Mike Broyles, BSPharm, PD, PharmD
Director of Pharmacy and Laboratory Services
Five Rivers Medical Center
Pocahontas, AR

Understand 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

Seriousness of sepsis
Difficulties with the diagnosis of sepsis
Procalcitonin
(PCT)
• Biomarker
• Kinetics
Comparison to other biomarkers
Application of PCT into sepsis management

• 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

•
•
•

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

• Temperature > 100.4F (38C) or < 96.8F (36C)
• Heart rate > 90 beats/minute
• Respiratory rate > 20 breaths/minute or
PaCO
2
< 32 mm Hg
• WBC o > 12,000/mm 3 o < 4000/mm 3 o > 10% immature (band) forms

• Tachycardia – 718 possibilities
• Tachypnea - 371 possibilities
• Increased/Decreased Temperature – 1380 possibilities
• Increased/Decreased WBC – 350 possibilities
541 possible diagnoses with 2 or more of the criteria www.diagnosispro.com

• 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…
SIRS Sepsis
Severe
Sepsis
Septic
Shock
Bone RC, et al . Chest 1992 Jun;101(6):1644-55.

100% 100% 100%
> 90%
PCT 2.0
40%
0%
Pretest situation: only clinical assessment is available
PCT 0.3
0%
Assessment of individual features and addition of
PCT
< 10%
0%
Post-test situation:
Individually adjusted risk assessment
Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis

• 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

Highly specific induction – Produced all tissue
Healthy Sepsis
Calcitonin:
Source of production in healthy people
PCT:
Source of
Production in Septic
Patients
In relevant bacterial infection, PCT is produced and released into circulation from the entire body
Müller B. et al., JCEM 2001

PCT
1 2 6 12
Time (Hours)
24 48 72
• 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
Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892 17

0.05 ng/ml
0.5 ng/ml
2 ng/ml
Healthy
Individuals
Local
Infections
Systemic
Infections
(Sepsis)
Severe
Sepsis
Septic
Shock
• 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

Elevated or rising PCT values
• Systemic response to bacterial infection o Progressing infection o 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 smallcell carcinoma and bronchial carcinoma
• Newborn < 48hr - increased PCT values (physiological peak)

Age (hours)
0 – 6 hours
6 – 12 hours
12 – 18 hours
18 – 30 hours
30 – 36 hours
36 – 42 hours
42 – 48 hours
PCT (ng/ml)
≤ 2
≤ 8
≤15
≤ 21
≤ 15
≤ 8
≤ 2
Chiesa et al., Council & Institute of Ped (1998) 45: 89-97

• 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
• Advantages:
• Rheumatic
• Inflammatory diseases
• Malignancy
• Tissue Injury, Necrosis
• Steroid Treatment
• Liver Failure
• Obesity o Rises in 4 to 6 hours
• Disadvantages: o Non-specific o No correlation to SOFA Scores, o Slow Kinetics (peak 36-50h)
Vingishi et al., J Clin Invest. 1993 Apr ; 91(4): 1351-7
Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1
Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79

)
• Pro-inflammatory cytokine (messenger protein)
• Blood, monocytes, and endothelial cells
• Advantage o Quick rise – one hour o Decreases rapidly
• Disadvantage o Any inflammatory process can increase IL-6 o Affected in immune-compromised patients o Sample must be cooled and spun immediately o 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): 1351-7
Pepys et al., J of Clin Invest. 2003g 1807 col 2 para 2, pg 1808 col 1 para 1
Standage et al., Expert Rev Anti Infect Ther. 2011 Jan 9(1): 71-79

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

Diagnostic accuracy of PCT compared to other biomarkers used in sepsis

“BE”: UTI Case: Lactate Specificity
5
4,5
4
3,5
4,3
3
2,7
2,5
2
ABX Ceftriaxone Zosyn-Tobramycin Vancomycin
1,5
1
0,5
BP
0
142/82
0,05
90/58
0,05
98/60
0,05
1,51
PCT
Lactate
Troponin

