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b -blockade in Critical Care and Perioperatively: Guidelines

b -blockade in Critical Care and Perioperatively: Guidelines. Figen Esen Professor of Anesthesiology and Intensive Care University of Istanbul, Istanbul Medical Faculty. Pharmacokinetic profiles of iv beta blockers. Beta-Blocker Uses. Hypertension Arrhythmias

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b -blockade in Critical Care and Perioperatively: Guidelines

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  1. b-blockade in Critical Care and Perioperatively:Guidelines Figen Esen Professor of Anesthesiology and Intensive Care University of Istanbul, Istanbul Medical Faculty

  2. Pharmacokinetic profiles of iv beta blockers

  3. Beta-Blocker Uses • Hypertension • Arrhythmias • Angina/Coronary artery disease • Acute coronary syndromes • Congestive Heart Failure • Postmyocardial infarction • Perioperative use

  4. Physiologic rationale for perioperative use • Stress induced by the surgery, • Catecholamine-mediated peri-operative myocardial ischaemia and infarction • Oxygen demand and supply mismatch • Tachycardia and hypertension related to surgical stress, postoperative pain, use of sympathomimetic drugs • Surgery can be associated with hypotension, vasospasm, and anemia • Stress induced plaque rupture • Hypercoagulability, leukocyte activation and increased inflammatory response, thrombus formation, and occlusion

  5. Perioperative cardiac complications ~40 million surgical procedures in EU per anum • Postoperative myocardial infarction rate: 1% or 400.000 patients • Cardiovascular mortality rate: 0.3% or 133.000 patients • 30-day incidence of cardiac events (perioperative myocardial infarction or cardiac death) of 2.5% in unselected patients > 40 years • In vascular surgery patients even higher 6.2% • The risk of perioperative cardiac complications is the summation of the individual patient’s risk and cardiac stress related to the surgical procedure

  6. Revised Cardiac Risk Index 7 clinical risk factors • Ischaemic heart disease • History of congestive heart failure • History of cerebrovascular disease • Insulin therapy for diabetes • Preoperative serum creatinine > 2.0 mg/l • High-risk type of surgery (thoracic, intraperitoneal, supra-inguinal vascular) Rates of major cardiac complications (cardiac death or MI) • No risk factor 0.4 [0.05-1.5] • 1 factor 0.9 [0.3-2.1] • 2 factors 6.6 [3.9-10.3] • ≥ 3 factors 11.0[5.8-18.4] (Lee et al. Circulation 1999; 100:1043-9)

  7. Surgical Risk Estimate Low (cardiac risk < 1%) • Breast • Dental • Endocrine • Eye • Gynecological • Reconstructive • Orthopedic – minor (knee…) • Urological – minor Intermediate (cardiac between 1% and 5%) • Carotid • Peripheral arterial angioplasty • Endovascular aneurysm repair • Head- and neck surgery • Neurological • Orthopedic – major (hip and spine surgery) • Pulmonary • Renal / liver transplant • Urological- major High (cardiac risk > 5%) • Aortic and major vascular surgery • Peripheral vascular surgery

  8. How do they protect? • Decrease cardiac oxygen demand (by reducing force of contraction and heart rate) • Increase oxygen supply (by increasing the duration of diastole) • Antiarrhythmic effect (improves supply/demand) • Reduce the shear stress across atheromatous plaque and reduce the incidence of rupture • Influence on cell signaling – inflammation (affect the response to reperfusion injury)

  9. THE CLINICAL EVIDENCE Initial supportive data high risk and intermediate risk pts noncardiac surgery (vascular surg, other)

  10. Peri-Operative Beta-Blockers in High-Risk Patients (I) 200 patients with known CAD or ≥2 risk factors atenolol vs. placebo 40% major vascular surgery Reduction in peri-operative ischaemia (24% vs. 39%, p=0.03) No difference in the short term outcome Decrease in late mortality (p=0.019) and late events (p=0.008) (Mangano et al. N Engl J Med 1996; 335:1713-20)

