Transcript PROCALCITONIN: Contributing to IMPROVED CLINICAL …

Sepsis in the Rural Setting:
Early Recognition
and Management
Mike Broyles, BSPharm, PD, PharmD
Director of Pharmacy and Laboratory Services
Five Rivers Medical Center
Pocahontas, AR
No Disclosures
Objectives
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
Outline
Seriousness
of sepsis
Difficulties
with the
diagnosis of
sepsis
Procalcitonin
(PCT)
• Biomarker
• Kinetics
Comparison
to other
biomarkers
Application
of PCT into
sepsis
management
Severe sepsis is costly and lifethreatening
• 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
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
Making the Diagnosis
• 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: 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…
SIRS
Sepsis
Severe
Sepsis
Septic
Shock
Bone RC, et al. Chest 1992 Jun;101(6):1644-55.
Probability of a Sepsis Diagnosis
100%
100%
100%
> 90%
PCT 2.0
40%
PCT 0.3
< 10%
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
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
Highly specific induction – Produced all tissue
Calcitonin:
Source of
production
in healthy
people
Healthy Sepsis
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
Plasma Concentration
PCT Kinetics
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
PCT values correlate directly with
severity of bacterial load
2 ng/ml
0.5 ng/ml
0.05 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
PCT as a response to bacterial
challenge
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
Procalcitonin release in the
absence 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)
Newborns less than 48 hours
PCT measurements
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
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-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
Interleukin-6 (IL-6)
• Pro-inflammatory cytokine (messenger protein)
• Blood, monocytes, and endothelial cells
• Advantage
o Quick rise – one hour
o Decreases rapidly
• Disadvantage
o
o
o
o
Any inflammatory process can increase IL-6
Affected in immune-compromised patients
Sample must be cooled and spun immediately
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
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
PCT
4.5
Lactate
4.3
4
Troponin
3.5
3
2.7
2.5
2
ABX
Ceftriaxone
Zosyn-Tobramycin
Vancomycin
1.5
1.51
1
BP
142/82
90/58
98/60
0.5
0
0.05
0.05
0.05
Case Presentations
Application of PCT use for
Sepsis and Antibiotic
Management
HW
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
Medications
CC: dysuria, mental status
changes, fever,
nausea/vomiting
CC/Hx/Presentation
73 Y/O female
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
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•
•
•
•
•
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?
WR
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
Labs/X-Ray/Plan
Occupation: Lineman
CC/Hx/Presentation
48 Y/O male
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
SrCr
Lactic Acid
7
6
6
5
5
4
4
3
3
2
2
1
1
0
ED @ 1130
SrCr
Day 1 @ 0530
2.1
5.1
0
Day 1 @ 1200
6.6
ED @ 1130
Day 1 @ 0800
Day 1 @ 1200
4.8
5.6
Lactic Acid
PCT
WBC
600
16
14
500
12
400
10
300
8
6
200
4
100
0
PCT
2
ED @ 1130
Day 1 @ 0530
Day 1 @ 0800
Day 1 @ 1200
21
330
444
550
0
WBC
ED @ 1120
Day 1 @ 0530
Day 1 @ 0800
13.1
13
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
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
Medications
CC: pain, tenderness, and fever
with recurrent cellulitis of left
great toe and shin just superior
to ankle
CC/Hx/Presentation
66 Y/O female
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
ST Blood Culture #1
Culture Report
Organism 01 Escherichia coli (esccol)
Antibiotics
Ampicillin
R
Ampicillin/Sulbactam
R
Ceftizoxime
R
Gentamicin
R
ESBL
POS
Cefoxitin
R
Ceftazidime
R
Ceftriaxone
R
Cefepime
R
Imipenem
R
Meropenem
R
Amikacin
S
Tobramycin
S
Piperacillin/Tazobactam
R
Levofloxacin
R
Trimethoprim/Sulfamethox
R
WBC
SrCr
30
3
25
2.5
20
2
15
1.5
10
1
5
0.5
0
Admissi Day 1
on
AM
WBC
12.8
14.4
Day 1
PM
Day 2
AM
Day 3
AM
Day 4
AM
Day 5
AM
16.8
24.8
22
18.5
11.2
0
Admissi
on
Day 1
AM
Day 2
AM
Day 3
AM
Day 4
AM
Day 5
AM
1.8
1.7
2.4
2.2
2
1.9
SrCr
PCT
90
80
70
60
50
40
30
20
10
0
PCT
Admis Day 1
sion
AM
0.6
16
Lactic Acid
Day 1
PM
Day 2
AM
Day 2
PM
Day 3
AM
Day 4
AM
Day 5
AM
26
77
64
39
16
7
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Lactic Acid
Day 1
PM
Day 2
AM
Day 2
PM
Day 3
AM
2.1
4.4
2.4
1.9
Day 4
AM
Day 5
AM
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
GM
CC: SOB
Worsening over 4 days
COPD (Gold Stage III)
Recent pneumonia
hospitalization
Pulse Ox 82%
RR 24
Prolonged expiration
Rhonchi bilaterally A/P
Chest film
WBC 3.2
CHF
Platelets 99,000
HTN
PCT 0.06
Fibromyalgia
Temp 102.4
GERD
BP 143/87
AAA Repair
Pulse 77
2 stents in 2012
BNP 489
Spine surgery X4
Presentation
Nursing home resident
CC/Hx
83 Y/O female
GM
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)
Pneumonia
• Infiltrates
• Productive cough
• Signs of infection/inflammation
COPD exacerbation
CHF exacerbation
Cefepime
Vancomycin
Methylpresnisolone
Hydrocodone/APAP 10mg qid
Furosemide
Duloxetine 60mg daily
Peripheral smear
Ipratropium/Albuterol qid
Albuterol prn q 2 hours
“Prednisone taper”
Assessment/Plan
Aspirin 81mg daily (was 325mg)
Medications
Ticagrelor 90mg bid
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
WBC
30
28.2
25
24.6
22.8
20
18.1
16.3
15
10.8
10
5
3.2
0
Admission
Admit
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
40mg q 8h
40mg q12h
40mg daily
Methylprednisolone
60mg q 6h
60mg q 6h
40mg q 6h
40mg q 8h
PCT
14
12.8
12
10
8
6
5.9
5.6
4
3.1
2
1.4
0
Admission
Day 1
Day 2
Day 3
Day 4
0.8
Day 5
0.4
Day 6
WBC
30
Lactate
6
28.2
25
5
24.6
22.8
20
4
18.1
16.3
15
3
10.8
10
5
5.7
2
2
2
1
3.2
0.5
0
0
Admission
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Admission
PCT
14
12.8
12
10
8
6
5.9
5.6
4
3.1
2
1.4
0
Admission
Day 1
Day 2
Day 3
Day 4
0.8
Day 5
0.4
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
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 Sensitivity
o Specificity
• Lactate should be used primarily for evaluation of
resuscitation efforts
• Educate staff
Five Rivers Medical Center
Outcomes Comparison: Control Vs. Procalcitonin
Date range 3 years
Case Mix: 40% coded to an ID related diagnosis
Sepsis related LOS
-50%
Sepsis related drugs costs
-50%
ICU admissions due to sepsis
Antibiotic exposure – sepsis related
GI related ADR’s (all reported)
-64%
-45%
-40%
Clostridium difficile infections
-54%
Summary
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
Questions