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procalcitonin: Advancing Decision Making in sepsis. Sean-Xavier Neath, M.D., Ph.D. Assistant Clinical Professor of Medicine Department of Emergency Medicine University of California, San Diego. Objectives. Explore the scope of sepsis, its costs and effects on the healthcare system

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procalcitonin advancing decision making in sepsis

procalcitonin: Advancing Decision Making in sepsis

Sean-Xavier Neath, M.D., Ph.D.

Assistant Clinical Professor of Medicine

Department of Emergency Medicine

University of California, San Diego

objectives
Objectives
  • Explore the scope of sepsis, its costs and effects on the healthcare system
  • Identify the difficulties associated with the rapid diagnosis of sepsis with a focus on the differentiation of bacterial from non-bacterial causes of SIRS
  • Utilize the performance characteristics of the biomarker procalcitonin (PCT) as a marker of sepsis or significant bacterial infection
  • Interpret PCT levels and understand current PCT utilization in the hospital
disclosures
Disclosures

1) Consultant relationships with biomedical companies working on biomarkers in acute disease states

Thermo Fisher Scientific

BRAHMS

2) Employed by the University of California, San Diego Medical Center as an Assistant Professor of Clinical Medicine, Department of Emergency Medicine

what is sepsis
What is Sepsis?
  • Whole Body Inflammatory State plus Infection
systemic inflammatory response syndrome sirs
Systemic Inflammatory Response Syndrome (SIRS)
  • Systemic inflammatory response to a variety of severe clinical insults. Manifested by two or more of the following:
  • Temperature >38ºC or <36ºC
  • Heart rate >90 beats/min
  • Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg
  • WBC >12,000/mm3, <4000/mm3, or >10% immature (band) forms

ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-1655.

sepsis accp sccm definitions
Sepsis: ACCP/SCCM Definitions
  • Sepsis
    • Systemic response to infection – i.e., confirmed or suspected infection plus 2 SIRS criteria
  • Severe Sepsis
    • Sepsis associated with organ dysfunction, hypoperfusion, or hypotension
  • Septic Shock
    • Severe Sepsis that cannot be resuscitated or stabilized with IV fluids alone

ACCP/SCCM Consensus Statement. Chest. 1992;101:1644.

slide7

Infection

Parasite

Severe

Sepsis

Virus

SIRS

Sepsis

Fungus

shock

Trauma

Severe

SIRS

Bacteria

BSI

Burns

Adapted from SCCM ACCP Consensus Guidelines

population adjusted incidence of sepsis usa
Population Adjusted Incidence of Sepsis (USA)

Martin GS et al. NEJM 2003;348:1346

cases of sepsis by pathogen usa
Cases of Sepsis by Pathogen (USA)

Martin GS et al. NEJM 2003;348:1346

infection source in severe sepsis
Infection Source in Severe Sepsis

Angus DC et al. Crit Care Med. 2001; 29:1303

determinants of mortality
Determinants of Mortality
  • Source control is most vital factor
  • Resuscitation/re-establish perfusion in 6 hrs
  • Appropriate antibiotic therapy within 1 hr of hypotension
treatment of septic shock
Treatment of Septic Shock
  • Source Control When Possible
  • Based on Early Goal Directed Therapy
  • Broad, high dose, rapid administration of antibiotics
  • Consider Activated Protein C
  • Minimal role for steroids

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2008. Critical Care Med

difficulties in diagnosis and treating sepsis in the emergency department
Difficulties in Diagnosis and Treating Sepsis in the Emergency Department
  • Differentiation between sepsis and non-infectious causes of SIRS is complicated
  • The large number of patients presenting to the ER at the same time can limit the ability to obtain comprehensive histories and physical examinations
difficulties in diagnosis and treating sepsis in the emergency department1
Difficulties in Diagnosis and Treating Sepsis in the Emergency Department
  • Scoring systems and commonly available diagnostic tools provide limited value in determining which patients will have a poor outcome
  • Initial vital signs can be incomplete, an accurate core temperature can be lacking
  • These limitations often result in the delayed diagnosis of sepsis which in turn delays treatment, increases hospital length-of-stay, increases costs and leads to increased preventable mortality
slide15

