The Dyspneic Patient in the ED Which Biomarkers should we use and how THIS COULD BE YOUR MOTHER

Size: px

Start display at page:

Download "The Dyspneic Patient in the ED Which Biomarkers should we use and how THIS COULD BE YOUR MOTHER"

Elizabeth Stafford
6 years ago
Views:

1 The Dyspneic Patient in the ED Which Biomarkers should we use and how THIS COULD BE YOUR MOTHER

2 Diagnostic Biomarkers BNP Mid-region proanp Procalcitonin NGAL BIVA

3 Prognostic Biomarkers Troponin Adrenomedulin ST-2

4 Acute Heart Failure Magnitude of the Problem 1 million admissions annually in the U.S. ( 50% over the past 10 years) Most common admitting diagnosis for patients 65 years Hospitalization costs are considerable (>60% of amount spent on heart failure)

5 Dyspnea Pie

Syndrome DKA Metabolic acidosis Asthma COPD exacerbation FB Aspiration Subdiaphrag Abcess Breast

6 Musculoskeletal Pain Pneumomediastinum Mediastinitis IVDA Pulm Infarction Anxiety Pulmonary Embolus Panic Attack Cyanide poisoning Pneumothorax Empyema Pneumonia MetHgb Tietze s disease Mondor s Syndrome DKA Metabolic acidosis Asthma COPD exacerbation FB Aspiration Subdiaphrag Abcess Breast Cancer Chemical Exposure Amniotic Fluid Embolus Lung Cancer Heart Failure (45% of pie!) Anemia Anaphylaxis

7 Signs and Symptoms of HF Shortness of breath Edema Neck vein Distension S-3 Francis G.S. A M J Med. 2001; 110 (suppl 7A):

8 A chest x-ray can NEVER rule out acute heart failure! Misses 20% of Echocardiogram proven cardiomegaly Even worse if done portable Diagraghm not well distended

9 Well, Bob, it looks like a paper cut, but just to be sure. Let s get an echo.

10 Number of Cases How sure are we about the diagnosis of AHF?? Significant Indecision Exists 43 % Pretest Probability of CHF McCullough, Maisel et al. Circulation. 2002;106:

11 mortality (%) What happens if we misdiagnose the acute breathless patient? Dyspnea of respiratory origin P<0, Wuerz. Ann Emerg Med 1992;21: bronchodilators No therapy CHF Therapy

12 Diagnostic Biomarkers BNP Procalcitonin NGAL BIVA

13 Pre-Pro-BNP Pro-BNP N-terminal Pro-BNP 1-76 BNP t 1/2 = 18 min WALL STRESS Pro-BNP 1-108

14 NT-proBNP? BNP?

15 Breathing Not Properly STUDY

16 Sensitivity Accuracy is 90% Optimal cut-off point 100 pg/ml BNP=50 pg/ml BNP=80 pg/ml BNP=100 pg/ml BNP=125 pg/ml BNP=150 pg/ml Positive predictive value=75% BNP 100 pg/ml Test positive BNP <100 pg/ml Test negative Final Diagnosis Heart Failure Final Diagnosis NOT Heart Failure Sensitivity =90% 615 Specificity =73% Negative predictive value=90 % Specificity Maisel AS et al. N Engl J Med. 2002;347:

17 Indecision Clarification of Diagnosis & BNP 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 43% Clinical Evaluation BNP reduces clinical indecision by 74% * P < % Clinical Evaluation and BNP

18 BNP levels adds to the physician s ability McCullough, Maisel et al., Circulation :

19 Cost-Effectiveness of BNP at ED: The BASEL Study P=0.001 $8000 $6000 $4000 1,545 Savings/Patient Biosite Triage BNP (in pg/ml) $2000 Muller C, et al. N Engl J Med. 2004;350:

20 You can t win them all (ask R.Federer) : Caveats to NP testing Dry versus wet BNP Gray Zone Renal dysfunction Obesity Heart Failure with normal levels

21 BNP level (pg/ml) BNP level = baseline BNP(dry) plus change due to increased volume(wet) Wet (Change due to volume overload) Dry ( NYHA Euvolemic state) NYHA Class - Euvolemic (Dry) BNP

22 Maisel, Valle, Aspromente et Al EJHF 2009 Obesity There appears to be a linear inverse relationship between BMI and NP levels Patients who are obese (BMI >35kg/m 2 ) should have their NP doubled to use the standard cutpoints.

