The recent big fluid trials Sibylle A. Kozek-Langenecker M.D. Professor MBA Department of...
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The recent big fluid trials
Sibylle A. Kozek-Langenecker M.D. Professor MBADepartment of Anaesthesia and Intensive Care
Evangelical Hospital Vienna
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Honoraria for lectures and travel reimbursement:
B. BraunFresenius KabiCSL Behring
Conflicts of interest
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European Medicines Agency EMAPharmacovigilance Risk Assessment Committee PRAC
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CMDh Statement: Information for healthcare professionals(1) Because of the risk of kidney injury and mortality HES solutions must no longer be used in
patients with sepsis, burn injuries or critically ill patients.
(2) HES solutions should only be used for the treatment of hypovolaemia due to blood loss when crystalloids alone are not considered sufficient.
(3) There is a lack of robust long-term safety data in patients undergoing surgical procedures and in patients with trauma. The expected benefit of treatment should be carefully weighed against the uncertainties with regard to long-term safety, and other available treatment options should be considered. Additional studies will be performed with HES solutions in patients with trauma and in elective surgery.
(4) HES solutions should be used at the lowest effective dose for the shortest period of time. Treatment should be guided by continuous haemodynamic monitoring so that the infusion is stopped as soon as appropriate haemodynamic goals have been achieved.
(5) HES solutions are now contraindicated in patients with renal impairment or renal replacement therapy. The use of HES must be discontinued at the first sign of renal injury. An increased need for renal replacement therapy has been reported up to 90 days after HES administration. Patients’ kidney function should be monitored after HES administration.
(6) HES solutions are contraindicated in severe coagulopathy. HES solutions should be discontinued at the first sign of coagulopathy. Blood coagulation parameters should be monitored carefully in case of repeated administration.
CMDh: Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human
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Contraindications of HES 130 (after PRAC/CMDh 10/2013):
SepsisBurn traumaRenal insufficiency or RRTintracranial or cerebral bleedingCritical illness (on ICU)Hyperhydratation, incl. pulmonary edemaDehydratationSevere coagulopathySevere liver dysfunction
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good drug kept in treatment repertoire
medico-legal relevance of restrictions
CI against initial volume resuscitation in sepsis irrational
problem: „not bad drug but bad use of a drug“
problem: „only bad news are good news“
restrictions in surgery/trauma irrational & not practicable
renal function 90 days postOP, severe coagulopathy …
use of alternatives: less investigated/risky/expensive …
Personal Interpretation
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Population Design
VISEP 537sepsis, septic shock
multi-center, two-by-two factorial RCTGermany
CRYSTMAS 196severe sepsis
multi-center, double blind RCTGermany, France
6S 804severe sepsis
multi-center, blinded, parallel group RCTDenmark, Norway, Finland, Island
CHEST 7000ICU patients
multi-center, blinded, parallel group RCT Australia, New Zealand
CRISTAL 3000ICU patients
multi-nationale, pragmatic, parallel group, open-label RCT; France, Canada, North-Africa
BaSES 241sepsis, septic shock
single-center, double blind, RCTSwiss
Recent big fluid trials in critical illness
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Big trial in critical illness efficacy of initial colloidal volume therapy
Annane. JAMA 2013;310:1809-17
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Control Outcome
CRYSTMAS tetrastarch130/0.4 vs. NaCl 0,9%
volume requirement: colloid* < crystalloidtime until stabilisation: 12 vs. 14 h (NS)renal failure: 25 v. 20% (NS)AKIN, RIFLE, NGAL, b-NAG, a-microglobulin: (NS)
6S tetrastarch 130/0.42 vs.Ringer acetate
90 day-mortality: 43 vs. 51% (*colloid worse)90 day- RRT: 16 vs. 22% (*colloid worse)severe bleeding: 6 vs. 10% (NS)
CHESTtetrastarch 130/0.4 vs. NaCl 0,9%
renal failure: 10 vs. 9% (NS) RRT: 5.8 vs.7.0% (*colloid worse); length of RRT (NS)FFP-requirements: colloid* > crystalloid (18 ml)volume requirements: colloid* < crystalloid (90ml/day) ICU-mortality: 17 vs. 18% (NS)
CRISTAL crystalloids vs. colloids volume requirement: colloid = 2x crystalloid90 day-mortality: 34 vs. 31% (*colloid better)RRT: 13 vs. 11% (NS)
BaSES tetrastarch 130/0.4 vs.Ringer lactate/NaCl 0,9%
volume requirements: 5,6 l vs. 5,0 l (NS)ICU-mortality: 29 vs. 28% (NS)AKI: 44 v. 49% (NS)LOS: 28,5 vs. 20 days (*colloid better)
Results
? cause of death ?
