Controversies in Treating Cardiogenic Shock Martha Burk, MD, MS BAMC/Wilford Hall/UTHSCSA Combined Pulmonary Fellows Conference Cardiogenic Shock Inadequate perfusion of tissue with relatively decreased cardiac dysfunction is the most common cause of death in patients hospitalized for AMI of AMI complicated by cardiogenic shock remains It Treatment Two Minute Assessmen t Evidence of Low Perfusion Narrow pulse pressure Pulsus paradoxus Cool extremities Altered mental status Hyponatremia Worsening renal function Evidence for Congestion Orthopnea Elevated JVP Gallop Edema Ascites Rales Hepatojugular reflux Congestion at rest? No Yes Warm and Wet No Low Perfusion At Rest? Yes Warm and Dry Drug-related hypotension Cold and Dry Cold and Wet Nohria, et al JAMA 2002 Causes of Cardiogenic Shock Acute MI – Pump failure Large infarction Infarct expansion Reinfarction Myocarditis Severe septic shock LV outflow obstruction – Aortic stenosis – Hypertrophic LV Mechanical complications – Acute MR/papillary muscle rupture – Ventricular wall rupture – Ventricular septal defect – Pericardial tamponade Valvular disease – Mitral stenosis – Left atrial myxoma Myocardial contusion Hypothyroid state Prolonged CABG End-stage cardiomyopathy Adapted from UpToDate and Hollenberg, et al Ann Intern Med 1999 Epidemiology Acute MI is most frequent cause ~10% AMI results in shock SHOCK – (Should we emergently revascularize Occluded Coronaries for shocK) trial registry – 1160 pts with AMI and shock 75% with LV failure 8% had MR 5% had ventricular septal defect 3% had RV failure 2% had tamponade or cardiac rupture 8% had shock for other reasons – Infarctions 55% anterior, 46% inferior 21% posterior, 50% multiple Hollenberg, et al Ann Intern Med 1999 Davies QJ Med 2001 Mortality TRACE study – – – – Trandolapril Cardiac Evaluation protocol 6676 pts non-invasively managed for AMI 59% pts developed shock within 48 hrs 30 day and 6 year mortality Without shock 9%/45% With shock 62%/88% Euro-Heart-Survey-ACS – – – 10,136 patients presenting with ACS 549 had cardiogenic shock on presentation Mortality of pts presenting with/without shock 50%/3% with STEMI 53%/1% with NSTEMI Lindholm, et al European Heart Journal 2003 Iakobishvili, et al American Heart Journal 200 Mortality In TRACE Lindholm, et al European Heart Journal 2003 Katayama, et al Circ J 2005 Pathophysiolog y Impaired Thrombolysis Microthrombi develop Vasoconstrictors released from microthrombi Vasospasm results in increased flow resistance No reflow phenomenon Davies QJ Med 2001 Coronary occlusion Impaired coronary flow Infarct Dysfunction results in hypotension Aortic pressures <85mmHg Extension of infarct/muscle necrosis Neuroendocrine Activation Neuroendocrine system activated – Increase cardiac output – Include renin, aldosterone, catecholamines, BNP, ANP and adrenomedullin – Adrenomedullin produced unregulated in ischemia, hypotension Increased demand on myocardium Inadequate coronary flow Increased myonecrosis – Inability to meet increased oxygen demand Davies QJ Med 2001 Katayama, et al Internal Medicine 2004 Regulation of Vascular Smooth Muscle Tone Landry NEJM 2001 Neuroendocrine Markers of Mortality Katayama, et al Internal Medicine 2004 Myocardial Dysfunction Systolic Diastolic ↓ CO ↓ SV ↓Systemic Perfusion Hypotension ↓ Coronary Perfusion Vasoconstriction Pressure Fluid retention Progressive Myocardial Dysfunction Ischemia Death Hollenberg et al, Annals of Internal Medicine 1999 Ischemic myocardium Cell death Reperfusion Significant residual stenosis Segments with Stunning and Hibernation Segments with Hibernating myocardium Segments with Myocardial stunning No return Of function Inotropic Support Relief of Ischemia Return of Myocardial function Hollenberg et al, Annals of Internal Medicine Reperfusion Injury Free radical production Increased neutrophil adhesion – Complement formation Free fatty acid metabolism restored – Further decreases intracellular pH – Increased calcium influx due to Na-K exchange Result: further myonecrosis during first 2 hours after reperfusion Davies QJ Med 2001 Diagnosis Diagnosis requires – Documentation of myocardial dysfunction – Exclusion of alternative causes Hypovolemia Sepsis PE Tamponade Aortic dissection Valvular disease Severity of Heart Failure in AMI Classification Killip – Class I No clinical heart failure < 5% mortality – Class IV Cardiogenic shock