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Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Malte Book Department of Anaesthesiology and Pain Medicine.

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Präsentation zum Thema: "Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Malte Book Department of Anaesthesiology and Pain Medicine."—  Präsentation transkript:

1 Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Malte Book Department of Anaesthesiology and Pain Medicine

2 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Ann Thorac Surg 2004;77:496 Özal et al. Ann Thorac Surg 2005;79:1615 Identical (!) definition in both papers MAP < 50 mmHg CVP < 5 mmHg, PCWP < 10 mmHg CI > 2.5 l/min/m 2 SVR < 800 dyn/s/cm -5 vasopressor requirement What is Vasoplegic Syndrome Post CPB? VPS ? -- or differential diagnosis: - hypovolemia with good LV function ? - hemodilution (crystalloid cardioplegia) ? - central-peripheral AP gradient ? - inodilator overdose ? - SIRS ? - a-v shunting (cirrhosis, dialysis) ? - treatment defines diagnosis here ? Levin et al Circulation. 2009;120:1664 Post-CPB vasoplegia (retrospectively !) defined as : epi/norepi >150 ng kg-1 min-1; dopamine >10 mgkg-1min-1; or vasopressin > 4 U/h.

3 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Vasoplegic syndrome after cardiac surgery Definition ? Hypotension Cardiac output or Systemic vascular resistance Fluid and vasopressor requirement Incidence ? 5% to 25% Levin et al. Circulation Oct 27;120(17): I think both definition and incidence of VS are quite subjective and institutional Hypotension: Wide differential Dx, see previous slide Cardiac output: at which preload ? O2 consumption? SVR: How low ? Supported by high SvO2, TEE ? Who determines requirement ? Is 1-2 VS/week truly realistic ??? Who sees that in his/her practice ?

4 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Circulation. 2009;120: Klar, sind die Kränkeren (CHF): Confounded, beweist per se nichts Klar, grössere OP an kränkeren Pt: Beweist per se nichts Trasylol wurde seinerzeit v.a. bei Blutungsrisiko- Ops gegeben, klar …

5 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Carrel T, Englberger L, Mohacsi P, Neidhart P, Schmidli J. Low systemic vascular resistance after cardiopulmonary bypass: incidence, etiology, and clinical importance. J Card Surg Sep-Oct;15(5): Vasoplegia in CABG, valve surgery (n=800): None, 78%; mild, 14%; severe, 7.5% No effect on hospital mortality cause for delayed extubation and prolonged ICU LOS Predictors in logistic regression analysis: temperature and duration of CPB, cardioplegic volume reduced LVF preoperative ACE-I treatment Diese Arbeit zitieren sie alle nicht, obwohl gar nicht so schlecht: Die Inzidenz ist nicht wirklich hoch (schwer = 7.5%, find ich realistisch) Der Mortalitätseffekt ist bestimmt durch die Krankheitsschwere, nicht durch das Syndrom Predictors: Alles Surrogat- Prädiktoren für lange, grosse Eingriffe (CPB T/dur, Cardioplegie) bei kranken Pt (CHF-Therapie, schlechte EF)

6 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Methylene Blue, the new magic bullet ?

7 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine WIKIPEDIA 2012 sagt: Methylenblau wurde erstmals 1876 von dem Chemiker Heinrich Caro bei der BASF synthetisiert. [1] Ein Jahr später erhielt die BASF für Methylenblau das erste Deutsche Reichspatent für einen Teerfarbstoff. Heinrich CaroBASF [1] Reichspatent Um 1900 wurde Methylenblau auch als ein Medikament gegen psychische Erkrankungen versucht. WIKIPEDIA 2022 könnte lauten: Um 2000 wurde Methylenblau auch als ein Medikament gegen Alzheimer und verkorkste Herzchirurgie versucht ….. MB History

8 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine MB Mode of action Inhibitor of (inducible) NO Synthase NO scavenger Inhibitor of Guanylate Cyclase, cGMP cGMP mediated vasodilation Interleukin-1 dependent Superoxide dependent

9 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine MB Side Effects Cardiac arrhythmias Coronary vasoconstriction Angina/precordial pain Cardiac output Renal/mesenteric blood flow Methemoglobinemia Hemolysis Monoamine oxidase inhibitor Interference with oximetry

10 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Contraindications Severe renal impairment Glucose 6 Phosphat Dehydrogenase deficiency Serotoninergic medication Erst mal mögliche Indikationen in der Medizin listen, bevor man über KI redet: S. Kommentarfeld unten: Die Evidenzlage ist nicht wirklich überzeugend …

11 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Evidence?

