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Bi omarkers i n Cri ti cal I l l ness

Mitchell M. Levy, MD
Guest Editor
Prompt diagnosis and early intervention in critically ill patients have come to be appre-
ciated as perhaps the primary determinant in good outcomes across several critical
disease states: Early institution of appropriate antibiotics for sepsis, minimizing time
to balloon dilatation for acute coronary syndrome, initiation of rapid, aggressive fluid
resuscitation in severe sepsis and shock have all been shown to improve outcomes
in critically ill patients.
In addition, accurate risk assessment to guide treatment
and disposition, such as identifying and treating patients with right ventricular failure
or submassive and massive pulmonary embolism, has also been recognized as
a crucial ingredient in the early management of the critically ill patient. Of course,
the daunting challenge that bedside critical care practitioners face daily is how to iden-
tify these patients rapidly and with precision. Increasingly, the use of biomarkers in crit-
ically ill patients is being recognized as essential adjuncts in this process.
biomarkers have long been established as the driving force, along with ECG moni-
toring, to dictate immediate therapies for acute coronary syndrome. More recently
biomarkers are now being incorporated in algorithms that guide the management of
pulmonary embolism and sepsis.
The use of biomarkers for diagnosis is also under
active investigation and several published reports, discussed in this issue of Critical
Care Clinics, have demonstrated the value of procalcitonin (PCT), and triggering
receptor expressed on myeloid cells (TREM)-1, as well as composite markers or
biomarker panels (PCT, TREM-1) for the diagnosis of bacterial infection.
Another important aspect in the management of critically ill patients is early risk
assessment to guide triage and therapeutic intervention. Lactate and neutrophil gelat-
inase associated lipocalin are two such biomarkers that will be reviewed in this issue.
There is also potential benefit in using biomarkers to limit therapy. Limiting exposure
when infection is absent will become exceedingly important as drug resistance
increases. There are several published studies that suggest that PCT may be effective
in reducing the duration of antibiotic therapy, which will also be reviewed in this issue.
Crit Care Clin 27 (2011) xiiixv
0749-0704/11/$ see front matter 2011 Elsevier Inc. All rights reserved.
Biomarkers in the Critically Ill Patient
Finally, and just as important, the use of vital signs and the routine variation in vital
signs must not be forgotten in the search for the holy grail of biomarkers. Vital signs,
whichwill alsobereviewedinthis issue, present a readily accessibleportrait of thephys-
iology of the critically ill and the change in variation in these vital signs is often ignored.
A biomarker is defined as a characteristic that is objectively measured and evaluated
as an indicator of normal biological processes, pathogenic processes, or pharmaco-
logic responses to a therapeutic intervention.
What do clinicians and clinical trialists
expect from an ideal biomarker? Several characteristics come to mind: to be highly
sensitive and specific for the disease state being evaluated, to have prognostic value,
to indicate the severity and the course of illness, and to be biologically plausible. In
septic patients, biomarkers should ideally allow the differentiation between infectious
and noninfectious causes of inflammation and predict the onset of the clinical signs of
organ dysfunction and shock. Biomarkers are an appealing addition to the care of the
critically ill patient since they are noninvasive and ideally rapidly available and may be
followed over a patients course.
Prior to the widespread use of a marker of interest, it must endure validation (ie,
have known characteristics, be well-standardized and accurate) and qualification
(ie, be integral to the disease process and clinical endpoints).
Depending on the in-
tended use, the validation and qualification process may be more or less rigorous.
Assay reliability, the establishment of cutoffs, and timely, affordable processing
must be considered and addressed prior to the widespread adoption of a given
marker. This important concept is also covered later in this issue. As more studies
on biomarkers in the critically ill are published, it becomes essential for clinicians to
be cognizant of how to interpret these studies and so make a careful clinical judgment
as to the value of incorporating the use of these markers into routine bedside practice.
Convincing evidence now exists that biomarkers may become useful adjuncts to the
clinician and may ultimately serve as targets in large, randomized, controlled trials for
newtherapeutic agents and management strategies. Newunderstanding of inflamma-
tory mediators and pathways, immunity, and genetic variability in critical illness will
further inform and enhance the search for appropriate biomarkers.
With this issue, we hope to offer the clinician a summary of the current biomarker
literature and to identify the markers most likely to prove useful in clinical practice. No
single marker has been shown to possess all the ideal qualities mentioned here, but
there are encouraging signs in the literature that we are on the right path toward finding
a marker or set of markers that will facilitate diagnosis, risk assessment, and manage-
ment in critically ill patients.
Mitchell M. Levy, MD
Division of Pulmonary and Critical Care Medicine
Rhode Island Hospital
The Warren Alpert Medical School of Brown University
593 Eddy Street, MICU Main 7
Providence, RI 02903, USA
E-mail address:
Preface xiv
1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med 2001;345:136877.
2. Levy MM, Macias WL, Vincent JL, et al. Early changes in organ function predict
eventual survival in severe sepsis. Crit Care Med 2005;33:2194201.
3. Kumar A, Roberts D, Wood K, et al. Duration of hypotension before initiation of
effective antimicrobial therapy is the critical determinant of survival in septic
shock. Crit Care Med 2006;34:158996.
4. Marshall JC, Vincent JL, Fink MP, et al. Measures, markers, and mediators:
toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis
Roundtable, Toronto, Ontario, Canada, October 2526, 2000. Crit Care Med
5. Konstantinides S, Geibel A, Olschewski M, et al. Importance of cardiac troponins
I and T in risk stratification of patients with acute pulmonary embolism. Circulation
6. Meyer T, Binder L, Hruska N, et al. Cardiac troponin I elevation in acute pulmo-
nary embolism is associated with right ventricular dysfunction. J Am Coll Cardiol
7. Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment
model in acute pulmonary embolism. Eur Heart J 2005;26(20):216672.
8. Douketis JD, Leeuwenkamp O, Grobara P, et al. The incidence and prognostic
significance of elevated cardiac troponins in patients with submassive pulmonary
embolism. J Thromb Haemost 2005;3(3):50813.
9. Pruszczyk P, Bochowicz A, Torbicki A, et al. Cardiac troponin T monitoring iden-
tifies high-risk group of normotensive patients with acute pulmonary embolism.
Chest 2003;123(6):194752.
10. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic
therapy in community-acquired pneumonia: a randomized trial. Am J Respir
Crit Care Med 2006;174:8493.
11. Gibot S, Cravoisy A, Kolopp-Sarda MN, et al. Time-course of sTREM (soluble trig-
gering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive
protein plasma concentrations during sepsis. Crit Care Med 2005;33:7926.
12. Reinhart K, Brunkhorst FM. Meta-analysis of procalcitonin for sepsis detection.
Lancet Infect Dis 2007;7:5002.
13. The Biomarker Definitions Working Group. Biomarkers and surrogate endpoints:
preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:
14. Wagner JA, Williams SA, Webster CJ. Biomarkers and surrogate end points for fit-
for-purpose development and regulatory evaluation of new drugs. Clin Pharmacol
Ther 2007;81:1047.
Preface xv