Myocardial dysfunction in sepsis Prof. Jean-Louis TEBOUL Medical ICU Bicetre hospital University Paris XI France
septic shock patients Early depression of LVEF that persisted for up to 4 days and returned to normal within 7-10 days in survivors Time days (days) Parker et al Ann Intern Med 1984
Sepsis-related cardiac dysfunction Incidence Mechanisms Diagnosis Treatment
LV EF % LV EF % LV EF % Day 1 Day 2 Day 3 after vasopressors weaning Day 1 Day 2 Day 3 after vasopressors weaning Day 1 Day 2 Day 3 after vasopressors weaning 40% of pts 40% of pts 20% of pts
Sepsis-related cardiac dysfunction Incidence Mechanisms Diagnosis Treatment
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Intrinsic cellular mechanisms
Supracellular mechanisms Coronary blood flow Generally, coronary blood flow is not decreased during sepsis but in patients with prior coronary artery disease, avoid profound fall in diastolic blood pressure (driving pressure for left coronary blood flow)
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Coronary blood flow Circulating factors
J Clin Invest 1985; 1539-1553 extent of shortening of rat myocardial cells Serum from septic shock patients contained substances that were able to depress cardiac contractility
J Clin Invest 1985; 1539-1553 70 60 recovery phase 50 40 30 20 10 0-10 acute phase -20-30 -40-50 -60-70 % changes in the extent of myocardial cell shortening Serum from septic shock patients contained substances In the recovery phase, this phenomenon no longer existed that were able to depress cardiac contractility
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Coronary blood flow Circulating factors TNF-, IL 1, others?
absence of plasma Cardiac contractility can be decreased during sepsis in the absence of plasma. This argues against a major role of a circulating myocardial depressant factor but rather supports an intrinsic alteration in the myocardium as the predominant mechanism of septic cardiac dysfunction. After Rabuel and Mebazaa Intensive Care Med 2006
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Intrinsic cellular mechanisms Coronary blood flow -adrenergic receptors Circulating factors
cardiomyocyte membrane 1 agonist camp 1 receptor AMP Adenylate cyclase + PKa Ca 2+ Tn myosin-actin bridges + cytosol Ca 2+ sarcoplasmic reticulum
Chest 1993; 103:81-85 3 2.5 2 Cardiac Index L/min/m 2 * * * 1.5 1 0 5 10 15 Dobutamine dose (µg/kg/min)
Crit Care Med 1993; 21:31-39 non severe sepsis septic shock Cardiac Index 6 5 4 * * ns L/min/m 2 3 2 0 5 10 0 5 10 dobutamine dose (µg/kg/min)
Crit Care Med 1993; 21:31-39 camp response to isoproterenol volunteers sepsis septic shock impairment of -adrenergic receptor responsiveness * * # sepsis, septic shock
Decreased efficacy of dobutamine in patients with septic shock Crit Care Med 1993; 21:31-39 camp response to isoproterenol volunteers sepsis septic shock * * # impairment of -adrenergic receptor responsiveness sepsis, septic shock camp response to Na-fluoride sepsis septic shock impairment of * # post -adrenergic receptor signal transduction septic shock
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Intrinsic cellular mechanisms Coronary blood flow Circulating factors -adrenergic receptors Calcium and myofilaments
1 agonist camp cardiomyocyte membrane Hypothesis: during sepsis, reduced sensitivity of myofilament to Ca ++ due to reduced ability of Ca ++ to combine Tn 1 receptor AMP Adenylate cyclase + PKa Ca 2+ Tn Myosin-Actin bridges + cytosol Ca 2+ sarcoplasmic reticulum
This suggests an alteration of Ca ++ myofilament responsiveness
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Intrinsic cellular mechanisms Coronary blood flow Circulating factors -adrenergic receptors Calcium and myofilaments Nitric oxide and peroxynitrite pathways