? RRT-trigger ?
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HES crystalloid
RRT 235 196no RRT 3117 3179
p = 0.044
HES crystalloid
RRT 234 197 no RRT 3118 3178
p = 0.054
X² Test
CHEST: Statistical concernsJ. Kreutziger, AIC 2013
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HES crystalloid
RRT 87 65no RRT 311 335
p = 0.044
HES crystalloid
RRT 87 66 no RRT 311 334
p = 0.054
X² Test
6S: Statistical concernsJ. Kreutziger, AIC 2013
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Randomisation AFTER initial stabilisation
CHEST6S
NEJM 2012; 367;124-34NEJM 2012;367:1901-11
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Recommendations against initial colloidal volume resuscitation cannot be derived from 6S, CHEST, VISEP
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ethics committee approval: use in known contraindication
informed consent to use in known contraindication
financial and intellectual conflicts of interest
EMA: no data inspection before suspension/restriction
NEJM, meta-analyses, Cochrane review:
no concerns on ethics, methodological & statistical concerns
Open questions
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Lesson learned from VISEP, CHEST and 6S:
prolonged colloidal volume therapy without indication according to preload a/o in the presence of contraindications
must be avoided
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Not only 1 single magic bullet …
? surgery with muscle relaxant only ?
? infusion therapy with colloids only ?
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No indication for colloids• absence of intravascular hypovolaemia
„indiscriminate drug administration“
misuse, ban, prohibition …
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Indication for colloids
hypovolaemia with impaired tissue
perfusion
„goal-directed therapy (GDT)“ tailor drug administration in its indication
CHALLENGE of MONITORING
intravascular filling status,
microcirculation in organs,
endothelial barrier function…
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Eur J Anaesthesiol 2013; 30: 270-382
http://esa.perioperativebleeding.org
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We recommend avoiding hypervolemia with crystalloids or colloids to a level exceeding the interstitial space in steady state, and beyond an optimal cardiac preload
1B
Avoid hypervolaemia
Eur J Anaesthesiol 2013; 30: 270-382
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Preload optimization
We recommend aggressive and timely stabilisation of cardiac preload throughout the surgical procedure, as this appears beneficial to the patient
1B
Eur J Anaesthesiol 2013; 30: 270-382
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Tissue perfusion
We recommend repeated measurements of a combination of Hk/Hb,
serum lactate, and base deficit in order to monitor tissue perfusion,
tissue oxygenation and the dynamics of blood loss during acute
bleeding. These parameters can be extended by measurement of
cardiac output, dynamic parameters of volume status (e.g. SVV,
PPV) and central venous saturation
1C
Eur J Anaesthesiol 2013; 30: 270-382
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Monitoring MAP, CVP, HR:Crystalloid:colloid ratioscannot be derived from 6S, CHEST, VISEP
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Systematic reviews and meta-analyses: pooling of study limitationsnot helpful
Zarychanski R. JAMA. 2013;309(7):678-688
Patel A. Intensive Care Med 2013; DOI 10.1007/s00134-013-2863-6
Haase N. BMJ 2013;346:f839 doi: 10.1136/bmj.f839
…
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EVIDENCE from Cochrane Analyses 2013:
„… hard to see how the use of colloids can be justified …“
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„… no evidence that one colloid solution is more effictive or safe than any other…“
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„… hard to see how the use of albumin can be justified …“
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Crit Care 2013; 17: R166
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Fluids In Resuscitation in Severe Trauma
James. Br J Anaesth 2011;107:693
The FIRST Study: Lactate clearance
•similar static hemodynamic measurements between groups
•superior tissue perfusion after HES compared to saline
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CI, cardiac indexCVP central venous pressure SVV, stroke volume variation
PEEP, positive end-expiratory pressureVt, tidal volume
Benes. Crit Care 2010;14;R118
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GDT: improved tissue perfusionBenes. Crit Care 2010;14;R118
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GDT: less complicationsBenes. Crit Care 2010;14;R118
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Van der Linden. Anaesth Analg 2013;116:35-48 n = 4.529
Big trial in elective surgery colloidal volume therapy & patient safety
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risk difference acute renal failure
serum creatinineextreme values
Big trial in elective surgery colloidal volume therapy & renal function
Martin. Anesthesiology 2013; 118: 387-94n = 1.230 in 17 studiesn = 1.230 in 17 studies
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……..Coriat, Guidet, de Hert, Kochs, Kozek, van Aken
71 co-signatories
……..Coriat, Guidet, de Hert, Kochs, Kozek, van Aken
71 co-signatories
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Alternatives? Perfusion monitoring?