HW
73 Y/O female
CC: dysuria, mental status changes, fever, nausea/vomiting
S/P laparoscopic cholecystectomy: 4 days post procedural complication r/o
Temp 103.4
RR 19
BP 86/52
HR 95
WBC 28.4 w/4 bands
SrCr 1.6 w/ BUN 38
Mini-cath UA
• Nitrite positive
• 4+ bacteria
Amlodipine 10mg daily
Benazepril 20mg daily
Propranolol LA 160mg daily
HCTZ 25mg daily
Aspirin 81 mg daily
Furosemide 40mg prn daily for leg edema
Oxybutynin 5mg bid
Alprazolam 0.5mg tid
Dicyclomine 10mg prn tid for irritable bowel
Meloxicam 15mg daily
Zolpidem 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 1 st generation cephalosporins and resistant to quinolones (day2)
• Changed to cephalexin

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

WR
48 Y/O male
Occupation: Lineman
CC: Worsening right thigh and knee pain
Five scratches on leg, 2 -3 cm in length from thorns/briars
Pain is not proportional to visual presentation
Started 24 hours ago
Complains area is “pulsing”
Patient states: “Some swelling in last 18 hours”
Temp 99.2
Pulse 80-90
WBC 13.1
SrCr 2.1
PCT 21
Plain Film
US: Subcutaneous edema suggesting cellulitis, but no localized collections
MRI: Myositis involving vastus lateralis muscle with overlying cellulitis. Most likely etiologies from infection or trauma
Surgery consult
Antibiotics

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

WR

WR
SrCr
7
6
5
4
3
2
1
0
SrCr
ED @ 1130
2,1
Day 1 @ 0530
5,1
Day 1 @ 1200
6,6
PCT
600
500
400
300
200
100
0
PCT
ED @ 1130
21
Day 1 @ 0530 Day 1 @ 0800 Day 1 @ 1200
330 444 550
Lactic Acid
16
14
12
10
8
6
4
2
0
WBC
2
1
0
Lactic Acid
6
5
4
3
ED @ 1130 Day 1 @ 0800
4,8
WBC
ED @ 1120
13,1
Day 1 @ 0530
13
Day 1 @ 1200
5,6
Day 1 @ 0800
13,4

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

ST
66 Y/O female
CC: pain, tenderness, and fever with recurrent cellulitis of left great toe and shin just superior to ankle
Second day of recurrent infection that had “resolved” two weeks ago
Adult onset insulin dependent diabetic
Neuropathy in legs/feet
Mild CHF
HTN
Glargine insulin 32 units daily
Regular insulin Sliding Scale
Sitagliptin 100mg daily
Lisinopril 20mg bid
Furosemide 20mg bid
Carvedilol 25mg bid
Gabapentin 400mg tid
Pregabalin 150mg bid
Alprazolam 0.5mg prn tid
“Aleve” 440mg prn bid on
“most days”
Hydrocodone/Acet 5mg/325mg prn q 4h for pain

• 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
• WBC 24.8
• PCT 77
• Lactate 4.4
• SrCr 2.4
• Worsened hemo-dynamically: increased LVP rate
• Added Tobramycin 7mg/kg
• PCT 64
• Lactate 2.2

ST clinical course
Day 3 - AM
• WBC 22.0
• PCT 39
• Lactate 1.9
• First blood Cx and sensitivity completed
• Escherichia coli: CRE

ST Blood Culture #1
Culture Report
Organism 01 Escherichia coli (esccol)
Antibiotics
Ampicillin
Ampicillin/Sulbactam
Ceftizoxime
R
R
Gentamicin
R
R
ESBL
Cefoxitin
Ceftazidime
Ceftriaxone
Cefepime
Imipenem
Meropenem
Amikacin
Tobramycin
Piperacillin/Tazobactam
Levofloxacin
Trimethoprim/Sulfamethox
R
R
S
S
R
POS
R
R
R
R
R
R

