Which fluid and when aagbi wsm
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Transcript of Which fluid and when aagbi wsm
Which fluid and when?
Craig MorrisDerby
Consultant Intensivist and AnaesthetistHonorary Lecturer Universities Derby and Teesside
Housekeeping
• Non-promotional• Corporate educational material• No conflicts• Retraction Boldt
A&A 2009;109:1752-62>200 publications…
http://www.bmj.com/content/341/bmj.c7026.full
www.derbyintensivecareecho.co.uk(DICE)
Content: which fluid and when?
• Resuscitation not maintenance• Colloid
Starch• Crystalloid
“Balanced” solutions• Recommendations?
To debate hot issues in fluid management, including
• Does the third space exist?
• Blood transfusion triggers?
• Are old RBCs ok?
• Do colloids cause renal failure?
• Acidosis – good or bad?
• Do I have to use 1:1 FFP:RBCs in massive haemorrhage?
• What is the haemodynamic monitor of choice?
• Does saline really harm patients?
http://www.ebpom.org/
SizesRBC7 μ
Capillary width 5 μ
Endothelial cell thickness0.2 μ
Large pore 40 nm
Small pore 5 nm
Albumin 3.5nm K+ 0.15nmNa+ 0.10 nm
Starch fragments 4.5nm
The “size” of colloid is not what keeps it put!!!
Relative sizes…
RBC 7μ
Colloid 5nm (1/10 pore)
Large pore 40nm
Small pore 5nm
1mm muscle32 endothelial cells10 000 small pores2 large poresPore area <0.05% surface area
Molecular weights
Modern HES 140 kDa
Biological HES70kDa
Albumin 70 kDa
Older HES >500 kDa
Dextran40 (10%)- 70 (6%) kDa
GelatinesMW 30kDa
Crystalloid< 1 kDa
Renal threshold
HES amylase fragments50 kDa
Colloid kinetics
Basement membrane negative charge stops leak NOT sizeAlbumin net negative charge -15
Pores 5- 40 nmAlbumin < 5 nm
Brief colloid/ HES
• Big and not leaky• Inert (glycogen)• Osmolality 6%• Renal clearance• No “surprises” eg coagulation
Hydroxyethyl Starch (HES)
Wax Corn Starch amylopectin
Amylopectin
Analogue molecule to the human glycogen
Extraction and
Hydrolysis of desired
MW Hydroxyethylation
Molecular weight
• MW (weight average MW)= viscosity• MN (number average MW or median)=
oncotic effect• Monodisperse (eg albumin)• Polydisperse (MW/MN= index)
Voluven 130 +- 20kDa in vitro
HES substitution
Increases water bindingResists amylase“Chose”• MW• Proportion glucose HE• Position
Water bindingcapacity20 ml g-1 HES
O
O
CH2OH
OOH
6
HO
O
OOH
OHCH2
2
OH
O
CH2--O-CH2-CH2-OHOOH
6
HO
O
OOH
CH2OH
2 O
OOH
OHCH2
2
-O-CH2-CH2-OH
O
CH2OH
OOH
HO
O
CH2OH
OOH
HO
OOH
6
HO
O
OOH
OHCH2
2
-O-CH2-CH2-OH
O
OOH
OHCH2
OH
O O
O
CH2OH
OOH
6
HO
O
OOH
OHCH2
2
-O-CH2-CH2-OH
O
CH2--O-CH2-CH2-OHOOH
6
HO
O
OOH
CH2OH
2 O
OOH
OHCH2
2
-O-CH2-CH2-OH
O
CH2OH
OOH
HO
O
CH2OH
OOH
HO
OOH
6
HO
O
OOH
OHCH2
2
-O-CH2-CH2-OH
O
OOH
OHCH2
OH
O O
Degree of substitution of 0.5= 5 of 10 HE groups
0.4=4 of 10 HE groups
The higher the degree of substitution the longer duration in blood
Position HES groups
• Hydroxyethyl groups C2 and C6
• C2 resistant amylase
• ↑ C2/C6 ratio ↑ intravascular space
Substitution Pattern 9:1= 9 hydroxyethyl C2 and 1 C6
Substitution Pattern 5:1= 5 hydroxyethyl C2 and 1 C6
O
CH2OH
OOH
6
O
OOH
OHCH2
2O
OOH
6
O
OOH
CH2OH
2O
OOH
OHCH2
2 O
CH2OH
OOH O
CH2OH
OOH
CH2OH
OOH
6O
OOH
OHCH2
2O
OOH
OHCH2
OH
O O
O
CH2OH
OOH
6
O
OOH
OHCH2
2O
OOH
6
O
OOH
CH2OH
2O
OOH
OHCH2
2 O
CH2OH
OOH O
CH2OH
OOH
CH2OH
OOH
6O
OOH
OHCH2
2O
OOH
OHCH2
OH
O O
OH
OH
OH
OH
Starting macromolecule
Amylase smaller molecules
50kDa renal thresholdRenally eliminated
In vitro MW Eg Hemohes 200 kDaVoluven 130 kDa
In vivo MW Eg Elohes 145 kDaVoluven 65 kDa
Aim to have in vivoMW above renal thresholdLysis increases osmotic effect!!!
