NE refractoriness: From Definition To Treatment... Prof. Alain Combes
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1 NE refractoriness: From Definition To Treatment... Prof. Alain Combes Service de Réanimation ican, Institute of Cardiometabolism and Nutrition Hôpital Pitié-Salpêtrière, AP-HP, Paris Université Pierre et Marie Curie, Paris 6 alain.combes@psl.aphp.fr
2 Conflict of interest Principal Investigator: EOLIA trial VV ECMO in ARDS NCT Sponsored by MAQUET, Getinge Group Received honoraria from: MAQUET, Gambro, ALung
3 Definition of catecholamine-resistant septic shock
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5 Severe Shock: Need for Norepinephrine mcg/kg/min in most studies
6 Refractory Shock: Need for Norepinephrine >1 mcg/kg/min Or Persitent hypotension with NE> 1 mcg/kg/min Or Death with persitent hypotension despite NE> 1 mcg/kg/min
7 Incidence of catecholamine-resistant septic shock
8 20-25% of the patients will die with refractory shock
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12 Incidence of NE > 0,5 mcg/kg/min 48/689 = 7%
13 Prognosis of catecholamine-resistant septic shock
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15 Mortality 50-90% Depending on definition And populations evaluated
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18 Logistic fit analyzed of survival according to maximum doses of vasopressor As vasopressor dose increases, there is a direct increase in patient mortality
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20 Significant risk factors for mortality
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25 HIGH-DOSE NOREPINEPHRINE TREATMENT: DETERMINANTS OF MORTALITY AND FUTILITY IN CRITICALLY ILL PATIENTS Döpp-Zemel, American Journal of Critical Care. 2013
26 HIGH-DOSE NOREPINEPHRINE TREATMENT: DETERMINANTS OF MORTALITY AND FUTILITY IN CRITICALLY ILL PATIENTS Döpp-Zemel, American Journal of Critical Care. 2013
27 HIGH-DOSE NOREPINEPHRINE TREATMENT: DETERMINANTS OF MORTALITY AND FUTILITY IN CRITICALLY ILL PATIENTS Döpp-Zemel, American Journal of Critical Care. 2013
28 Pathophysiology of catecholamine-resistant septic shock
29 Vascular hyporesponsiveness to catecholamines Nitric oxide overproduction Upregulation of prostacyclin Excessive activation of ATPsensitive potassium channels Desensitization of alpha adrenoreceptors
30 Reversible myocardial dysfunction during sepsis Parker MM, Ann Intern Med 1984
31 Reversible myocardial dysfunction during sepsis Parrillo et al., JCI 1985
32 Reversible myocardial dysfunction during sepsis Circulating Myocardial Depressant Substance (MDS) Endotoxine? TNF-α? IL-1β? IL-6? NO? Parrillo et al., JCI 1985
33 Reversible myocardial dysfunction during sepsis Half of the nonsurvivors developed a decreasing cardiac index, with no change in heart rate or ejection fraction, (..) and become those nonsurvivors who die of a cardiogenic shock-like state. Parker MM, J Crit Care 1989
34 Continuum in several consecutive phases Early phase: Low-flow state related to hypovolemia Volume expansion increases cardiac output and improves patient s perfusion Second phase: Hyperdynamic state High cardiac output Low systemic vascular resistance Third phase: Decreased cardiac output Increased systemic vascular resistance Progressive metabolic acidosis
35 Understanding cardiac failure in sepsis Antoine Vieillard-Baron M. Cecconi ICM, 2014
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37 PEHR prolonged elevated heart rate, ami acute myocardial ischemia and cell damage; TA tachyarrhythmia, RedSBF reduction in systemic blood flow
38 Quartiles of catecholamine load: I, <0.12 mcg/kg/min; II, mcg/kg/min; III, mcg/kg/min; IV, >0.46 mcg/kg/min
39 Reversible myocardial dysfunction during sepsis Role of catecholamines? Reversible Left Ventricular Dysfunction Takotsubo Cardiomyopathy Related to Catecholamine Cardiotoxicity Akashi, Journal of Electrocardiology 2002
