1.40.8 0.4

PCT

Admission Day 1 Day 2 Day 3 Day 4 Day 5 Day 60

1

2

3

4

5

6

2

5.7

2

0.5

Lactate

Admission Day 1 Day 2 Day 3 Day 4 Day 5 Day 60

5

10

15

20

25

30

3.2

18.1

22.8

28.2

24.6

16.3

10.8

WBC

GM Clinical Perles

• WBC may be a poor biomarker affected by immune state, diseases, and steroids

• When LOS permits, use PCT follow up algorithms to stop antibiotic therapy sooner

• Decrease ABX exposure• Selection for resistance• Adverse event reduction

Keys to Success: Early Recognition and Treatment

• Process in place to avoid loopholes and achieve consistency

• Protocol or Order Sets• Appropriate biomarkers with clinical presentation

o Sensitivityo Specificity

• Lactate should be used primarily for evaluation of resuscitation efforts

• Educate staff

Five Rivers Medical Center

Outcomes Comparison: Control Vs. ProcalcitoninDate range 3 yearsCase Mix: 40% coded to an ID related diagnosisSepsis related LOS -50%Sepsis related drugs costs -50%ICU admissions due to sepsis -64%Antibiotic exposure – sepsis related -45%GI related ADR’s (all reported) -40%Clostridium difficile infections -54%

The most important indications for PCT levels• Diagnosis of sepsis, severe sepsis, and septic shock• Differential diagnosis of clinically relevant bacterial

infections and sepsis• Evaluation of the severity of a bacterial infection and

systemic inflammatory reactions• Monitoring of the course of treatment of patients with

sepsis• Evaluation of progression and control of antibiotic

treatment

Summary

Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis

Questions