The life of HES
In vivo lysis
HES 6%, 450/ 0.65 3:1
Br J Clin Pharm `1979;7:505- 9
HES: a few numbers
• Concentration (%)• MW (kDa)• Substitution (coagulation)• C2/C6 (coagulation)• Suspending solution
Starch name Strength, solution
MW* Substitution(Coagulation)
C2/C6(Coagulation)
Voluven (FK) 6% saline 140 0.40 9:1
Volulyte (FK) 6% “balanced” “ “ “
Elohaes (FK) 6% saline 200 0.62 4:1
Haes steril (FK) 6 and 10% saline
200 0.50 5:1
Venofundin (B) 6% saline 130 0.42 6:1
Tetraspan (B) 6% balanced 130 0.42 6:1
Hemohes (B) 6 and 10% saline
200 0.50 5:1
Hextend 6% lactate 650 0.70 4:1
Hespan 6% saline 450 0.70 4:1
Hyperhaes (FK) 6% starch7.2% saline+
200 0.50 5:1
Rheohes 6% balanced 70 0.50 3:1
*in vitro, kDa+ 2464 mOsmolkg-1
Potato vs maize?
• Potato ↑ amylose, esters, P and 20% amylase• “= pentastarch + HES 130/0.4/9 : 1 colloid
osmotic.. + haemodilution”• HES 130/0.42/6 : 1 fastest clearance• ↑ Viscosity• No head to head• Tetraspan vs albumin CRF
http://clinicaltrials.gov/ct2/show/NCT00936247http://www.bbraun.com/cps/rde/xchg/bbraun-com/hs.xsl/plasma-volume-replacement.htmlhttp://adisonline.com/drugsrd/Abstract/2007/08040/Bioequivalence_Comparison_between_Hydroxyethyl.3.aspx
• Contained 2 studies• 10% Pentastarch 200/ 0.5 in 0.9% saline
(Hemohes) vs lactated Ringer’s • Stopped early
Ringer’s Lactate (Sterofundin, B. Braun). 1000 ml Na+140, K+ 4.0, Ca++ 2.5 Mg++ 1.0, Cl- 106 lactate- 45.0(mmol)VISEP group NEJM 2008;358:125- 39
VISEP- a problem?
Outcome HES RL p
90 day mort (%) 41.0 33.9 0.09
RENAL SOFA 0.67 0.42 0.02
ARF (%) 34.9 22.8 0.002
RRT 31.0 18.8 0.001
Parameter HES RL p
CVS SOFA 1.80 1.76 0.51
Vasopressor free days
17 17 0.52
Whatever HES 200/0.5 does, it is not improved haemodynamics!
Dose dependent
250mlkg-1
18litres
The whole point isYou are meant to give less!!
Hyperoncotic colloids
AKI assoc hyperoncotic starch, albumin,dextran… mannitol
But not saline!
Shortgen. Intensive Care Med 2008;34:2157- 68Ragaller et al, J.Am.Soc.Nephrol. 2001
VISEP- should I worry?
YES!X2 rates CRRTNo benefitAlternatives existConsistent previous workWould you use it as a “drug”?
NO!Complex designLactated solution vs chlorideHyperoncotic colloidNot representative “current” HES
Perhaps AKI is only with higher doses 10% 200/0.5...It doesn’t improve heamodynamics, costs more and assoc death
I don’t do ICU...
• Sick laparotomy• Pressors• AKI• Elderly, gent, CT...• Avoid 10% 200/ 0.5• Await further studies?...