40 Two different clinical scenarios Persistent vasoplegia and hypotension Low vascular resistance Hyperdynamic LV Preserved cardiac output Marked vasoconstriction Elevated vascular resistance Low EF Decreased cardiac ouput = Cardiogenic shock
41 Treatment options for catecholamine-resistant septic shock
42 Catecholamines
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44 Mean blood pressure Arterial lactate
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46 Vasopressin
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49 Low-dose hydrocortisone
50 Effects of low-dose hydrocortisone therapy on mortality at 28 days
51 Effects of low-dose hydrocortisone therapy on shock reversal
52 NO synthase inhibitors
53 Lopez et al, Crit Care Med 2004; 32:21 30
54 Lopez et al, Crit Care Med 2004; 32:21 30
55 Lopez et al, Crit Care Med 2004; 32:21 30
56 Effect of tilarginine, an isoformnonselective NOS inhibitor in patients with MI and refractory cardiogenic shock despite establishment of an open infarct artery
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58 Angiotensin II
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61 Fever control
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65 Shock reversal in the ICU
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69 High Volume Hemofiltration
70 11 septic shock patients with MOF Randomized crossover 8 h HVHF; 6 l/h 8 h CVVH; 1 l/h Random order
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75 ECMO and Septic Shock Data in Adult Patients
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79 c c c
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81 Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock Venoarterial ECMO n=222 Venoarterial ECMO n=222 Bréchot et al, Crit Care Med, 2013 Refractory septic shock n = 14 Refractory septic shock
82 14 septic shock patients 7 M/ 7 F, 45 years (28-66) 6 Immunocompromised 12 CA, 2 nosocomial 11/14 severe bacterial pneumonia 8/14 ECMO via Mobile team
83 6/14 Streptococcus pneumonia 2 Legionella pneumophila 2 Staphylococcus aureus
84 Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock Bréchot et al, Crit Care Med, 2013 Patients n=14 Value Age, yr, median (range) 45 (28 66) ECMO implantation by UMAC, n 8 Shock onset-to-ecmo interval, hrs, median 24 (3 108) Femoral ECMO, n 14 Left ventricular ejection fraction (%), median 16 (10 30) Catecholamine dose, g/kg/min, median Dobutamine, n= (6 30) Norepinephrine, n= ( ) Epinephrine, n= ( ) Pre-ECMO mean arterial pressure, mmhg, median 72 (53-105) Pre-ECMO central venous pressure, mmhg, median 18 (10-35) Pre-ECMO cardiac index, L/min/m 2, median 1.3 ( ) Pre-ECMO systemic resistance vascular index, 3162 ( ) SOFA score, median 18 (8 21) ph, median 7.16 ( ) Blood lactate, median 9 (2 17) N-Terminal pro-brain natriuretic peptide, pg/ml 29,788 (1,843 35,000)
85 Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock Bréchot et al, Crit Care Med, 2013 Patients n=14 Value Age, yr, median (range) 45 (28 66) ECMO implantation by UMAC, n 8 Shock onset-to-ecmo interval, Very hrs, median specific 24 (3 108) Femoral ECMO, n 14 Left ventricular ejection fraction (%), median 16 (10 30) hemodynamic profile Catecholamine dose, g/kg/min, median Dobutamine, n= (6 30) Norepinephrine, n= ( ) Low LVEF Epinephrine, n= ( ) Pre-ECMO mean arterial pressure, mmhg, median 72 (53-105) Pre-ECMO central venous pressure, mmhg, median 18 (10-35) Low Pre-ECMO cardiac index, L/min/m 2 CI, median 1.3 ( ) Pre-ECMO systemic resistance vascular index, 3162 ( ) SOFA score, median 18 (8 21) High vascular resistance ph, median 7.16 ( ) Blood lactate, median 9 (2 17) N-Terminal pro-brain natriuretic peptide, pg/ml 29,788 (1,843 35,000)
86 Conclusion NE-resistant septic shock encountered in <10% of the case Associated with very high mortality Possible treatment options? Association of catecholamine, vasopressin Low-dose steroids Mild hypothermia Angiotensin II? VA-ECMO to rescue these dying patients In patients with low CI, low LVEF 70% survival if treated early Rapid recovery of LV function
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