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

Kumar A. et al., Crit Care Med 2006, 34:1286

slide17

Key Areas of Sepsis Management

  • Initial Resuscitation
  • Diagnosis
  • Antibiotic therapy
  • Source Control
  • Fluid therapy
  • Vasopressors
  • Inotropic Therapy
  • Steroids
  • Recombinant Human Activated Protein C (rhAPC) [drotrecogin alfa (activated)]
  • Blood Product Administration
  • Mechanical Ventilation
  • Sedation, Analgesia, and Neuromuscular Blockade in Sepsis
  • Glucose Control
  • Renal Replacement
  • Bicarbonate Therapy
  • Deep Vein Thrombosis Prophylaxis
  • Stress Ulcer Prophylaxis
  • Limitation of Support

Dellinger, et. al. Crit Care Med 2004, 32: 858-873.

why procalcitonin
Why Procalcitonin?

Integrated use of PCT with other clinical and laboratory informationpermits:

  • Increased accuracy of clinical diagnosis of relevant bacterial infection / sepsis
  • Improved clinical decision making and patient management
slide20
Procalcitonin – A biomarker for the assessment of critically ill patients at risk for severe bacterial infection and sepsis
  • Simple blood test specific for bacterial infection
  • During severe bacterial infections and sepsis, blood levels rise rapidly (up to x100K) – no elevation from viral infections
  • Is the Standard of Care for much of Europe in the management of infection and sepsis

Morgenthaler N. et al., Clin Lab 2002, 48: 263-270

procalcitonin normally an intermediate product in the synthesis of calcitonin
Procalcitonin – normally an intermediate product in the synthesis of Calcitonin

Thyroid

After P. Linscheid, Endocrinology 2003

N-Pro

Calcitonin

Katacalcin

N

C

1

57 60

91 96

116

LOWPCT values in the blood of healthy persons: 46.7 pg/ml (97.5 percentile); median = 12.7 pg/ml*

Morgenthaler N. et al., Clin Lab 2002, 48: 263-270

procalcitonin presence of bacterial infection stimulates pct production
Procalcitonin – Presence of Bacterial Infection Stimulates PCT Production

Alternative synthesis of PCT

  • Bacterial toxins (gram+/-) and cytokines stimulateproduction of PCT in all parenchymal tissues
  • PCT is immediatelyreleased into bloodstream
  • This process can be blocked during viral infections

Adapted from Christ-Crain et al. 2005

highly specific induction and release of pct due to bacterial infection
Highly specific induction and release of PCT due to bacterial infection
  • In bacterial infection, PCT is produced and released into circulation from the entire body

Healthy

Sepsis

Calcitonin:

Sources of

production

in healthy

people

PCT:

Sources of

Production

in Septic

Patients

Müller B. et al., JCEM 2001

pct level increase increased significance of bacterial infection
PCT Level Increase = Increased Significance of Bacterial Infection
  • In critically ill patients, PCT levels elevate in correlation to the severity of bacterial infection
  • In healthy people, PCT concentration are found below 0.05ng/ml
  • Concentrations exceeding 0.5ng/ml can be interpreted as abnormal
highly specific induction and release of pct due to bacterial infection1
Highly specific induction and release of PCT due to bacterial infection
  • IFN-released in viral infection, blocks the activation of PCT production, therefore in viral infection PCT levelsremain normally low

Adapted from Christ-Crain et al. 2005

benefits and limitations of other sepsis diagnostic tools
Benefits and limitations of other Sepsis diagnostic tools

Microbiology (Blood Culture)

Standard of care, time to result, ?Sens., ? Spec.