HES 130/ 0.4
Boussekey et al., Critical Care, 2010
N= 363Retrospective2 organ failuresHES 130/ 0.4France, non-protocolised763 ml HES 48 hrs, 1.4l 21 daysBoth identical >6l crystalloidPRC 2.8 vs 3.9
Starches: max “dose”Preparation Daily dose (ml)
Hemohes 6% 2500
Hemohes 10% 1500
Haes-setril 10% 1500
Generic Hetastarch 6% 450kDa
500- 1000Max daily 1500
Tetraspan 6% 50mlkg-1
Tetraspan 10% 30mlkg-1
Venofundin, Voluven, Volulyte 6%
50mlkg-1
Even with modern LMW tetrastarches 50 mlkg-1
Albumin
• SAFE overall =• Cochrane= SAFE• Crystalloid 1.4:1 colloid not 3:1• Possible benefit sepsis?
RR 0.77 controlled• Possible harm trauma?
Finfer S. NEJM 2004;350:2247- 56Vincent JL. CCM 2004;32:2029- 38
HyperCl-
• Associated n+v• Cells sepsis• Splanchnic perfusion• Pyloric dysfunction• Renal effects• Coagulation
Handy JM. BJA 2008;101:141- 50
Keyser Soze
I don’t believe in the devil, but that doesn’t mean I’m not scared of him…
Alternatives
Morris CG et al. Anaesthesia 2009;64:703- 5
The irony!
Gelofusine® is a 4% solution of modified fluid gelatine. It contains 154 mmol/l sodium but only 120 mmol/l chloride because of the substantial negative charge of the gelatine molecules…
http://www.iv-partner.com/index.cfm?2A450D1AB7B24C098978DB9F6D6602DB
Safer than Cl- ?
• Acetate→ hypotension• Lactate assoc hypotension• Osmotic effects• Direct toxicity• Glucose and protein metabolism• Chloride effects?
Morris CG et al. Anaesthesia 2009;64:703- 5Handy JM. BJA 2008;101:141- 50
Demand more!
• “Ringer’s” few flavours!• Manufacturer: cheap + stable in solution…
(Acetate, malate, gluconate, lactate)• Clinician: try again…
http://www.ncbi.nlm.nih.gov/pubmed/16163918?dopt=Abstract&holding=f1000,f1000m,isrctn http://www.ajinomoto.com/about/rd/pharmaceutical.html
CRRT solution
• HCO3- separate pouch
• Mix administration
Component mEql-1
Na 140
K 4
Ca 3.5
Mg 1
Cl 113.5
HCO3- 32
Lact 3
Bicarbonated Ringer’s
HCO3- rapid→ CO2 + CaCO3 ppt
Add citrate 5mEql chelate Ca1 mEql MgAdd CO2 pH 7.0
Component mEql-1
Na 135
K 4
Cl 113
Ca 3
Mg 1
HCO3- 25
Citrate 5
What fluids and when?
I (and no one else) can make a level 1 recommendation for practice…
GIFTASUP: periop
http://journal.ics.ac.uk/pdf/1001013.pdf
What about Shortgen, VISEP, Cochrane, sepsis, renal impairment,
and lack of improved outcomes?...
Compared with Gelofusine, the perioperative pulmonary function
of patients treated with HES (Elohaes) after AAA was better.
Rittoo. BJA 2004Beyer BJA 1997Shramko. Perfusion 2010Linden CJA 2004
Ortho HES 200 0.5 vs 3% gelatineComparable COP, clinical expansion
the haemodynamics in the two colloid groups appeared to be similar, but superior to the Ringer’s acetate group (alb 4% vs 6% 130/0.4)
3.5% urea-linked gelatin is as effective as 6% HES 200/0.5 for volume management in cardiac surgery patients…HES could result in a higher need for allogeneic blood transfusion.
Periop confused?... You will be!
• N= small, equivocal or contradictory• Surrogates or basic science• Non-inferiority healthy volunteers• Gelatine vs HES very close• Lap chole 1l Gelo vs Voluven (4 hrs!)
http://clinicaltrials.gov/ct2/show/NCT00868062?term=gelatin+and+hydroxyethyl+starch&rank=1
Sub-specialty Comments
Cardiac http://chestjournal.chestpubs.org/content/126/1/311.full.pdf+html
Trauma, transfer, pre-hospital http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151863/
Neuroanaesthesia http://www.braintrauma.org/pdf/protected/Guidelines_Management_2007w_bookmarks.pdf
“General” http://www.bapen.org.uk/pdfs/bapen_pubs/giftasup.pdf
Ambulatory http://www.guideline.gov/content.aspx?id=15334#Section420
Vascular http://www.vasgbi.com/library.phphttp://www.scribd.com/doc/26129150/Hydroxyethyl-Starch-HES-Versus-Other-%EF%AC%82uid-Therapies
Obstetric http://www.ncbi.nlm.nih.gov/pubmed/19859776http://www.ncbi.nlm.nih.gov/pubmed/17054153
Paediatrics http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9592.2008.02505.x/fullhttp://www.nrls.npsa.nhs.uk/resources/?entryid45=59809
Colorectal/ optimisation
“Critical care”
Transplantation http://www.anesthesia-analgesia.org/content/109/3/924.fullhttp://www.ics.ac.uk/intensive_care_professional/standards_and_guidelines/organ_and_tissue_donation_2005
Mortality end point?