WBC
30
25
20
15
10
5
0
Admissi on
WBC 12,8
Day 1
AM
14,4
Day 1
PM
16,8
Day 2
AM
24,8
Day 3
AM
22
Day 4
AM
18,5
Day 5
AM
11,2
3
2,5
2
1,5
1
0,5
0
SrCr
Admissi on
1,8
Day 1
AM
1,7
SrCr
Day 2
AM
2,4
Day 3
AM
2,2
Day 4
AM
2
Day 5
AM
1,9
PCT
90
80
70
60
50
40
30
20
10
0
Admis sion
PCT 0,6
Day 1
AM
16
Day 1
PM
26
Day 2
AM
77
Day 2
PM
64
Day 3
AM
39
Day 4
AM
16
Day 5
AM
7
5
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
Lactic Acid
Day 1
PM
2,1
Lactic Acid
Day 2
AM
4,4
Day 2
PM
2,4
Day 3
AM
1,9
Day 4
AM
Day 5
AM

• 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

GM
83 Y/O female
Nursing home resident
CC: SOB
Worsening over 4 days
COPD (Gold Stage III)
Recent pneumonia hospitalization
CHF
HTN
Fibromyalgia
GERD
AAA Repair
2 stents in 2012
Spine surgery X4
Pulse Ox 82%
RR 24
Prolonged expiration
Rhonchi bilaterally A/P
Chest film
WBC 3.2
Platelets 99,000
PCT 0.06
Temp 102.4
BP 143/87
Pulse 77
BNP 489

GM
Ticagrelor 90mg bid
Aspirin 81mg daily (was 325mg)
Pregabalin 75mg bid
Carvedilol 6.25mg bid
Atorvastatin 40mg daily
Amiodarone 100mg daily
Enalapril 20mg bid
Mirtazapine 15mg hs
Furosemide 40mg daily (doubled last 4 days)
Hydrocodone/APAP 10mg qid
Duloxetine 60mg daily
Ipratropium/Albuterol qid
Albuterol prn q 2 hours
“Prednisone taper”
Pneumonia
• Infiltrates
• Productive cough
• Signs of infection/inflammation
COPD exacerbation
CHF exacerbation
Cefepime
Vancomycin
Methylpresnisolone
Furosemide
Peripheral 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

14
12
10
8
6
4
2
0
30
25
20
15
10
5
0
WBC
28,2
24,6
22,8
18,1
16,3
10,8
3,2
Admission
Admit
60mg q 6h
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Methylprednisolone
60mg q 6h 40mg q 6h 40mg q 8h 40mg q 8h 40mg q12h 40mg daily
PCT
12,8
5,6
Admission Day 1 Day 2
5,9
3,1
Day 3 Day 4
1,4
Day 5
0,8
Day 6
0,4

WBC
30
25
20
15
10
5
0
3,2
Admission Day 1
18,1
Day 2
22,8
Day 3
28,2
Day 4
24,6
Day 5
16,3
Day 6
10,8
4
3
2
1
6
5
2
0
Admission Day 1
5,7
Day 2
2
Lactate
0,5
Day 3 Day 4 Day 5
14
12
10
8
6
4
2
0
5,6
Admission Day 1
12,8
Day 2
5,9
PCT
Day 3
3,1
Day 4
1,4
Day 5
0,8
Day 6
0,4
Day 6

• 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

• Process in place to avoid loopholes and achieve consistency
• Protocol or Order Sets
• Appropriate biomarkers with clinical presentation o Sensitivity o Specificity
• Lactate should be used primarily for evaluation of resuscitation efforts
• Educate staff

Outcomes Comparison: Control Vs. Procalcitonin
Date range 3 years
Case Mix: 40% coded to an ID related diagnosis
Sepsis related LOS
Sepsis related drugs costs
ICU admissions due to sepsis
Antibiotic exposure – sepsis related
GI related ADR’s (all reported)
Clostridium difficile infections
-50%
-50%
-64%
-45%
-40%
-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
Michael Meisner; Procalcitonin-Biochemistry and Clinical Diagnosis