Mechanisms of sepsis-related cardiac dysfunction Supracellular mechanisms Intrinsic cellular mechanisms Coronary blood flow Circulating factors -adrenergic receptors Calcium and myofilaments Nitric oxide and peroxynitrite pathways Apoptosis At the initial phase of sepsis, a cytokine effect mainly contributes to myocardial depression At a later phase, other mechanisms are likely to be predominant
Sepsis-related cardiac dysfunction Incidence Mechanisms Diagnosis Treatment
Diagnosis of sepsis-related cardiac dysfunction a LVEF of 50% suggests a mild myocardial depression if SBP is 130 mmhg. but suggests a profound myocardial depression if SBP is 80 mmhg Echocardiography PiCCO BNP Key method LVEF For a correct interpretation, take also into account the SBP (afterload)
Diagnosis of sepsis-related cardiac dysfunction Echocardiography PiCCO BNP
PiCCO technology Transpulmonary thermodilution 1- Cardiac output CFI: 2- Global end-diastolic volume (GEDV) Index of 3- Cardiac function index (CFI) = CO/GEDV cardiac systolic function
A low CFI can alert the clinician CFI for detecting LVEF 35% 96 simultaneous measurements CFI (PiCCO) and LVEF (echo) and incite to perform an echo
Repetitive measurements of CFI allow following changes in cardiac function with therapy
Diagnosis of sepsis-related cardiac dysfunction Echocardiography PiCCO BNP
Plasma BNP BNP release LV myocyte stretch RV myocyte stretch
In septic patients, BNP levels can be elevated in the absence of LV dysfunction High BNP values Normal LVEF values Sepsis
Inflammatory cytokines (TNF-, IL-1, IL-6) BNP clearance Plasma BNP BNP release LV myocyte stretch RV myocyte stretch
Inflammatory cytokines (TNF-, IL-1, IL-6) BNP clearance Renal failure Plasma BNP BNP release LV myocyte stretch RV myocyte stretch
Sepsis-related cardiac dysfunction Incidence Mechanisms Diagnosis Treatment
Treatment of sepsis-related cardiac dysfunction To treat or not to treat?
However beneficial effects of dobutamine are unpredictable (potential decreased efficacy)
Dobutamine increased LVEF by more than 10% only in 35% of pts
Dobutamine and septic myocardial dysfunction beneficial effects are unpredictable (potential decreased efficacy) detrimental effects may occur (arrhythmias, vasodilation, etc) administration of dobutamine should be restricted to patients: - with low LVEF test the response to dobutamine before any prolonged administration - and low SvO 2 (< 65-70 %) despite fluid resuscitation and vasopressive therapy
Treatment of sepsis-related cardiac dysfunction To treat or not to treat? Alternatives to dobutamine?
cell membrane 1 agonist camp Ca 2+ sensitizers 1 receptor AMP Adenylate cyclase + PKa Ca 2+ Tn Myosin-Actin bridges + cytosol Ca 2+ sarcoplasmic reticulum
ml/m 2 44 42 40 38 36 SI Stroke index * Levosimendan Dobutamine 34 32 Baseline 24 hrs
ml/m 2 LVEF 52 47 42 * * Levosimendan Dobutamine 37 32 27 Baseline 24 hrs
Is Levosimendan the magic drug? Not sure
Treatment of sepsis-related cardiac dysfunction To treat or not to treat? Make sure that the patient is not still hypovolemic assess fluid responsiveness Alternatives to dobutamine? static measures of preload (i.e. CVP) are not appropriate dynamic indices of preload responsiveness are reliable In any case, before giving inotropes Make sure that hypotension is corrected
Conclusion Mechanisms contributing to septic cardiac dysfunction are complex and intricate. Treating or not cardiac dysfunction is still a matter of debate (place of echo and SvO 2 ). In any case, first correct hypovolemia and hypotension. When the decision to treat is made, dobutamine is recommended,. but it can be ineffective in most severe patients. The place of Ca ++ sensitizers needs further evaluation. Thank you