23 McCullough PA,Maisel AS et al. For the BNP Multinational Study Investigators. American Journal of Kidney Disease2008 Mean BNP by egfr- you can still diagnose heart failure cgfr, ml/min/1.73 m 2

24 Normal levels of BNP Heart failure Mistaken for HF Flash pulmonary edema Acute atrial fibrillation Acute papillary muscle rupture Cardiac Tamponade Constrictive pericarditis

25 Mortality Mortality vs. Diuretic Time & BNP Level N=14,900 BNP pg/ml Time to Diuretic

26 Diagnostic Biomarkers BNP Mid-region proanp Procalcitonin NGAL BIVA

27 NH 2 - The Mid- regional assay detects the corresponding prohormone fragment: midregional pro-anp M D G R G F C S S R R L S R I G A Q G L C G N S F R Y ANP (diuretic, vasodilator) -C O NH 2 MR - proanp Mid-regional - proanp ANP prohormone (fragment) can be easily measured by standard sandwich immunoassay technology MR-proANP is a reliable surrogate marker of the mature hormone Peptides are instable in vivo and ex vivo, therefore not suitable for clinical diagnosis. Morgenthaler NG et al., Clin Chem. 2004;50: Morgenthaler NG et al., Clin Chem. 2005;51:

30 Gray Area Analysis

31 Diagnostic Biomarkers BNP Mid-region proanp Procalcitonin NGAL BIVA

32 Infection Source in Severe Sepsis-RESPIRATORY 10.8% 6.0% 8.0% 2.2% 6.6% 8.6% 9.1% 17.3% 44.0% Respiratory Bacteremia GU Abdomen Soft tissue Device CNS Endocarditis Other Angus DC et al. Crit Care Med. 2001; 29:1303

33 Heart Failure + infection Heart failure plus pneumonia is present about 10-15% of time Heart failure plus any infection may occur in up to 20% of hospitalized heart failure patients. Hospital Mortality may be up to 20% (versus 5%) in heart failure patients with untreated infections

34 PCT Level Increase = Increased Significance of Bacterial Infection 0.5 ng/ml 2 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 In healthy people, PCT concentration are found below 0.05ng/ml Concentrations exceeding 0.5ng/ml can be interpreted as abnormal

35 BNP [ng/ml] AHF, no Pneumonia (n=539) AHF and Pneumonia (n=29) no AHF, no Pneumonia (n=947) Pneumonia, no AHF (n=126) 0 0 0,05 0,1 0,15 0,2 0,25 PCT [ng/ml]

36 Diagnostic Biomarkers BNP Mid-region proanp Procalcitonin NGAL BIVA

37 Time Course of Development of Increasing Creatinine in Hospitalized HF Patients % Cr X Cardiorenal Syndrome X X X X X X X X X X X X X X Days Cr, serum creatinine. Gottlieb SS et al. J Card Fail. 2002;8:136. Smith G, J Card Fail Feb;9(1):13-25

38 What can NGAL detect? NGAL Creatinine Marker of Renal Injury High Sensitivity for Injury Moderate Specificity for underlying nephropathy

39 NGAL Predicts WRF in ADHF N=91 38% dev AKI/WRF Aghel et al, J Cardiac Failure, Vol. 16 No

40 GALLANT-CHF n GAL evaluation Along with NaTiuretic peptides in CHF BNP N-GAL

41 NG AL < 100, BNP < 330 NG AL < 100, BNP > 330 NG AL > 100, BNP < 330 NG AL > 100, BNP > Days

42 AKINESIS: Acute Kidney Injury N-gal Evaluation of Symptomatic heart failure Study

44 BNP Troponin Procalcitonin Adrenomedulin NGAL BIVA

45 How it works. Injected current Sensed current

46 Ohm s Law The flow of an electrical current (I) is equal to a voltage drop (E) between the two ends of a circuit divided by the resistance or impedance (Z) to current flow. I = E/Z or Z =E/I

48 Correct Body Position

49 Vector BIVA patterns for clinical use From Kg & Liters to the distance from the mean Major axis => tissue hydration, minor axis => soft tissue mass

Normally hydrated Tissue H20 72.7% -74,3% Dehydration 72.

51 Normally hydrated Tissue H % -74,3% Dehydration % = slight 71-69% = moderate <69% = severe Hyperhydration % = slight 81 and 87% = moderate >87% = H20 overload (sub clinicial edema) >87% = severe water overload

52 Total Body Water in CHF 22 CHF patients Body composition measured by Dual-energy X-ray absorptiometry (DXA) Deuterium dilution BIVA r =0.93 p=0.01 Uszko-Lencer NHMK. European Journal of Heart Failure 8 (2006)

53 BNP and NGAL to aid in euvolemia and prevent renal dysfunction BNP level Stop diuretics or add vasodilators Creatinine Begin diuretics N-GAL BIVA for guidance

54 Prognostic Biomarkers Troponin Adrenomedulin ST-2

55 Risk Stratification is of Limited Value to Individual Patients Great news! I can predict you will live 4.5 months with a p value of 0.04!