12 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Ann Thorac Surg 2004;77:496 –9 Hypotension MAP < 50 mmHg CVP < 5 mmHg and PCWP < 10 mmHg CI > 2.5 l/min/m 2 SVR < 800 dyn/s/cm -5 Vasopressor requirement Levin benutzt wortwörtlich dieselbe VS-Definition wie Özal (derselbe Stall): eigentlich handelt es sich nur um hypovoläme, hämodiluierte Pat mit guter systolischer Funktion, die unnötigerweise mit Vasopressor kosmetisiert wurden.

13 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Ann Thorac Surg 2004;77:496 –9 638 patients, 56 with vasoplegic syndrome Randomization:3 hours after arrival in the recovery room 1.5 mg/kg methylene blue Also ehrlicherweise ein Vergleich 28 zu 28 Pt ! UNBLINDED, inadequate randomization procedure (admission number). Levins 4% Mortalität in ihrer Low-Risk CABG/Valve Population (Control) ist grottenschlecht, international liegt das um 1-2 %. Overall mortality was 27/638 patients (4.2%), 6 of these patients in the VS population (10.7%) versus 21 patients in the nonvasoplegic group (3.6%)

14 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine 100 patients at risk for vasoplegia o ACE inhibitors o Calcium channel blockers o Heparine 1 hour preoperative 2 mg/kg methylene blue (UNBLINDED, inadequate randomisation proc)

15 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine SVR during cardiopulmonary bypass Özal et al. Ann Thorac Surg 2005;79:1615–9 Mit kristalloider St Thomas Kardioplegie ( > 400 ml) ist so ein MAP Abfall an der ECC oder so ein SVR post ECC (wenn man nicht filtriert) völlig erwartbar, hier in 26%. Zudem waren alle Pt postCPB hypovoläm (CVP < 5, LAP < 10). Fazit: Massive Hämodilution ( SVR) und Hypovolämie wurden in der einen Gruppe mit MB kosmetisiert, in der andern mit Nor, Crystalloid, Kolloid und EK. In 6 % ihrer recht gesunden CABG-Pt (Nor-refractory) brauchten sie sogar Nor-Dosen von 0.5 mcg ·kg1 · min1 = 2100 mcg/h !!! Komplett abwegig. Vergleichbare Pt bei uns (Eto-Studie) brauchen weder Nor noch MB, und nur 0-1 EK. Und Özals 4% Mortalität in Low-Risk CABG ist wie Levins absolut unterirdisch, international liegt das um 1 %.

16 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Korean J Anesthesiol 2012 August 63(2): Preoperative Prophylactic Methylene blue before CPB No differences in:MAP, MPAP, CI, PCWP, SVR Need for vasopressor/inotrope Less erythrocyte/platelet concentrates Fewer PRBC transfused, less FFP transfusion exposure with MB Das ist der einzige kleine (21 vs 21) korrekt randomisierte und verblindete RCT, noch dazu in Pt mit etwas höherem Risiko: -- und da kommt nix raus, ausser mean RBC reduction und Delta FFP- Exposure p = !!!!

17 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Several Two severely flawed (but abundantly cited) studies showed postulate potential benefit in treatment or prevention of vasoplegic syndrome, one (underpowered) RCT found no benefit. The rest are great case reports and enthusiastic reviews. Evidence good enough, for you ? Özal und Levin: komplett wertlos als Evidenz: Unblinded, nicht korrekt randomisiert, ungeeignetes Low-Risk-Kollektiv, Fehldefinition des Syndroms und der Eingangskriterien, Outcomes in den Kontrollgruppen absolut substandard im internationalen Vergleich. Cho: negatives Ergebnis (kein Benefit im primary endpoint Nor-Reduktion)

18 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine MB Indication in the Cardiac OR Question: After composite graft/hemiarch repair w/ DHCA, pt rewarmed, ventilated, partial ejection radial pressure 60/40, CVP 8, flow index 2.6 l/min/m 2 norepi running at 0.1 mcg/kg/min (400 mcg/h) surgeon wants to get off pump --- What do you do next ? Time for MB ?