Stuporous systolic BP < 90 decreased urine output pulmonary edema and cold clammy skin mortality near 80% – Class II Rales bilaterally in up to 50% of lung fields isolated S3 good prognosis – Class III Rales in all lung fields acute mitral regurgitation aggressive management required www.ahcpub.com Management Goals Early recognition Early reperfusion Maintenance of adequate preload Decreased afterload Pfisterer Lancet 2003 Initial Diagnostic and Therapeutic Steps History and Exam Oxygenate/Ventilate ECG ECHO Labs CXR PAC Venous access ECG Pain control Hemodynamic support Tissue perfusion Remains inadequate Inotropes IABP Adequate perfusion Without congestion Adequate perfusion With pulmonary congestion Reperfusion Card cath available Cardiac cath Angioplasty CABG Continued No card cath available Thrombolytics and IABP Clinical management Hollenberg, et al Ann Intern Med 1999 Utility of ECHO Evaluate – LV function and myocardium at risk – Screen for ventricular septal rupture – Screen for severe mitral regurgitation – Look for tamponade/rupture – Assess right ventricular function – Look for aortic dissection Menon and Hochman Heart 2002 Echo Survival and Response Predictors in Cardiogenic Shock 169 pts with MI randomized w/in 12 hrs of diagnosis of shock to receive – early emergency revascularization PTCA or CABG was performed w/in 6 hrs IABP was recommended – initial medical stabilization – Echo performed w/in 24 hrs of randomization, and 7 days later – Study designed and powered to detect 20% difference in overall 30 day mortality LVEF >/= 28% and Grade 0/1 MR were associated with improved survival – Odds Ratio 4 and 3, respectively Picard, et al Circulation 2003 Pulmonary Artery Catheters UpToDate Importance of Position UpToDate Respiratory Variation With PEEP 0 PEEP 15 PEEP 20 PEEP UpToDate WP is a reliable indicator of LVEDP only when ventricular compliance is stable UpToDate PACs in High Risk Surgical Patients 1994 pts – – – ≥60 years old Deemed ASA class III or IV risk Undergoing elective or urgent major abdominal, thoracic, vascular or hip frax surgery and requiring intensive care – Randomized to receive treatment w/ or w/o PAC guidance Conclusion Class III = Severe disease, but not incapacitating Class IV = Severe disease that is a constant threat to life – No benefit to therapy directed by PAC versus standard care NEJM 2003 Complications of PAC Pneumothorax Hemothorax Hematoma Arrhythmias Heart block Arterial laceration Pulmonary artery perforation Valvular damage Catheter site infection Thrombosis Infarction Endocarditis Thrombocytopenia Layon Chest 1999 Perioperative Use in Cardiac Surgery Conditions in which there is general agreement that RHC is warranted Differentiation between causes of low CO – Hypovolemia v ventricular dysfunction – Echo is inconclusive – Echo is inconclusive Differentiation between L v R heart failure and pericardial tamponade Guidance of management of low CO state Diagnosis and management of PAH in patients with systemic hypotension and impaired organ perfusion J American College Cardiology 1998 Conditions In Which Reasonable Differences of Opinion Exist Guidance of inotropic and/or vasopressor therapy after patients with significant cardiac dysfunction have achieved hemodynamic stability Guidance of management of hypotension and evidence of inadequate organ perfusion when a therapeutic trial of intravascular volume expansion and/or vasoactive agents is associated with moderate risk J American College Cardiology 1998 Intra-Aortic Balloon Pump Reduces systolic afterload Augments diastolic perfusion pressures Increases cardiac output Improves coronary artery perfusion – Not true for critically stenosed vessels Decreases reocclusion and cardiac events after emergency angioplasty for AMI No increase in myocardial oxygen demand IABP Initially improves hemodynamic status – Impact temporary 80% mortality in patients with CS treated with – IABP placement, CCU monitoring and vasopressor Fornaro, et al retrospectively studied 15 patients admitted for AMI with cardiogenic shock – All pts underwent IABP, angiography followed by PTCA, CABG and cardiac surgery or medical treatment – 5 pts (33%) died Fornaro, al Ital Cardiol ~18% patients in Euro-Heart-SurveyetinGCSHeart J1996 had Iakobishvili, et al Am 2005 Benchmark Counterpulsation Outcomes Registry Prospective registry of all patients who receive