Sepsis - die nächsten 30 Jahre Genetische Therapie als Innovation? Malte Book Klinik für Anästhesiologie und Schmerztherapie

Sepsis - die nächsten 30 Jahre

Genetische Therapie als Innovation?

Malte Book

Klinik für Anästhesiologie und Schmerztherapie

Malte Book - Genetische Therapie als Innovation?

Klinik für Anästhesiologie und Schmerztherapie, Inselspital, Universitätsspital Bern

Vasoplegic syndrome (VS) after cardiac surgery




Pretreatment with interleukin-6 small interfering RNA can improve the survival rate of polymicrobial cecal ligation and puncture mice by down regulating interleukin-6 production.Mostafa Anower AK, Shim JA, Choi B, Sohn S.SourceLaboratory of Cell Biology, Ajou University Institute for Medical Sciences, Suwon 443‐721, Republic of Korea.

Shock. 2012 Jan;37(1):77-84.Small interfering RNA targeting focal adhesion kinase prevents cardiac dysfunction in endotoxemia.Guido MC, Clemente CF, Moretti AI, Barbeiro HV, Debbas V, Caldini EG, Franchini KG, Soriano FG.SourceDepartment of Emergency Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.

J Mol Biol. 2003 Apr 4;327(4):761-6.Gene silencing by systemic delivery of synthetic siRNAs in adult mice.Sørensen DR, Leirdal M, Sioud M.SourceDepartment of Comparative Medicine, The National Hospital, Oslo 0310, Norway.

Cell. 2001 Nov 2;107(3):309-21.ATP requirements and small interfering RNA structure in the RNA interference pathway.Nykänen A, Haley B, Zamore PD.SourceDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.Abstract
























Alternative definition of VS

• Epi-/norepinephrine >150 ng kg-1 min-1

or

• Dopamine >10 μg kg-1min-1

or

• Vasopressin > 4 U/hLevin et al Circulation. 2009;120:1664-1671

Treatment defines diagnosis



Levin et al. Circulation. 2009;120:1664-1671

CHF patients?

Sepsis?Low volume?

More serious surgical procedures?

Finally: Serious ill patients are at risk for postoperativeinotrope/vasopressor dependency



Methylene Blue,

the new magic bullet?





Mode of action

• Inhibitor of NO Sythase

• NO scavenger

• Inhibitor of Guanulate Cyclase, cGMP

• cGMP mediated vasodilatation

• Interleukin-1 dependent

• Superoxide dependent



Side effects

• Cardiac arrhythmias

• Coronary vasoconstriction

• Angina/precordial pain

• Cardiac output

• Renal/mesenteric blood flow

• Methemoglobinemia

• Hemolysis

• Monoamine oxidase inhibitor

• Interference with oximetry



Contraindications

• Severe renal impairment

• Glucose 6 Phosphat Dehydrogenase deficiency

• Serotoninergic medication



Evidence?



Levin et al. Ann Thorac Surg 2004;77:496 –9

• MAP < 50 mmHg

• CVP < 5 mmHg and PCWP < 10 mmHg

• CI > 2.5 l/min/m2

• SVR < 800 dyn/s/cm-5

• Vasopressor requirement




638 patients, 56 with vasoplegic syndrome

Randomization: 3 hours after arrival in the recovery room 1.5 mg/kg methylene blue




Limitations?

• Unblinded procedure

• Liberal inclusion criteria/VS definition

• Anaesthetic drugs in the recovery room?

• Volume therapy? Vasopressin?

• High overall mortality (4.2%)



• 100 patients at risk for VS

o ACE inhibitors

o Calcium channel blockers

o Heparine

• 1 hour preoperative 2 mg/kg methylene blue



SVR during cardiopulmonary bypass

Özal et al. Ann Thorac Surg 2005;79:1615–9



Limitations?

Crystalloid (ml)

Colloid (ml)

RBC

FFP

Methylene blue Placebo

• Unblinded procedure

• Liberal inclusion criteria/VS definition

• Volume therapy intra- and 6 hour postoperative

• 26% in the placebo group Norepi. ≥ 0.5 μg kg-1 min-1

• Need for RBC/FFP/Norepi. substandard

Özal et al. Ann Thorac Surg 2005;79:1615–9



Cho et al. Korean J Anesthesiol 2012 August 63(2): 142-148

• Prophylactic Methylene blue before CPB (2 mg/kg)

• No differences in: MAP, MPAP, CI, PCWP, SVR

Need for vasopressor/inotrope

• Fewer PRBC transfused, less FFP exposure with MB



Two questionable studies postulate potential

benefit in treatment/prevention of vasoplegic

syndrome (and were constantly cited)

One underpowered RCT showed no influence

on primary endpoint (vasopressor need)



Indication pre/post CPB

• No evidence-based indication

• Off label

o Rescue in vasoplegic syndrome

(refractory to norepinephrine/vasopressin)

• Problem:

Inconsistent definition of vasoplegic syndrome



Timing + dosing

• No evidence-based timing of administration

o Preoperative

o Intraoperative

o During CPB

o Postoperative

• No evidence-based dosing

o 1.5 to 7.0 mg/kg bolus

o Continuous infusion



Data quality + safety

• Few questionable, underpowered RCTs

• Conflicting results

• Mainly case reports/case series

• None phase 1 study

• Documented Adverse Effects

o IMA contraction in clinically

achieved concentrationsUlusoy et al. J Cardiothorac Vasc Anesth. 2008 Aug;22(4):560-4



Ultimate MB indication in cardiac surgery?

http://mirthbomb.com/wp-content/uploads/2012/09/Are-you-totally-lost-icon.jpg



Recommendation

• No use of Methylene Blue

• Application exclusively within clinical trials

• Consider as „last resort“ option only



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





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Sepsis - die nächsten 30 Jahre Genetische Therapie als Innovation? Malte Book Klinik für Anästhesiologie und Schmerztherapie