the recent big fluid trials sibylle a. kozek-langenecker m.d. professor mba department of...

The recent big fluid trials

Sibylle A. Kozek-Langenecker M.D. Professor MBADepartment of Anaesthesia and Intensive Care

Evangelical Hospital Vienna

www.perioperativebleeding.orgsibylle.kozek@aon.at

Honoraria for lectures and travel reimbursement:

B. BraunFresenius KabiCSL Behring

Conflicts of interest

European Medicines Agency EMAPharmacovigilance Risk Assessment Committee PRAC

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

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

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

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

Big trial in critical illness efficacy of initial colloidal volume therapy

Annane. JAMA 2013;310:1809-17

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 ?

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

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

Randomisation AFTER initial stabilisation

CHEST6S

NEJM 2012; 367;124-34NEJM 2012;367:1901-11

Recommendations against initial colloidal volume resuscitation cannot be derived from 6S, CHEST, VISEP

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

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

Not only 1 single magic bullet …

? surgery with muscle relaxant only ?

? infusion therapy with colloids only ?

No indication for colloids• absence of intravascular hypovolaemia

„indiscriminate drug administration“

misuse, ban, prohibition …

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…

Eur J Anaesthesiol 2013; 30: 270-382

http://esa.perioperativebleeding.org

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

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

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

Monitoring MAP, CVP, HR:Crystalloid:colloid ratioscannot be derived from 6S, CHEST, VISEP

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

…

EVIDENCE from Cochrane Analyses 2013:

„… hard to see how the use of colloids can be justified …“

„… no evidence that one colloid solution is more effictive or safe than any other…“

„… hard to see how the use of albumin can be justified …“

Crit Care 2013; 17: R166

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

CI, cardiac indexCVP central venous pressure SVV, stroke volume variation

PEEP, positive end-expiratory pressureVt, tidal volume

Benes. Crit Care 2010;14;R118

GDT: improved tissue perfusionBenes. Crit Care 2010;14;R118

GDT: less complicationsBenes. Crit Care 2010;14;R118

Van der Linden. Anaesth Analg 2013;116:35-48 n = 4.529

Big trial in elective surgery colloidal volume therapy & patient safety

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

……..Coriat, Guidet, de Hert, Kochs, Kozek, van Aken

71 co-signatories

……..Coriat, Guidet, de Hert, Kochs, Kozek, van Aken

71 co-signatories

Alternatives? Perfusion monitoring?

www.perioperativebleeding.orgsibylle.kozek@aon.at

Thank you for your attention !