  11. Peri-Operative Beta-Blockers in High-Risk Patients (II) • 112 patients scheduled for vascular surgery, with ≥ 1 risk factor and positive dobutamine stress echocardiography • Bisoprolol started 1 wk before surgery and continued (~37 days) • The dose was titrated to a goal heart rate • Reduction in peri-operative: • Mortality (3.4 vs. 17%, p=0.02) • Myocardial infarction (0% vs. 17%, p<0.001) • Primary composite endpoint (3.4%vs. 34%, p<0.001) (Poldermans et al.N Engl J Med 1999; 341:1789-94)

  12. Peri-Operative Beta-Blockers in Intermediate Risk Patients(I) • POBBLE trial • 103 patients randomised to metoprolol or placebo • Infrarenal vascular surgery • 13% vs. 15% cardiac events (death, myocardial infarction or stroke) at 30 days (p=0.78) • MaVS trial • 496 patients randomised to metoprolol or placebo • Revised cardiac index (Lee) ≤ 2 in 90% of patients • Vascular surgery • 10% vs. 12% cardiac ivents (death, myocardial infarction, hearth failure, arrhythmias or stroke) at 30 days (p=0.57) (Brady et al. J Vasc Surg 2005; 41: 602-9) (Yang et al. Am Hearth J 2006; 152: 983-90)

  13. Peri-Operative Beta-Blockers in Intermediate Risk Patients(II) • DIPOM trial • 921 patients aged >39 with diabetes randomized to metoprolol or placebo • “Major “ non-cardiac surgery • 6% vs. 5% cardiac events (death, myocardial infarction, unstable angina, heart failure) at 30 days (p=0.66) (Juul et al. BMJ 2006; 332: 1482-5)

  14. Discrepancies in the Effect of Peri-Operative Beta-Blockade • Patients characteristics and type of surgery (risk of post-operative cardiac events) • Beta-blocker therapy • Type of drug • Dose • Timing of onset • Dose titration • Duration after surgery • Endpoints

  15. In 2007, The AHA/ACC guidelinesFleisher LA et al. J Am Coll Cardiol 50:159-241 Class II a recommendation with B level of evidence “benefit > risk, it is reasonable to perform” for high risk pts for vascular surgery Class IIb recommendation with C level of evidence “benefit ≥ risk, may be considered” for intermediate risk pts for intermediate risk surgery

  16. POISE Trial (the largest RCT) • 8351 patients randomized to extended-release metoprolol or placebo • Known cardiovascular disease, major vascular surgery or 3 clinical risk factors • 82% of patients with atherosclerotic disease • 100 mg metoprolol 2-4 h. Before surgery, up to 400 mg during the first 24 h. • 5.8% vs. 6.9% cardiac events (death, myocardial infarction, cardiac arrest) at 30 days (p=0.04) • 3.1% vs. 2.3% total 30 day mortality (p=0.03) (POISE Study Group Lancet 2008;371:1839-47

  17. POISE Trial CV death / MI / cardiac arrest HR 0.84 [0.70-0.99] Myocardial infaction HR 0.73 [0.60-0.89] Primary endpoint according to risk factors Stroke HR 2.17 [1.26-3.74] All-cause death HR 1,33 [1.03-1.74] Stroke was associated with perioperative hypotension (POISE Study Group Lancet 2008;371:1839-47)

  18. POISE TrialControversies related to the interpretation • Reduction in perioperative cardiac events, but increased risk of stroke • Trial design and patient population • Admission criteria may have been too broad • Study drug initiated only a few hours before surgery • Dose may have been too high • Tight postoperative control of heart rate was lacking • Attention to perioperative hemodynamics may decrease complications 18

  19. In 2009, ACCF/AHA Guidelines and European Society of Cardiology Guidelines (endorsed by ESA)on Perioperative Beta Blockade

