Download BIOMARKERS What do they tell us that we don*t already

BIOMARKERS
What do they tell us that we don’t already know?
Michele Domico, MD
Medical Director, CVICU
Children’s Hospital of Orange County, California
Disclaimer
“But my patient is an adult”
CHOC inpatient does not take care of adults with CHD
Knowledge and familiarity with biomarkers
Biomarker Defined
• In medicine, a biomarker is a measurable indicator of the
severity or presence of some disease state
• Biomarkers can be specific cells, molecules, or genes, gene
products, enzymes, or hormones.
• Biomarkers are useful in a number of ways, including
measuring the progress of disease, evaluating the most
effective therapeutic regimes
Uses of Biomarkers
• Risk stratification
• Effective clinical practice and decision making
• Predictive capacity for mortality
Ideal Biomarker in the CICU
• Identify states of:
– Low cardiac output
– Decreased oxygen delivery
– Myocyte strain or injury
• Facilitate:
– Early intervention
– Improve patient outcome
Biomarkers in the CICU
Lactate
BNP
Troponin
Lactate
Allen. Ped Crit Care Med 2011; (12) s43-49
Lactate
• Elevated in response to inadequate cellular
oxygen delivery
• There is no difference between adult and
pediatric patients
Lactate is produced when DO2 falls
beneath a certain threshold
Lactate
Produced by
Metabolized by
• Skeletal muscle
• Liver (50%)
• Brain
• Renal Cortex (20%)
• Renal Medulla
• Heart
• RBC’s
• Brain
Effects of Cardiac Surgery on Lactate Levels
• Bypass and Cross-Clamp
– Increase lactate production (tissue hypoxia)
– Inflammatory mediated lactate production
• Catecholamines
– Epinephrine accelerate glycolysis
• Decreases lactate clearance
– Impaired liver function
– Decreased liver and renal blood flow
DeBacker ICM (2003) 29:699-702
Transient Lactate Elevation
• Crystalloid (bloodless) prime is associated with
higher lactate levels after CPB
• Pulmonary lactate rises up to 6 hours post CPB
• Washout of lactate from regional tissues after
cross clamp released
Toda et al. Crit Care Resus 2005; 7:87-91
Amark et al. Ann Thorac Surg 2005; 80:989–994
Leavy et al. JAMA 1988; 260:662–664
Lactate prognostic significance
• Admission lactate
– Low lactate highly predictive of survival (PV 97%)
– High lactate is variable predictor of mortality (16-43%)
• Lactime is a strong predictor of mortality
Duke JCTS 1997, Basaran JCVA 2006, Siegal ICM 1996, Toda CC Resus 2005, Jackman ICM 2009,
Hatherill ICM 2000, Shemie Pres 1996, Charpie JCTS 2000, Kalyanaraman et al. PCCM 2008; 9(3): 28588
What does lactate tell us
that we don’t already know
Lactate is a late marker
DO2 has already dropped past the critical point
Ideally you would detect increasing oxygen
extraction before the lactate starts to climb
Lactate Summary
• Adult and pediatric patients are the same
• It is a late marker of inadequate oxygen delivery
• Lactime is more important than a single level
• Transient elevations of lactate associated with CPB
– Bloodless prime, pulmonary lactate, washout,
inflammatory mediated, catecholamine induced,
decreased renal and liver blood flow
Troponin
Adult medicine utilizes troponin very
differently than pediatrics does
Troponin
• The utility of troponin as a marker of myocardial injury
stems from its origin specifically from cardiac muscles
• Highly sensitive and specific markers of myocardial
damage (cTnI and cTnT)
Elevations of troponin
• Acute coronary syndrome
• Sepsis/ Septic shock
• Myocardial infarction
• AKI / renal failure
• Congestive Heart Failure
• Trauma
• Post CPB
• Pulmonary embolism
• Myocardial contusion
• Stroke
Troponin in the post op CICU
• Degree of troponin elevation
correlates with
– CPB duration
– Cross clamp time
– Cardioplegia techniques
– Surgical severity
– Ventriculotomy
– Open chest
Post op Cardiac Surgical Patient
• Post op troponin elevation predicts mortality
and morbidity
– Need for inotropic support
– Severity of renal dysfunction
– Duration of intubation
Immer et al. JACC 1999; 33: 1719-23, Fellahi et al. Crit Care 2007; 11(5):R106,
Adabag et al. Ann Thor Surg 2007; 83:1744-50, Buse et al. Circulation 2014; (12):948-57
Troponin T measured on 1st post op day was a strong
independent predictor of death at 30 days
cTnT > 5.9 mcg/L predicted death (OR 10.7, CI 5.2 to 22.1)
Ann Thorac Surg 2006; 82:1643-9
Can you have the double whammy of
congenital heart disease (CHD) and coronary
artery disease (CAD) simultaneously?
• Number of adult congenital heart disease patients
(ACHD) increases by 5% per year
– Greater than 1 million individuals in the US
• HTN, hyperlipidemia
• Incidence of CAD in adults with CHD is 1-9%
• Some CHD lesions are at increased risk for
development of CAD
– CoA, TOF, TGA, Fontan
Coronary artery disease has been implicated as
the leading cause of death after repaired
coarctation of the aorta in adults
CAD was detected earlier in patients
with CoA versus any other CHD
Mean age 48 years
What does troponin tell us
that we don’t already know?