56 Prognostic Biomarkers Troponin Adrenomedulin ST-2

57 Potential Mechanisms for Cardiac Troponin Elevations in Neurohormones Myocardial Stretch Inflammatory Cytokines Myocardial Ischemia Oxidative Stress Abnormal Calcium Cycling HF Reversible Injury with Altered Cell Permeability Myocardial Cell Necrosis Apoptosis Troponin Degradation Products Cardiac Troponin I or T Detected

59 Troponin I (ng/l) Changes in hsctnl (Nanosphere) and Mortality in Acute Heart Failure Event free (106 subjects) Sample Euro J Hrt Failure, January 2011 Mortality and readmission (38 subjects)

95 Stable or decreasing troponin (65 subjects) 0.90 0.

60 Survival Changing hsctnl (Nanosphere) and Mortality in Acute Heart Failure Stable or decreasing troponin (65 subjects) Increasing troponin (41 subjects) Euro J Hrt Failure, Jan 2011 Days

61 Prognostic Biomarkers Troponin Adrenomedulin ST-2

62 MR-proADM is a reliable surrogate marker of Adrenomedullin -Peptide hormone consisting of 52 amino acids Adrenomedullin: -vasodilator, important for microcirculation & endothelial (dys)function - - ADM measurement is not suitable for clinical routine diagnosis assessment due to its ex vivo instability (immediate binding to receptors, 22min half-life time) - mid regional pro-adm (MR-proADM) is a stable and reliable surrogate marker for ADM release N-terminal peptide PAMP Adrenomedullin NH2- Pro-Adrenomedullin ELRMSSSYPTGLADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARIRV O // -C \ OH Struck J et al., Peptides. 2004; Morgenthaler NG et al., Clin Chem MR-proADM

63 Survival in AHF - Prognostic Utility in Patients with AHF Results of multivariable Cox regression: MR-proADM is more important than either BNP or NTproBNP in survival models using Cox Regression. Predictor (multivariable) HR 95% CI p log MR-proADM <0.001 log BNP Predictor (multivariable) HR 95% CI p log MR-proADM <0.001 log NT-proBNP

64 Cumulative Survival Cumulative Survival Survival in AHF - MR-proADM Quartiles MR-proADM < 2.07 pmol/l nd 1st 3rd st-3rd th MR-proADM 2.07 pmol/l th Days Days Risk is great in the highest quartile of MRproADM Quartile HR 95% CI p 1st 1 reference 2nd rd th Quartile HR 95% CI p 1st-3rd 1 reference 4th <0.001

65 Survival in AHF - Area Under the ROC Curve Comparison MR-proADM predicts short term (30 day) survival exceptionally well. AUC 30 days 90 days MR-proADM NT-proBNP BNP

66 Prognostic Biomarkers Troponin Adrenomedulin ST-2

67 % Mortality ST2 Concentrations as a Function of One Year Mortality in Acute HF 50.0% 45.0% 40.0% 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% 5.0% 0.0% Presage ST2 (%) MBL ST2 (%) Decile

0.80 Value of sst2 for prognosis in acute dyspnea AUC 0.76 0.76 0.73 0.70 0.69 0.69 0.67 0.65 0.

68 0.80 Value of sst2 for prognosis in acute dyspnea AUC ST2 NT-proBNP CRP BUN Hemoglobin reatinine clearance Galectin-3 Creatinine ctnt Eotaxin Apelin-1

69 Additive Value of ST2 to NP s in Acute HF The combination of an elevated ST2 and natriuretic peptide was a considerably stronger predictor of death than either alone.

sst2 (ng/ml) ST2 Trends as a Function of Mortality 0.7 0.6 0.5 0.4 0.3 Death 0.2 0.

70 sst2 (ng/ml) ST2 Trends as a Function of Mortality Death Survival First Day 2 Day 3 Day 4 Day 5 Last Maisel, et al, J Card Failure, 2008 Time

73 Thank You!

Biomarkers in the Assessment of Congestive Heart Failure

Biomarkers in the Assessment of Congestive Heart Failure Mid-Regional pro-adrenomedullin (MR-proADM) vs BNP & NT-proBNP as Prognosticator in Heart Failure Patients: Results of the BACH Multinational Trial