IABPs at participating centers 1996-2001 22,663 patients 21% all cause mortality 12% mortality/balloon in place 0.05% IABP-related mortality 1% major limb ischemia 1% severe bleeding 4% balloon failure/leak Cohen, et al European Heart Journal 2003 – 185 US sites, 65 non-US sites – 4314 had cardiogenic shock – Primary endpoints Major limb ischemia Severe bleeding IABP failure All cause in-hospital mortality Risks of IABP Arterial – – – – – Perforation Thrombosis Embolization Limb ischemia Visceral ischemia Miscellaneous – – – Hemorrhage Infection Entrapment Balloon – Rupture – Incorrect positioning – Gas embolization Overwalder The Internet Journal of Thoracic and Cardiovascular Surgery 1999 ACC/AHA Guidelines Class I recommendations STEMI patients with BP <90 – Or 30mm Hg below baseline – No response to other interventions Level B Evidence STEMI patients with low output states As a stabilizing measure for angiography and revascularization Class II recommendations Level STEMI patients with refractory pulmonaryC Evidence congestion Antman, et al JACC 2004 Reestablishing Perfusion NEJM 2002 Benefits of Thrombolysis in AMI Impact of Blood Flow on Survival TIMI 0 absence of any antegrade flow beyond a coronary occlusion. TIMI 1 faint antegrade coronary flow beyond the occlusion although filling of the distal coronary bed is incomplete. TIMI 2 delayed or sluggish antegrade flow with complete filling of the distal territory. TIMI 3 normal flow which fills the distal coronary bed completely. Absolute Reduction in Mortality UpToDate TIMI 0 TIMI 1 Occlusion Penetration 12 10 TIMI 2 Slow Flow P=0.003 vs TIMI 0/1 TIMI 3 Normal Flow 9.3% % Mortality 8 6 4 2 GUSTO 1 6.1% p<0.0001 vs TIMI 0/1 p<0.0001 vs TIMI 2 3.7% GUSTO 1 TAM I 1-7 GUSTO 1 German Team 2 German TAM I 1-7 TAM I 1-7 Team 2 Team 2 German Sample Size of Pooled Analysis: 5,498 Gibson 1998 TIM I 1,4 5,10B TIM I 1,4 5,10B TIM I 1,4 5,10B 0 10 16 33 34 44 4 8 27 13 19 9 15 18 29 34 Both Culprit and Non-Culprit Flow are Abnormal in Acute MI 40 35 30 25 CTFC 20 15 10 5 0 n =1,322 n = 232 n =1,589 n = 78 36.8 + 22.3 6 frames 30.6 + 13.4 30.6 + 14.6 9 frames 21.0 + 3.1 Even PTCA of the culprit artery residual stenosis restores flow only to that observed in the non-culprit (30 frames) and not to normal flow (21 frames) The difference between culprit & non-culprit flow is only 6 frames; the difference between nonculprit and normal flow is 9 frames Culprit Culprit post PTCA Non-Culprit Normal In 25% of cases, flow is slower in the non-culprit than culprit In 33% of cases, flow is abnormal following stent placement Gibson et al, JACC 1999; 34: 974-82 Thrombolytic Therapy in CS Less benefit once cardiogenic shock occurs Mortality unaffected by type of thrombolytic – GISSI trial 30 day mortality 70% for each group Increased risk of significant bleeding with streptokinase versus alteplase – International Study Group Streptokinase v recombinant Tissue Plasminogen Activator Lancet 1990 Risks of Thrombolysis Bleeding Bleeding Bleeding Not Thrombolytic Therapy in STEMI – Coronary arteries not usually occluded – IF PTCA not available within 2 hours – Patients w/o contraindications – Present w/in 12 hours of symptom onset – Greatest benefit if given w/in 2 hours of symptoms beneficial in NSTEMI Useful ACC/AHA recommends thrombolytics Approximately 50% will achieve normalized return of blood flow (TIMI grade 3) – 90% of patients undergoing PCI achieve TIMI grade 3 flow UpToDate 30 Day Mortality of Early v Late PTCA GUSTO-1 Trial Berger, et al Circulation 1997 Markers of TIMI 2/3 Flow Decrease in chest pain – TAMI study PPV 57% TIMI 3 NPV 86% TIMI 3 <50% decrease in ST – AND absence of arrhythmias at 2 hours after thrombolytics – Predicted LACK of TIMI 3 flow Sens 81% Spec 88% PPV 87% NPV 83% ECG changes – >50% decrease in ST elevation in the lead with the most elevation – PPV 66% – NPV 86% Mb, CK-Mb, Troponin – Ratio of baseline/60minute myoglobin ≥4 predicts 90% probability of TIMI 3 flow Oldroyd Heart 2000 Is Thrombolysis Obsolete? Nearly all patients with AMIs are eligible for cardiac catheterization PCI identifies anatomy involved Acts as a triage for CT surgery IABPs can be placed in the cath lab 90% pts achieve TIMI 3 flow with PCI Grines, et al Circulation 2003 Revascularization SHOCK trial – 302 pts with cardiogenic shock (largely due to LV dysfunction) randomized to early revascularization