• Major non-cardiac (n= 90)• LR vs 6% HES vs 6% balanced• Thio + sux
Morretti. A+A 2003;96:611- 7
OR 7mlkg-1 loading and 5mlkg-1 hr-1 RL intraop
Outcomes
CRF exclusion!6% Hetastarch: Hextend 650/0.7/4:110% difference mortality n= 5 700
CostsFluid Cost per bag/unit Units used 2007 Cost
Crystalloids
Sodium chloride 0.9% 1L 49.4p 103,241 £47,323
Sodium Chloride 0.9% 500ml
47p 56,121 £24,431
Hartmann’s 1L 73p 37,476 £26,200
Hartmann’s 500ml 60p 779 £462
Colloids
Gelofusin 500ml £2.88 13,500 £38,676
Albumin 20% 100ml £30 1,615 £46,971
Voluven 500ml £8 1,650 £13,248
>£200 000 annually!!!
Condition Crystalloid Gelatine HES Comment
Periop SV guided
Control # NOFColrectal1,2,3
Cardiac# NOF4,5
Evidence base gelatine or HES
1Venn R et al. BJA 20022Wakeling HG et al. BJA 20053Noblett SE. BJS 2006
4Sinclair S. BMJ 19975McKendry M. BMJ 2004
Gelatine
Wakeling HG. BJA 2005 Noblett BJS 2006Succinylated 4% gelatine (Volplex)
HES
McKendry M. BMJ 2004Mixture colloids: Hespan 450/0.7
Sinclair S. BMJ 1997# NOFHES 3mlkg-1
FRACTALE
• #NOF• ODM guided• 30% ↓ death + complications• N= 800, >70• HES 130/0.4
Cholley B et al http://www.clinicaltrials.gov/ct2/show/NCT00444262?term=trauma+and+hydroxyethyl+starch&rank=11
Critical CareCondition Crystalloid HES Albumin Comment
Sepsis syndrome
SAFE VISEP SAFE RR 0.8 sepsis
Heterogenous patients
ARDS Data suggest improved mechanicsAssoc renal failure
Hyperoncotic albumin + diuretic improved O2
FACCT -ve balance established ARDS
Trauma First line.Excess assoc ↑ death
Small studies or animal work.PRCT underway*
SAFE RR 1.3 and TBI 1.6
Higher Hct?
Renal impairment
SAFE: concerns hyperoncotic 0.9% saline
Caution esp oliguria and high MW
Generally safe- microalbuminuria
CRRT remove crystalloid easily!
*CIST http://www.clinicaltrials.gov/ct2/show/NCT00890383?term=trauma+and+hydroxyethyl+starch&rank=3
Surviving Sepsis Campaign
CCM 2008, SAFE 2004http://www.survivingsepsis.org/About_the_Campaign/Documents/Final%2008%20SSC%20Guidelines.pdf
Gelatine vs HES sepsis (2001)
http://wwdaa.com/adqi/web_users/akin4/references%20AKIN%20wg%204/Shortgen. Lancet 2001
HES 200/ 0.6 (Elohes) vs 3% gelatin (Plasmagel)
ARF, creatinine and oliguria all higher HES
HES independent risk factor ARF X 2.57
ARDS: Replacement albumin with HES
http://www.springerlink.com/content/h765t1llj424518m/http://www.pptaglobal.org/
Red= RR ARF/ ARDS Black albuminGreen HES (200 to 2002→ 130N= 44
Burns
Bechir M. Crit Care 2010;14:R123
N= 30Hemo Haes 10% 200/0/5 vs crystallloid (LR)11.2 vs 7.1 (1.6:1)RR death 7.12 CRRT 25% vs 7% ARDS identicalVentilators 7 vs 12 (HES)
CrystalloidVs colloidWhich type colloidUnresolved…
Management of Major Trauma
• Crystalloids initially (1B)• Consider hypertonic solutions (2B)• Suggest addition of colloids in unstable (2C)
“modern HES or gelatin”Avoid dextran or albumin
• Retrospective aggressive resuscitation→ compartment syd
• Pre-hospital assoc coagulopathy (>40% 2l, >70% 4l)
Rossaint et al: Trauma and bleeding a European Guideline. Crit Care 2010;14:R52Maegele et al. Injury 2007;38:298- 304
EAST: Pre-hospital
Level 2...vascular access at the scene of injury...delays
patient transport to definitive care and... benefit is lacking • Iv fluids... Withheld... pre-hospital... patients with penetrating
torso injuries• Level 3:
(a) Iv fluid resuscitation... withheld until active bleeding/hemorrhage addressed(b) Iv fluid... titrated for palpable radial pulse using (250ml) boluses of fluid rather than fixed volumes or continuous administration
http://www.east.org/tpg/FluidResus.pdf
NICE 2004: Hypovolaemic shock
• Ie absent radial or central pulse• Boluses crystalloid to return pulse• Shouldn’t delay transport (ie en route)• “...only healthcare professionals who have
been appropriately trained in advanced life-support techniques and pre-hospital care should administer intravenous fluid therapy in the pre-hospital setting”
https://www.nice.org.uk/niceMedia/pdf/2004_006_prehospfluidtherapy.pdf
If fluid is given which type?
