Colloids - The end of the end for starches in the critically ill ??

Dr Andrew FergusonConsultant in Anaesthetics and Intensive Care Medicine, Craigavon Area Hospital

Myburgh JA, et al. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care. NEJM 2012; 367:1901-1911

The CHEST Study

Philosophical Disclosures

• I’ve used HES, and I quite liked it

• I like albumin• I believe all iv fluids are potentially harmful

• No other conflicts to declare

Confessions

How this Piggy got to Market

• Approval based on small clinical studies– Underpowered

– Limited clinical settings

– Limited follow-up duration

– Limited comparators – better than ancestors

• Approval based on what came before– Previously approved colloids/HES

– Assumption of “a HES is a HES is a HES”

What happened when Piggy got there?

• Novelty• Marketing• Reinforcement by small positive trials• Usage outside original study settings• Impression of benefit => clinical bias• Increased usage• Positive poor-quality reviews

The CHEST trial

Maize-based

Who was in?• Consent obtained (pro-or retrospectively)• Fluid resuscitation required based on at least one of:

• HR > 90 bpm

• SBP <100 mmHg or MAP < 75 mmHg or 40% fall from baseline

• CVP < 10 mmHg

• PCWP < 12 mmHg

• SPV/MAPV > 5 mmHg

• Capillary refill time > 1 second

• U/O < 0.5 ml/kg for 1 hour

• Clinician content that HES and saline equally suited

Who was out?

Screening

Fate of randomised patients

Intervention• 6% HES 130/0.4/9:1 in 0.9% NaCl v 0.9% NaCl (saline)• Identical 500-ml Freeflex bags, composition checks• Staff blinded to allocation

• Used for all fluid resuscitation in ICU during the first 90 days following randomisation or until death

• Maximum daily dose 50 ml/kg/day • If upper limit exceeded during 24-hrs, open-label 0.9% NaCl

used until 24-h period lapsed, following which patient resumes allocated study fluid.

Data collection

RIFLE up to day 7, SOFA to day 28, RRT in ICU

Sample size (7000 patients)• Based on 90-day mortality of 26% in saline group

– Actual 90-day mortality 17%

• 90% power to detect absolute difference of > 3.5% in mortality with 5% loss to follow-up

• 90% power to detect an increase in the RR for renal failure by factor of 1.5 from expected 6% (saline group)

– Actual incidence 9.2% of RIFLE-F

– Actual incidence RRT 5.8%

Statistical analysis• Binary outcomes– Relative risk (95% CI) & Chi-square

• Continuous outcomes– Mean difference and unpaired t-tests

• Adjusted analysis– Baseline covariates trauma, age, admission source,

APACHE II, baseline creatinine– Binary outcomes - robust Poisson regression– Continuous outcomes - robust linear regression

• Survival times– Log rank presented as Kaplan-Meier curves

Primary Outcome – Death @ 90d

NO significant difference

Secondary Outcomes

More RRT, significantly less RIFLE-R and -ILower incidence of new CVS failureMore hyperbilirubinaemia

The piggy goes “wee….wee….wee”

Tertiary outcomes

No significant difference

Treatment related adverse effects

Effectively all cutaneous

Subgroup Analyses – Death @ 90d

Based on urine output

Fluid Intake

More fluid in Saline group

More blood in

HES group

Author’s conclusions

• No difference in 90 day mortality overall or sub-groups• 21% relative increase in RRT• Less new CVS failure

• No evidence of clinical benefit with HES

Criticisms put forward

• “All-comers” study - dilution of benefit and harm

• Indications for administration of fluid

• Use of a colloid in patients post-resuscitation phase

• Lack of goal-directed approach

• Lack of renal data past day 7 and no control of RRT

• No assessment of harm effect of PRBC transfusion

• No control of transfusion trigger

The bottom line for the patientYou’ll be less likely to need pressors, BUT

You’re just as likely to dieYou won’t get off the vent or out of ICU quickerYour creatinine is more likely to go upYou’re more likely to need “dialysis”You’re more likely to get a blood transfusionYou’re more likely to go a bit yellowYou’re more likely to get a rashYou’re more likely to get an itch and it may not go away

Where next?

• Enough evidence to guide practice inside ICU• Calls for – focus on pre-ICU resuscitation phase– more perioperative trials– better crystalloids– ditch HES altogether outside RCT

• Regulatory review

“It is a mistake to think you can solve any major problems just with potatoes”

Douglas Adams, Life, the Universe, and Everything

or maize!

Parting thoughts – Challenge assumptions

If you have never changed your mind about some fundamental tenet of your belief, if you have never questioned the basics, and if you have no wish to do so, then you are likely ignorant.

Before it is too late, go out there and find someone who, in your opinion, believes, assumes, or considers certain things very strongly and very differently from you, and just have a basic honest conversation. It will do both of you good.”

Vera Nazarian, The Perpetual Calendar of Inspiration

Not everyone agrees about efficacy• It works if you select the right end-point– What should that be? Haemodynamics? Volume?

Oedema?• It works in some conditions, not in others– Effects are disease-specific

• It works in some patients, not in others– Effects are patient-specific (for unknown reasons)

• It works if you don’t give too little or too much– Effects are dose-specific (dosing schedule unknown)

• It works if you give it at the right time– Effects are time-specific (best time-point unknown)

Not everyone agrees about safety• It is safe in some conditions, is harmful in others– Any harm is disease-specific

• It is safe for some patients, is harmful to others– Any harm is patient-specific (but who?)

• It’s benign, if you choose the right one– Any harm is molecule & structure-specific

• It is benign, but the carrier is harmful– Any harm is formulation-specific (no evidence)

• It is safe unless overdosed– Harm is dose-specific

Complex questions about HES

• Do we know when we should/shouldn’t use it?

• Do we know what we want it to do?

• Do we know how to measure/titrate its effect?

• Does it do what we want it to do?

– Even if it does, then:

• Is it as good as the alternatives?

• Is it as safe as the alternatives?

• Is it as cost-effective as the alternatives?

Fluid-related background signals…

• Acid-base abnormalities• Impaired coagulation • Fluid overload• Osmolality and tonicity issues• Allergic reactions• Direct organ toxicity• Effects on inflammation

Poor quality

Low event rates

Small patient numbers

Poor reporting of adverse events

Physiological effects

Outcome adjusted for age, APACHE, baseline creatinine trauma diagnosis

Remaining questionsMechanism? Are the issues secondary toa) Inappropriate use?b) Cumulative exposure?c) Dosing rate?d) Impact of endothelial glycocalyx disruption?e) Impact of blood product use?

Is HES still an option for EGDT in severe sepsis as a defined, time & volume limited therapy?