Availability, costs, variability of source detection

Imaging (X-Ray, Hr-CT)

Availability, costs, time to results

Molecular Biological Testing

Biopsy

Invasive, relatively expensive

Easy to measure, not invasive, relatively inexpensive

Biomarker Testing (PCT)

Slow kinetics , high impact of inflammation (specificity), suppressed by corticosteroids, relatively inexpensive

C-Reactive Protein (CRP)

diagnostic accuracy of pct compared to other biomarkers used in sepsis
Diagnostic accuracy of PCT compared to other biomarkers used in sepsis
  • PCT levels accurately differentiate sepsis from noninfectious inflammation*
  • PCT has been demonstrated to be the best marker for differentiating patients with sepsis from those with systemic inflammatory reaction not related to infectious cause

Sensitivity: 89%

Specificity: 94%

NPV: 90% / PPV: 94%

Simon L. et al. Clin Infect Dis. 2004; 39:206-217.

slide28
Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of sepsis
  • When PCT is used as a reference, the sensitivity and specificity of sepsis diagnosis can be significantlyincreased compared with conventional clinical parameters.

AUC with PCT: 0.94

AUC without PCT: 0.74

Harbarth S et.al. AM J Resp Crit Care Med. 2001; 164:396-402

pct levels increase according to severity of sepsis
PCT levels increase according to severity of sepsis
  • PCT can aid in the diagnosis and severity stratification in patients suspected of sepsis, severe sepsis, and septic shock.
  • In multiple studies, PCT has demonstrated a high sensitivity and specificity for the differentiation of sepsis from SIRS (Systemic Inflammatory Response Syndrome)
  • PCT levels can be useful for the management of patients after surgery or transplant and in peritonitis

Harbarth S et al. Am J Respir Crit Care Med 2001, 164: 396-402 ; Meisner M et al., Critical Care 1999, 3(1): 45-50 ; Krüger S. et al., Eur Respir J 2008; 31: 349–355

slide30
Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of infection post organ transplant
  • PCT used in early detection of infection after liver transplantation – differentiation from rejection

PCT plasma concentrations in 16 patients without postoperative complications after Liver-Transplantation, Tx: day of transplantation.

PCT plasma concentrations in infection and rejection (n = 11), day 0: day of diagnosis

Kuse ER et al., Crit Care Med 2000; 28: 555-559

pct kinetics provide important information on prognosis of sepsis patients
PCT kinetics provide important information on prognosis of sepsis patients
  • Clinical symptoms alone are often insufficient for early and accurate diagnosis
  • PCT levels, can be observed within 3-6 hours after an infectious challenge with a peak - up to 1000 ng/ml - after 6-12 hrs. Half-life: ~24hrs
  • Specific to bacterial origin of infection and reflects the severity of the infection

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

pct release in the absence of infection
PCT release in the absence of infection
  • Newborn < 48hr - increased PCT values (physiological peak)
    • On 3rd day after birth, normal adult reference ranges apply
  • Primary inflammation syndrome following trauma: multiple trauma, extensive burns, major surgery (cardiac, transplant, abdominal)
    • Rapid decrease (half-life 24hr) in the absence of bacterial infection
  • Medullary C-cell cancers of the thyroid, pulmonary small-cell carcinoma and bronchial carcinoma
  • Prolonged circulatory failure (e.g.. cardiogenic shock, hemorrhagic shock, thermal shock)
  • Treatments that can cause a cytokine storm e.g. OKT3, anti-lymphocyte globulins, etc.
slide34
Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of sepsis in Neonates
  • In early onset neonatal sepsis PCT provides a clear differentiation of infected from uninfected neonates in the first 2 days of life
  • In neonates the PCT values are physiologically and in relation to their age increased.
  • A peak is reached at 24 h with Median at 2 ng/ml and 95%-Percentile at 20 ng/ml.
  • After 3 days the normal values for children and adults apply.