within 6 hours, or initial medical stabilization – Primary end point was 30 day mortality No survival difference at 30 days (53% v 44%) 6 month survival 50% v 37% (p = 0.027) – Early revascularization v initial medical stabilization 12 month survival 47% v 34% (p = 0.025) At 1 year, 62% survived if TIMI flow grade 3 was achieved v 19% survival if PTCA was unsuccessful – Conclusion: Rapid revascularization is a survival predictor American College of Cardiology, American Heart Association guidelines recommend emergency revascularization for pts ≤ 75 years with AMI Menon Congest Heart Fail complicated by cardiogenic shock 2003 Webb, et al J Am Coll Cardiol Menon and Hochman Heart 2002 Barbash et al, Heart 2001 Outcome Predictors After PCI Factor Retrospective review of 113 pts who underwent PCI for AMI complicated by shock – PCI occurred w/in 12 hours of sx onset Prior MI No or Yes Age (years) <70 or ≥70 Failed Reperfusion No or Yes Disease Single/Multivess el In Hospital Mortality 41%77 v 46 v 72 p 5 OR < 0.001 0.02 4 OR 4 OR Factors w/o impact on survival – – – – Gender Smoking status Diabetes Time to intervention 6, 6-12, or >12 hours 36 v 72 29 v 57 <0.001 0.01 Sutton, et al Heart 2005 Another Look at Outcomes, PCI Patients with AMI and cardiogenic shock – – – – 152 underwent emergency revascularization 150 underwent medical stabilization Primary endpoint was 30 day mortality Secondary endpoint was 6 month survival Median time from AMI to shock was 5.6 hours Mean age of patients was 66 years 32% patients were female 30 day mortality (revascularization v medical treatment) – Not statistically significant (47 v 56%) 6 month mortality – 50 v 63% ( p = 0.027) Hochman, et al NEJM 1999 Predictive Value Troponin T Ohman, et al NEJM 1996 2004 ACC/AHA Guidelines on CABG Class I Recommendation – STEMI Pts who fail angioplasty and remain hemodynamically unstable (Level B evidence) At time of surgical repair of ventricular septal wall rupture or mitral valve insufficiency CS pts <75 with ST elevation or LBBB (Level B) or posterior MI who develop shock w/in 36 hrs (Level A) – LV dysfunction Significant left main stenosis (Level B) Left main equivalent stenosis (Level B) Proximal LAD with 2 or 3 vessel disease Novel Potential Therapies Nitric Oxide Synthase Inhibition Nitric oxide is a strong vasodilator Positive inotropic effect at low levels Negative inotropic effect at high levels Large MIs are associated with NO overproduction Could NO inhibition improve the hemodynamic status of patients with cardiogenic shock? Nitric Oxide Synthase Inhibitor 30 patients with AMI and shock – All received IABP, IVFs, pressors, and were immediately referred for coronary catheterization – Revascularization performed only by PCI – Swan-Ganz catheters used after revascularizaiton Pts in the treatment arm received L-NAME at 1 mg/kg/h x 5 h Primary end point 1 month Survival 73% v 33% 1 week survival 80% v 40% 4 month survival 73% v 33% Secondary end points – All cause mortality at 1 wk and 4 mos MAP improved by 25mm Hg Urine output 210 v 110cc/h – Time on mechanical ventilation Time on IABP 59h v 103h – Time on IABP Ventilation time 77 v 140h – Urine output at 24 hours – Change in cardiac index – All cause 30 day mortality Cotter, et al European Heart Journal 2003 Other Novel Therapies Monoclonal antibodies to CD11/CD18 – – – Inhibit neutrophil adhesion HALT-MI AMI pts from ER to cath lab Randomized by TIMI 0/1 flow to receive drug or placebo Primary end point: size of infarct by SPECT 5-9 days after MI and angioplasty No significant difference Na-H inhibition – -Guardian trial showed no benefit www.acc.org Assess volume status Treat sustained arrhythmias Mechanical ventilation as needed Inotropic/vasopressor support No Acute massive ST elevation Extensive Q waves Or new LBBB Yes No ST elevation Limited ST, Q changes Emergency ECHO with Color flow doppler Cath lab Immediately available Yes No Pump failure RV, LV, both Aortic dissection Tamponade Cath lab ST elevation -> Lysis No ST elevation -> GP IIbIIIa Aspirin, Heparin Acute severe MR VSR Critical AS/MS Rapid IABP Cardiac surgery CABG for severe 3v dz or L main Correct mechanical lesions PTCA for 1, 2, or mod 3 v CAD GP IIb/IIIa antag Coronary stent OR Coronary angio Pulmonary artery cath Menon and Hochman Heart 2002 Treasures of San Antonio
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