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)