UNINFECTED

INFECTED

PCT

(ng/ml)

PCT

(ng/ml)

Time (hours)

Time (hours)

C Chiesa et al. CID 1997

conditions of bacterial infection where pct may be low in the presence of bacterial infection
Conditions of bacterial infection where PCT may be low in the presence of bacterial infection

Low PCT levels in the presence of bacterial infection may occur:

  • Early course of infection: Re-measure in 6-12hrs
  • SubacuteEndocarditis
  • Localized infections
interpretation of pct levels
Interpretation of PCT levels
  • PCT values must always be interpreted within the clinical context of each individual patient
  • Serial measurement is preferred to assess the situation in real-time
  • Always pay attention to conditions that may influence the PCT level
  • Always consider the dynamics of the disease process (which affect onset of PCT production)
pct kinetics after an infectious challenge
PCT kinetics after an infectious challenge
  • Rapid kinetics: detectable 3 hours after infection has begun, with a peak after 6-12 hrs.
  • Peak values up to 1000 ng/ml
  • Half-life: ~ to 24 hrs
  • Non or minor dependence on renal function

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

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

pct reflects the response of the organism to the bacterial challenge
PCT reflects the response of the organism to the bacterial challenge
  • Elevated / rising PCT levels
    • Systemic response to the infection - indicates that infection is developing or is outside the control of the immune system
    • Risk for further progression
  • Low PCT levels despite clinical signs and symptoms
    • Self-limiting bacterial infection
    • Non-infectious cause
    • Early phase of infection
no pct increase in bacterial contamination only in real bacterial infection
No PCT increase in bacterial contamination, only in real bacterial infection
  • In addition to clinical and microbiological parameters, PCT may help discriminate blood stream infections from blood culture contamination due to coagulase-negative staphylococci
  • At a cut-off of 0.1ng/ml sensitivities and specificities were
  • Day –1 of BC: 86% and 60%
  • Day 0 of BC: 100% and 86%
  • CRP could discriminate only on day +1, but not as clear-cut as PCT

Schuetz P. et al., Infection 2007;35 (5): 352-5

pct levels predict bacteremia in patients with community acquire pneumonia cap
PCT levels predict bacteremia in patients with community acquire pneumonia (CAP)
  • Current guidelines recommend blood culture sampling from hospitalized patients with suspected CAP. Is there a way to reduce the patient harm, costs and errors associated with these recommendations?
  • Prospective cohort study with derivation and validation set including 925 patients with CAP who underwent blood culture sampling on hospital admission.

Muller et al. CHEST July 2010

pct predicts bacteremia in patients with cap patient flow in derivation and validation cohorts
PCT predicts bacteremia in patients with CAP: patient flow in derivation and validation cohorts

Muller et al. CHEST July 2010

slide43
PCT cutoff of 0.1 enables reduction of blood cultures by 12.6% and identifies 99% of Positive Blood Cultures

Muller et al. CHEST July 2010

pct levels predict bacteremia in patients with community acquire pneumonia
PCT levels predict bacteremia in patients with community acquire pneumonia
  • PCT levels accurately predicted blood culture positivity in patients with CAP.
  • PCT measurement demonstrated the potential to reduce the number of blood cultures drawn in the ED to better implement resources
  • The use of PCT in targeting rational blood culture utilization allows for more directing allocation of limited health-care resources.

Muller et al. CHEST July 2010

pct results provide important information on prognosis of cap patients in emergency room
PCT results provide important information on prognosis of CAP patients in emergency room
  • PCT can be used for Risk stratification of patients with CAP
  • Low PCT levels identify patients presenting in the ED with Pneumonia that have a low risk for mortality (N=1,651).

