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Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Malte Book
Department of Anaesthesiology and Pain Medicine
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;77:496Özal 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/m2
• 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.
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. 2009 Oct 27;120(17):1664-71
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 ?
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
Levin et al. Circulation. 2009;120:1664-1671
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 …
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. 2000 Sep-Oct;15(5):347-53..
“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 fürlange, grosse Eingriffe (CPB T/dur, Cardioplegie)bei kranken Pt(CHF-Therapie, schlechte EF)
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
Methylene Blue,
the new magic bullet ?
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.
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
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
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
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 …
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
Evidence?
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/m2
• 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.
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%)
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)
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 (800-850 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 %.
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): 142-148
• 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 = 0.049 !!!!
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“)
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/m2
• 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 ?
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 aorticpressure 85/40,just go off !
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.
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
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 concentrationsUlusoy et al. J Cardiothorac Vasc Anesth. 2008 Aug;22(4):560-4
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.
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
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
MB Indication in the Cardiac OR
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
Alternative
• Arginin Vasopressin (AVP)
oUp to 0.1 U/min
oHigher number of RCTs
investigated the clinical administration
oVasoplegia due to relative AVP deficiencyColson et al. Critical Care 2011, 15:R255
oPossibly causal therapy
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
ende
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
Malte Book - Methylene Blue: Vasoplegic Syndrome Finally Resolved ?
Inselspital, Bern University Hospital, Department of Anaesthesiology and Pain Medicine
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 blue Placebo
Volume therapy intra- and 6 hour postoperative
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
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/m2
• SVR < 800 dyn/s/cm-5
• Vasopressor requirement
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
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?
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 340
• 7 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