• Level 1:(a) There is insufficient data to recommend one solution or type of fluid...(b) Boluses (250 mL) of 3% and 7.5% hypertonic saline (HTS) areequivalent (...vascular expansion and hemodynamic changes) to largevolume boluses (one liter) of standard solutions such as
lactated Ringer’s (LR) or 0.9% normal saline (NS)
EAST resuscitation trauma
Level 1• There is insufficient data to formulate a level 1
recommendation.• Level 2• 1. During resuscitation, attempts should be made to increase
O2 delivery to normalize base deficit, lactate, or pHi during the first 24 hours. The optimal algorithms for fluidresuscitation, blood product replacement, and the use of inotropes and/or vasopressorshave not been determined.
http://www.east.org/tpg/endpoints.pdf
Ongoing studies
• 58 studies HES• CEASE: 6% Hetastarch vs 5% albumin ARDS• 6S Tetraspan HES vs Ringerfundin acetate
septic shock
http://clinicaltrials.gov/ct2/results?term=hydroxyethyl+starch http://clinicaltrials.gov/ct2/show/NCT00796419?term=hydroxyethyl+starch&rank=14http://clinicaltrials.gov/ct2/show/NCT00962156?term=hydroxyethyl+starch&rank=13
CHEST
• Saline vs 130/0.4 HES• All comers• N= 7000• Mortality, AKI and organ failures• SAFE with starch!
http://clinicaltrials.gov/ct2/show/NCT00935168?term=hydroxyethyl+starch+CHEST&rank=1
• Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products
• ...34 studies (2607 patients)... RR of kidney failure 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients
http://www.ncbi.nlm.nih.gov/pubmed/20091640?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=3 http://www2.cochrane.org/reviews/en/ab007594.html
Recommendations for practice…• No level 1• Fit volunteers tolerate anything• All fluids leak and come with baggage• Colloids expensive• SAFE colloid (4% albumin) vs crystalloid (0.9%
saline)=Ratio 1: 1.4No evidence superiority colloid
• Albumin ↓morbidity and mortality sepsis• Albumin ↑mortality trauma/ TBI
Recommendations for practice• “Routine” perioperative fluid→ Hartmann’s• Gelatine vs HES... Still going!• SV/ optimisation both→ gelatine cheaper, no AKI • AKI HES MW, substitution, osmolality/ lack crystalloid
(+ Sepsis, renal impairment)• VISEP 50% ↑CRRT, ↑mortality• CHEST ongoing (HES 130/0.4 vs saline)• Sepsis or kidney impairment avoid HES
Recommendations for practice
• ARDS pathogenesis + fluid→ controversial• ARDS established→ -ve balance• Little evidence colloid preventing ARDS• Impact hyperCl- unclear• Benefit “balanced” alternatives unclear• Demand better “balanced”
Summary
• HES fascinating→ evolving drugs• Lots volunteer, non-inferiority studies!• HES: origin, MW, substitution, C2:C6• Few level 1 recommendations • SAFE only robust crystalloid vs colloid
(saline/alb)• CHEST recruiting (HES/ saline)
Thank you
So, where does this leave us in the big fluid debate?The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture
and to better determine where each fluid fits. Although
we use these fluids every day, we still knowsurprisingly little about them.
http://www.anesthesia-analgesia.org/content/104/3/484.full.pdf+html
www.derbyintensivecareecho.co.uk(DICE)