PCT

PCT

Huang, et.al., Annals of Emergency Medicine, Vol 51, March 2008

slide46
Serial measurement of PCT provides a clearer picture of the patient’s response to antibiotic treatment.
  • Decreasing PCT levels in patients with sepsis indicate effective treatment of the underlying infection
  • Persistently elevated PCT levels indicate a possible treatment failure
  • When integrated into the management of septic patients, PCT can help clinicians to manage septic patients more efficiently

Stueber, F. University of Bonn, Lecture at ISICEM, Brussels 2001

pct guidance in antibiotic usage effects on length of stay
PCT guidance in antibiotic usage Effects on length of stay
  • Effect of PCT-guided management in patients with sepsis on ICU length of stay

Nobre V. et alAM Resp Crit Care Med 2008: 177:498-505

pct guidance on effect on length of icu stay
Pct Guidance on effect on length of icu stay
  • Effect of PCT-guided management in patients with sepsis on ICU length of stay

Nobre V. et alAM Resp Crit Care Med 2008: 177:498-505

slide49
PCT guidance in antibiotic usage has been shown to significantly shorten the time patients need to be on antibiotics

KEY TAKEAWAY:

Tailoring of AB treatment using PCT to the individual patient needs safely led to a reduction of average treatment duration from 12 to 5 days with same outcome

Nobre V. et al AM Resp Crit Care Med 2008: 177:498-505

effect of pct testing on antibiotic use a multicenter randomized control trial
Effect of PCT testing on Antibiotic use – a multicenter, randomized control trial

The ProHOSP Trial

  • Lower respiratory tract infections (LRTI)
    • Most frequent indication for antibiotic prescriptionsin the Northwestern hemisphere
    • 75% of patients are treated with antibiotics
    • Predominantly viral origin of infection
  • Procalcitonin (PCT) algorithm
    • Reduced antibiotic use in patients with LRTIs

Schuetz P et al. J Am Med Assoc. 2009;302:1059-66.

study design
Study Design
  • Multicenter, noninferiority, randomized controlled trial
  • Patients
    • Randomized to administration of antibiotics based on PCT algorithm
    • Cutoff ranges for initiating or stopping antibiotics (PCT group) or standard guidelines (control)
    • Serum PCT was measured locally
  • Main Outcome Measures
    • Composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection within 30 days
    • Antibiotic exposure and adverse effects from antibiotics

Schuetz P et al. J Am Med Assoc. 2009;302:1059-66.

rates of combined adverse outcomes and mortality by randomization group
Rates of Combined Adverse Outcomes and Mortality by Randomization Group

Schuetz P et al. J Am Med Assoc. 2009;302(10):1059-66.

slide53

Antibiotic Exposure in Patients Receiving Antibiotic Therapy

PCTControl

All Patients (n = 1359)

Community-acquired Pneumonia (n = 925)

100

80

60

Patients Receiving Antibiotic Therapy, %

40

20

0

0 1 2 5 7 9 11 >13

0 1 2 5 7 9 11 >13

Time After Study Inclusion, d

Time After Study Inclusion, d

No. of Patients PCT 506 484 410 306 207 138 72 46 Control 603 589 562 516 420 324 157 100

417 410 359 272 161 126 64 41461 453 444 428 361 292 146 91

Schuetz P et al. J Am Med Assoc. 2009;302(10):1059-66.

slide54

Antibiotic Exposure in Patients Receiving Antibiotic Therapy

PCTControl

Exacerbation of COPD (n = 228)

Acute Bronchitis (n = 151)

100

80

60

Patients Receiving Antibiotic Therapy, %

40

20

0

0 1 2 5 7 9 11 >13

0 1 2 5 7 9 11 >13

Time After Study Inclusion, d

Time After Study Inclusion, d

No. of Patients PCT 56 47 30 23 16 6 4 2 Control 79 78 67 56 40 20 5 4

16 11 9 3 3 1 1 141 38 35 19 8 3 0 0

PCT: ProcalcitoinCOPD: Chronic Obstructive Pulmonary Disease

Schuetz P et al. J Am Med Assoc. 2009;302(10):1059-66.

slide55

Adverse Outcomes

PCTControl

All Patients (n = 1359)

CAP (n = 925)