19 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Manecke GR et al Deep hypothermic circulatory arrest and the femoral-to-radial arterial pressure gradient. J Cardiothorac Vasc Anesth. 2004;18:175 Tell surgeon to stick needle into the ascending graft, … … central aortic pressure 85/40, just go off !

20 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine MB Indication post CPB NONE Off-label: o Reversal of Rescue in vasoplegic syndrome (refractory to noradrenalin/vasopressin) o Prevention of vasoplegic syndrome Problem: Inconsistent definition of vasoplegic syndrome Es gibt doch gar keine Zulassung, nicht mal eine Phase I Studie: Also gibt es keine Indikation. Und schon gar nicht prophylaktisch – das ist mE unethisch.

21 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Timing + dosing No standard evidence-based timing of administration o Preoperative o Intraoperative o During CPB o Postoperative No standard evidence-based dosing o 1.5 to 7.0 mg/kg bolus o Continuous infusion

22 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Data quality + safety Few flawed, underpowered RCTs Conflicting results (2 pos, 1 neg) Mainly case reports/case series/reviews No (not even) phase 1 studies Documented Adverse Effects (see slide 9) IMA contraction in clinically achieved concentrations Ulusoy et al. J Cardiothorac Vasc Anesth Aug;22(4):560-4

23 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Recommendation NO routine use of Methylene Blue Elective or prophylactic use: exclusively within clinical trials Consider as last resort option ONLY There is no such thing as MB deficiency: if you think you need it, better look for other serious problems in your practice first.

24 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine How We Do It Identify vasoplegia risks: endocarditis, LVAD, cardiac Tx, LVEF < 30% on ACE-I, DHCA, long CPB runs use of inodilators (milrinone, levosimendan) (sepsis, hepatic cirrhosis, dialysis fistula etc) On CPB: monitor SVRI, if <1200 prior to wean: ultrafiltrate, treat metabolic acidosis, optimize Hct on CPB monitor central aortic pressure simultaneously with radial AP (may add femoral AP) CPB-wean: monitor filling pressures, TEE, svO2, (CI) optimize rate, rhythm, contractility per TEE optimize preload per TEE (adjust to RV function, LV diastolic dysfunction, LVOTO etc) If SVRI low, CI and SvO2 high: Optimize afterload by stopping vasodilators, titrating vasopressors to normalize SvO2: 1° Noradrenalin to max 0.15 mcg/kg/min (~600 mcg/h) 2°Arginin-Vasopressin (AVP) 0.4 – 6 U/h (first to be weaned when pt improves) avoid shed blood reinfusion (use cell saver), avoid rapid FFP transfusion

25 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine MB Indication in the Cardiac OR

26 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Alternative Arginin Vasopressin (AVP) o Up to 0.1 U/min o Higher number of RCTs investigated the clinical administration o Vasoplegia due to relative AVP deficiency Colson et al. Critical Care 2011, 15:R255 o Possibly causal therapy

27 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine ende

28 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine

29 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine

30 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Limitations? Crystalloid (ml) Colloid (ml) RBC FFP Methylene bluePlacebo Volume therapy intra- and 6 hour postoperative

31 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Recommendation Few RCTs Mainly case reports/case series No phase 1 studies IMA contraction in clinically achieved concentrations

32 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Ann Thorac Surg 2004;77:496 –9 Inclusion criteria Hypotension MAP < 50 mmHg CVP < 5 mmHg and PCWP < 10 mmHg CI > 2.5 l/min/m 2 SVR < 800 dyn/s/cm -5 Vasopressor requirement

33 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Ann Thorac Surg 2004;77:496 –9

34 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Levin et al. Ann Thorac Surg 2004;77:496 –9 Limitations? Liberal inclusion criteria Anaesthetic drugs in the recovery room? Volume therapy? Vasopressin?

35 Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ? Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine Berner Lernkurve 555 interventionelle Aortenklappenprozeduren 425/111/11 transfemoral/transapikal/subclavia 85/340 GA/MAC Konversion MAC zu GA 22 von von 22 bei CPR 2 von 22 bei TEE Notwendigkeit 9 von 22 bei Unruhe 2 von 22 bei resp. Problemen 2 von 22 bei sonst. Problemen (= 13/340 = 3.8% anästhesiolog. Konversion) = GALA


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