While we are focusing on post operative physiology of
congenital heart disease…
it can redirect our focus to myocardial perfusion
particularly in adults with CHD and undiagnosed CAD
Troponin Summary
• Elevated troponin levels will be observed after
almost every cardiac surgery
• Your troponin level trend over time is important
– in the ACHD patient and pediatric patient
• CAD can coexist with CHD
(CoA, TOF, TGA, Fontan)
• Rising troponin should prompt further investigation
B-type natriuretic peptide
• BNP identified in 1988
• Secreted by ventricular myocytes
– Volume or pressure load
• Mechanism of action
– Increases cGMP
• Physiologic actions
– Diuresis, natriuresis
– Vasodilation
– Inhibit R-A-A system
B-type natriuretic peptide
Domico. Ped Crit Care Med 2011; 12 (4): s33-42
Elevation of BNP levels
Cardiac Etiology
Non-Cardiac Etiology
Congestive heart failure
Acute coronary syndrome
Cardiomyopathy
Myocarditis
Congenital heart disease
Kawasaki disease
Atrial fibrillation/ flutter
Diastolic dysfunction
Anthracycline toxicity
Acute OHT rejection
Sepsis/ Septic Shock
Pulmonary embolus
Pulmonary hypertension
ARDS
Pneumonia
COPD with cor pulmonale
Sleep apnea
Renal failure
Hyperthyroidism
Dexamethasone administration
Domico. Ped Crit Care Med 2011; 12 (4): s33-42
BNP in adults
• Integral biomarker for over 15 years in heart disease
• Successfully used as pre-op risk stratification
– Level 1 A evidence
• Used to guide therapy in CHF
• Predischarge BNP level > 700 pg/ml is a predictor of death
or readmission after decompensated CHF
Karthikeyan. JACC 2009; 54: 1599-606, Ryding. Anesthes 2009; 111: 311-9
Rodseth. Anaesth 2008; 63: 1266-33, Logeart. JACC 2004; 43:635-41
BNP as a prognostic biomarker
in children with CHD
• Can we prospectively identify those more
likely to have a poor outcome or complicated
post operative course?
Amirnovin JTCVS 2012, Walsh JTCVS 2008, Hsu JCTVS 2008, Hsu JCTVS 2007,
Shih JCTVS 2006, Nieder CHD 2010, Cantinotti PCCM 2013, Nahum IMAJ 2013,
Highest BNP levels in the CICU
• LV systolic dysfunction
– 500 – 1,000 + pg/ml
• Diastolic dysfunction
• Volume overload lesions
– 200- 500 pg/ml
• Pressure overload
– < 100 pg/ml
*caveat* sepsis may be the highest
Domico. Ped Crit Care Med 2008; 9(5): 478-83
BNP levels
• Pediatric
• Adults
• > 100 pg/ml = CHF
• > 200 pg/ml in healthy
neonates
• > 500 pg/ml in children
with CHD
Maisel. Crit Path Cardiol 2002; 1:67-73
Law. JACC 2009; 23:161-65
Why are pediatric BNP levels higher than
adults who are equally ill?
Adult BNP > 100 pg/ml everyone worries
Pediatric BNP level the same everyone relaxes
Is there any “burn out” of BNP in adults?
BNP in the Cardiac ICU
• Levels vary depending on
– structure and severity of heart disease
– Age of patient
• Concentrations change at various time points
– Pre vs post operative
• Absolute number may not be as useful as overall
trend for any particular patient
How useful is BNP in the acute
setting? (in the CICU)
BNP is used as “early warning”
biomarker in sepsis
Paratz et al. Crit Care Med 2014; (42)9:2029-36
B-type Natriuretic Peptide
Can BNP identify alterations
in volume or pressure load on the myocardium
before the ECHO or the astute bedside clinician?
BNP clinical scenario
• Term baby
• Unbal AVC, small left ventricle,
AA, MA, hypoplastic ascending
aorta, interrupted IVC, left
atrial isomerism, malrotation
• Pre-op BNP 913 pg/ml
• Norwood/ 3.5 BTS
• Open chest
BNP clinical scenarios
• Chest closed POD 2
• Extubated POD 3
– Sat 80% on RA
• Off all vasoatives POD 4
• Feeds started slowly, gut monitored POD 4
• ECHO mild-mod AVVR and low-nl function POD 5
• BNP 1999 on POD 6 (first post-op level)
• Plan to repeat BNP in a few days
BNP clinical scenarios
• Within 48 hours baby was irritable
• Feeds held. KUB unremarkable
• Arrest a few hours later
– Unable to resuscitate
• Mortality review
– Autopsy is inconclusive
– Only the BNP level was abnormal
• No NIRS placed, no blood gas obtained (no indwelling PICC line)
What does BNP tell us
that we don’t already know?
There may be some hemodynamic alterations
affecting the heart
which have not (yet) been identified
by ECHO or other testing
BNP Summary
• Useful for preoperative risk stratification
• Levels vary depending on structure and severity of
heart disease
• ? Can potentially be used as an “early warning”
biomarker for myocardial stress / strain before an
ECHO or other imaging is obtained
Limitations of Biomarkers
Lactate, Troponin, BNP
The use of these markers as a single measurement
is handicapped by the wide variety of clinical scenarios
in which they can be elevated
Biomarkers Conclusions
• Very high immediately post op  reassess patient
• Overall trend more useful
• Persistent or rising level more important than initial
high level
• Low level is not necessarily reassuring
• One of a cluster of markers, but may be able to alert
clinician to new evolving process
Thank You
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