0.2

0.2

0.1

0.1

Proportion with Combined

Proportion with Combined

Adverse Outcome

Adverse Outcome

0.0

0.0

0

10

20

30

0

10

20

30

Days Since Randomization

Days Since Randomization

No. at Risk

No. at Risk

PCT

671

605

579

568

PCT

460

408

394

386

688

Control

598

576

558

Control

465

396

383

371

Schuetz P et al. J Am Med Assoc. 2009;302(10):1059-66.

conclusions
Conclusions
  • An algorithm with PCT cutoff ranges was noninferior to clinical guidelines in terms of adverse outcomes in CAP:
    • Reduced antibiotic exposure
    • Reduced associated adverse effects
  • In countries with higher antibiotic prescription rates, PCT guidance may have clinical and public health implications

Schuetz P et al. J Am Med Assoc. 2009;302:1059-66.

case study h c
Case Study- H.C.
  • 31 year old female w/ multiple sclerosis on weekly plasmapheresis
  • Hospitalized in early July for possible catheter infection
  • Catheter removed, only 1 blood culture growing coagulase negative staph.
  • Transitioned from vancomycin to ofloxacin then to doxycycline
case study h c1
Case Study- H.C.
  • Seen in ER June 8 the night of hospital discharge. Patient still concerned about redness and itchiness near former line site
  • Given empiric dose of vancomycin after drawing blood cultures, CBC, PCT.
  • Discharged home to be followed by PCP and dermatology next day to determine if broad spectrum antibiotics needed to be continued.
  • June 9 dermatology clinic visit suggests patient w/ contact dermatitis; continues previous course of doxy
case study h c2
Case Study H.C.
  • Procalcitonin 0.11
  • PCT level provides reassurance that:
    • recurrence of systemic infection unlikely,
    • present narrow-spectrum antibiotic choice likely effective providing better antimicrobial stewardship
case study e p
Case Study E.P.
  • “classic” PCT benefit case
  • 72 yo male w/ valvular heart disease, sick sinus syndrome s/p pacemaker* to ED w/ acute SOB on July 8th middle of night shift.
  • Not known to our system, his primary hospital ER was on bypass, no old records or previous imaging available
  • O2, bronchodilators, empiric broad spectrum antibiotics after blood cultures, labs including PCT
  • Admitted to intermediate care unit for high flow O2, antibiotics, monitoring, bronchodilators, trial of diuretics.

*increasing prevalence of elderly patients with pacemakers or on betablockers reduces clinical vital sign effectiveness in diagnosis SIRS and Sepsis since heart rate may be artificially blunted

case study e p1
Case Study E.P.
  • Within 24 hours he required transfer to the ICU and intubation for respiratory distress and sepsis
  • PCT was 3.45 from ED draw but due to his nighttime arrival was not available until after admitted to floor.
case study e c
Case Study E.C.
  • 63 yo male w/ fever, chills, atrial fibrillation with RVR (HR 140s)
  • Treated with diltiazem and broad spectrum antibiotics
  • Symptoms resolved within two days and patient discharged home on azithromycin
  • Emergency department PCT was 0.12
  • Record review show patient's previous admission for afib with RVR was attributed to documented influenza A
  • No virology studies during this admission, only "positive" microbiological finding was a coag negative staph blood culture on hospital day 2.
  • Should patient have had virology screening done even though it was not flu season?
information from pct adds to the quality of the clinical decision making
Information from PCT adds to the quality of the clinical decision making
  • Understand the kinetics and limitations of any test in order to optimize its utilization!
  • Guidance of therapy
    • Decision on antibiotic initiation
    • Guidance of duration of therapy
  • Risk stratification of patients
    • Admission to hospital
    • Admission to ICU
    • Escalation of therapy
  • Guidance of diagnosis
    • More appropriate selection of who might need invasive diagnostic tests
    • Rational utilization of advance imaging modalities
    • Improved direction in choice of microbiology and virology studies