  20. Both Guidelines ESC vs ACCF/AHA Things in common • Pts on chronic treatment should be maintained on this medication • Perioperative high dose beta blockers without titration is either not recommended or labeled as “not useful and maybe harmful” • Beta blockers should be titrated toHR 60-70/min and arterial pressure >100 mmHg

  21. Summary of ESC vs ACCF/AHA • b-blockers only for high risk pts undergoing vascular surgery (Class IIa B) • b-blockers for pts with IHD and MI in any type of surgery (Class IB) • b-blockers for pts in high risk surgery without reference to the severity of cardiac risk (Class IB) Sear, et al., British Journal of Anaesthesia 104 (3): 273–5 (2010)

  22. Peri-Operative Use of Beta-Blockers • Patients- and surgery-specific risk assessment • Respect usual contraindications • Asthma, severe conduction disorders, symptomatic bradycardia or hypotension, decompensated HF • No contraindication if arteritis or COPD • Beta-blocker onset ideally 1 month before surgery • Favour 1-selective blockers without sympathomimetic activity • Dose titration • Adapted to achieve HR 60-70 /min and systolic BP> 100 mmHg • Post-operative period • Same goals, using IV route if needed • Need to identify and treat the cause of tachycardia • Duration > 1 month

  23. b- blockade in the ICU “Fight OR Flight response” meaningful reaction for survival Too much of it may do harm Sympathetic tone and mortality HEART RATE CONTROL Sympathetic Overstimulation During Critical Illness: Adverse effects of Adrenergic Stress

  24. HEART RATE CONTROL

  25. Effects of b-blockade on sepsis Normalization of Cellular Metabolism Beta Blockers in Sepsis Decreased Cardiac Dysfunction Cytokine Effects Improved Glucose Homeostasis

  26. Effect on Survival Before LPS 6 h after LPS • mortality reduction if given before a septic insult • time to death was increased in a CLP model • anti-inflammatory effects

  27. retrospective analysis of 40 patients with septic shock and cardiac depression. • Heart rate control was achieved with milrinone infusion and enteral metoprolol therapy in patients with septic shock and cardiac depression. • targeted heart rates of 65 to 95beats per minute • Enteral metoprolol therapy had no major adverse effects on cardiovascular or organ function. • • Mean arterial blood pressure increased despite decreasing norepinephrine, arginine vasopressin, and milrinone dosages. • • Cardiac function economized, resulting in a maintained cardiac index with a lower heart rate and a higher stroke

  28. Beta blockers and inflammation

  29. Background • Among severe burns, Higher catecholamine levels, metabolic rate, sympathetic activity is associated with worse outcomes; directionality uncertain • Improved glucose control, improved wound healing, fewer infections with lower sympathetic activity • Hypothesis of B-blockade to Lower Sympathetic Activity, decrease catabolism tested in 24 patients

  30. Herndon NEJM 2001

  31. 34 yrs, rectum tm, intraabdominal sepsis • due to anastomosis leakage • Avarage HR ~170 /min • Avarage MAP ~ 120 mmHg • Sepsis treatment • (source control, ABs, organ support…..) • Esmolol inf 20 day, mean 500 mg/hr (7.1 mg/kg/hr) • Metoprolol 100 mg 2x1 • Avarage HR ~110 /min • Avarage MAP ~ 90 mmHg

  32. Conclusion (I) • Peri-operative beta-blockers prescription should be adapted to the individual patients risk of cardiac events, previous treatment, and the type of surgery • Beta-blockers should be used in high risk surgery, but not in low-risk situations (low-risk surgery in patients without risk factors) • In all cases, treatment should be started long before surgery, at a low dose, followed by careful titration • More homogenous risk-assessment is needed for further trials to improve the level of evidence of debated issues

  33. Conclusion (II) • In the ICU, beta-blockers prescription should be considered in the postoperative patients to control hypertension and to ease extubation • In sepsis, the literature is far from clear and straightforward, however beta-blockade warrant approval for human trials in selected patients • Tailoring treatment according to the patients risk and hemodynamics

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