Procalcitonin guided antibiotic therapy in the ICU

John Muscedere, MD, FRCPCKingston General Hospital, Queen’s University

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Disclosures• No conflicts to declare

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Procalcitonin: Health

• Secretion normally confined to Thyroid C cells• Precursor of calcitonin

which is active in Ca++ metabolism

• PCT has no known biological activity• Cleavage of PCT only occurs in thyroid• Levels of PCT undetectable in serum

Schneider, Pathology 2007

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Procalcitonin: Inflammatory States

•Secretion of PCT is markedly increased. •Produced by non-neurodocrine cells throughout the body

• Lung, liver, kidney, fat, muscle

•Part of inflammatory cascade• Different timelines than othermarkers of inflammation • Increased in response to LPS, (endotoxin), IL-1

Becker, CCM 2008

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Procalcitonin: Causes of increased levels

Infection (Bacterial, Viral, Parasitic)

Localized Pneumonia,

Systemic Sepsis, severe sepsis, septic shock

Inflammatory

Pulmonary Aspiration, Inhalational injury

Non-pulmonary Pancreatitis, Heat Stroke, Connective tissue diseaseTissue Trauma

Surgery

Accidental Blunt trauma, Burns

Tumours

Neuroendocrine Medullary thyroid cancer, Small cell lung, Carcinoid

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Procalcitonin and Infection• In severe infections or sepsis, PCT

levels can vary over very wide ranges• PCT levels > 10 ug/L• May not be elevated in some with

severe infections• Statistically pts with sepsis, have

much higher levels than pts with SIRS but there is substantial overlap

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Biomarkers

Diagnostic Uncertainty

Diagnostic Certainty

Procalcitonin

SIRS

SEPSIS

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Procalcitonin• Two meta-analysis: ability of PCT to distinguish

SIRS from Sepsis• Uzzin 2006: 25 studies, 2966 patients

including shock, abdominal sepsis• Tang 2007: 18 studies, 2097 patients,

excluded shock, abdominal sepsis and “restrictive” subgroups such as pancreatitis, meningitis, cardiac surgery

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ProcalcitoninTang, 2007

Q value: .71DA OR: 7.79

Uzzin, 2006

Q value: .78DA OR: 15.8

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Procalcitonin“Procalcitonin cannot reliably differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome in critically ill adult patients. The findings from this study do not lend support to the widespread use of the procalcitonin test in critical care settings.” Tang et al, 2007

“Procalcitonin represents a good biological diagnostic marker for sepsis, severe sepsis, or septic shock, difficult diagnoses in critically ill patients. …Procalcitonin should be included in diagnostic guidelines for sepsis and in clinical practice in intensive care units.” Uzzan et al, 2006

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Procalcitonin- New paradigm

• Given the limited diagnostic utility of Procalcitonin in distinguishing infectious states from non-infectious states in the ICU can it help manage our patients better?

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Procalcitonin- management outside the ICU

Diagnostic uncertainty as to the role of bacterial infection

in patient’s RTI S&S

ProCalcitonin Guided Therapy

1. Christ-Crain, 2006: RCT, CAP

2. Stolz, 2007: RCT, COPD Exa.

3. Christ-Crain, 2004: Cluster RCT, LRTI

Uniform reduction in AB useNo Change in outcome

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Procalcitonin- in the ICU

• Literature Search: 5 RCTs• Total of 937 patients

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Procalcitonin- in the ICU

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Procalcitonin- in the ICU

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Procalcitonin- in the ICU

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Heyland et al, Crit Care Med 39(7):1792-1799,

Procalcitonin: reduction of antibiotic exposure

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Procalcitonin: effect on mortality

Heyland, Crit Care Med 39(7):1792-1799,

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Heyland, Crit Care Med 39(7):1792-1799,

Procalcitonin: cost-minimization analysis

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Heyland, Crit Care Med 39(7):1792-1799,

Procalcitonin: conclusion of meta-analysis

PCT use is associated with reduced antibiotic exposurePCT use as studied in the meta-analysis is cost effectiveKey issues that need to be addressed:

a. Comparator. Majority of studies used fixed comparator regimens.

b. Effect of PCT reminders unknown. Maybe reminders to stop antibiotics would have been effective.

c. Unable to exclude significant harm. Cannot exclude a 7% increase in mortality with the number of patients studied.

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Procalcitonin: PASS Study

• 1200 Patient Study• Patients expected to be in ICU > 48 hours• Randomized to usual care or PCT guided infection management algorithm, including antibiotics

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Procalcitonin: PASS Study

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Procalcitonin: PASS Study results• No difference in mortality between the groups

PCT group• No difference in rates of diagnosed infection• Increased utilization of broad spectrum antibiotics • Increased duration of Antibiotic therapy• Increased duration of mechanical ventilation• Increased duration of ICU Stay

Jensen, CCM 2011

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Conclusion• In spite of extensive study, role of

PCT in the ICU unclear• May be associated with reduction in

antibiotic utilization• Further research required

• Incremental utility above clinical judgement

• Threshold levels• Algorithms for use

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Questions?

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Procalcitonin (PCT)• Studied extensively for the diagnosis

of infection• Meta-analysis 2004:

• Mixed population (neonates, pediatrics, adults, ICU and non-ICU)

• Sensitivity 88% and Specificity 81%

Simon, Clin Inf Dis 2004

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Procalcitonin• Differences:

• studies included, • exclusion of studies such pancreatitis,

meningitis etc. (relative diagnostic certainty)

• Diagnostic uncertainty in studies (no reference standard for SIRS, infections)

Further studies (underway):1. PCT guided antibiotic discontinuation in severe sepsis2. PCT in diagnosing bacteremia in ER3. PCT and CRP with steroid treatment

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ProCalcitonin• Tang, 2007: Methodological quality

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Figure 2. Trial profile. PCT, placebo-controlled trial.

Jensen, CCM 2011

2 4Jensen, CCM 2011

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Figure 4. Subgroup analysis regarding 28-day all-cause mortality. Hazard ratios and 95% confidence intervals (CIs) for death in the 28 days after recruitment for the procalcitonin arm compared with the

standard-of-care-only arm.

Jensen, CCM 2011

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Table 4. Table 4. Organ failure and infection during follow-up

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2© 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Published by Lippincott Williams & Wilkins, Inc.

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Table 3.