Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

CHEST TRIAL - The Crystalloid versus HydroxyEthyl Starch Trial

John A. Myburgh et al

NEJM – NOV 15, 2012

Background

• Intravenous fluid of choice in ICU to increase intravascular volume is controversial.• Globally, 0.9% sodium chloride is the most commonly used fluid.• But colloids are administered as often as

crystalloids.• Hydroxyethyl starch (HES) is the most frequently used colloid. – Finfer et al CRITICARE 2010

Investigators like- • Schortgen F – LANCET - 2001• Brunkhorst FM - NEJM – 2008 • Dart AB – Cochrane database- 2010have proven that HES increases the risk of AKI in critically ill patients.But the HES used in all above studies was • 10 %• 200 kd mol. Wt.• MRS- Molar Substitution Ratio (the number of

hydroxyethyl groups per glucose molecule) of more than 0.5.

What we currently use is –• 6%• 130 kd• MRS- 0.38-0.45

It has not been compared with Normal saline as a resuscitative fluid in critically ill.

Additionally, the 6S trial - Scandinavian Starch for Severe

Sepsis/Septic Shockcomparing 6 %(130/0.42) HES vs Ringers lactate was significantly associated with increased mortality in patients with severe sepsis and septic shock.Anders Perner et al – NEJM April 2012

CHEST TRIALMulticenteric , prospective, blinded, randomized controlled trial in 32 hospitals in Australia and New Zealand by the Australian and New Zealand Intensive Care Society

Funding - National Health and MRC Australia New South Wales Ministry of Health Fresenius Kabi, the manufacturer of Voluven.

Funding agencies had no input into the design, conduct, data collection, statistical analysis, writing of the manuscript.Fresenius Kabi supplied the study fluids and distributed them to participating sites

Inclusion criteriaThe requirement for fluid resuscitation must be supported by AT LEAST ONE of the following clinical signs:

a. Heart rate >90 beats per minuteb. Systolic blood pressure < 100 mmHg or mean arterial pressure <75 mmHg or at least 40 mmHg decrease in systolic or MAP from the baseline

recordingc. Central venous pressure <10 mmHgd. Pulmonary artery wedge pressure <12 mmHge. Respiratory variation in systolic or mean arterial pressure of >5 mmHgf. Capillary refill time >1 secondg. Urine output <0.5 ml/kg for 1 hour

Exclusion criteria 1)Age less than 18 years.2) Previous allergic reaction to HES3) Intracranial hemorrhage4) Patients receiving renal replacement therapy or in

whom the ICU physician considers renal replacement therapy is imminent (i.e. RRT will start in 6 hrs)

5) Serum creatinine value >350 μmol/L and urine output averaging ≤10 ml/h over 12 hours

6) Severe hypernatremia (serum sodium >160 mmol/l)7) Severe hyperchloremia (serum chloride >130 mmol/l)8) Women of child-bearing age (18–49 years old)

9) Breastfeeding women10) Patients who have received >1000 mL HES

outside the ICU within the 24 hours before randomization

11) Patients admitted to the ICU following cardiac surgery burns or following liver transplant.

12) Life expectancy of less than 90 days13) DNR patients14) Transfer out from other ICU15) Already received fluids same as planned in

study

Study randomisation and treatmentSample size was planned to be 7000.Patients were randomly assigned to receive either 6% HES (130/0.4) in 0.9% saline (Voluven, Fresenius Kabi) or 0.9% saline in indistinguishable Freeflex 500-ml bags for all fluid resuscitation in the ICU until discharge, death, or till 90 days post randomization.Max dose of resuscitation fluid- 50ml/kg/dayFluid for maintenance- 0.9 % NS

Outcome MeasuresPrimary – All cause mortality 90 days post randomization The primary outcome was also examined in six subgroup pairs on the basis of baseline features:1) The presence or absence of diagnostic criteria for AKI

(RIFLE-R and RIFLE-I categories),2) The presence or absence of sepsis at randomization3) The presence or absence of trauma 4)With or without traumatic brain injury5)The score (<25 vs. ≥25) on the Acute Physiology and

Chronic Health Evaluation (APACHE) II 6)Receipt or nonreceipt of HES before randomization

Secondary- 1) Incidence of AKI as defined by RIFLE criteria2) Use of renal-replacement therapy3) New organ failures not present at baseline4) Duration of mechanical ventilation and RRT5) Cause-specific mortality.

Tertiary outcomes 1)Duration of ICU f/b hospital stay2) Rate of death in the ICU and hospital.

Statistical analysis

• Analyses were conducted on an intention-to treat basis

• Binary outcomes were compared using relative risks with 95% Ci & chi square tests

• Continuous outcomes were compared with the use of mean differences and unpaired t-tests.

Results • December 2009 - January 2012

• 7000 medical–surgical ICU patients

• 3500 patients assigned to receive 6% HES (130/0.4) in 0.9% saline (HES group)

• 3500 to receive 0.9% saline (Saline group)

• The two groups of patients had similar characteristics at baseline

Outcomes - First 4 daysHES group receiveda) Significantly lower 1) Study fluid- p < 0.0012) Non study fluid – p < 0.001

b) Significantly higher 3) Blood products – p <0.001

Though they had significantly lower positive fluid balance (p= 0.03) , net CVP was significantly higher (p<0.001).

Variables like HR, MAP and lactate levels were not significantly different

Outcomes

Primary – All cause mortality 90 days post randomization

18% patients died in HES group within 90 days after randomization vs 17.0% in the saline groupRR- 1.06; 95% CI- 0.96 to 1.18P = 0.27Not statistically significant

Subgroup anaylsis of primary outcome-

There was no significant heterogeneity in the effect of treatment on 90-day mortality in any ofthe predefined subgroups

Secondary outcomes A ) Incidence of AKI as defined by RIFLE criteria

Post hoc analysis

Showed thata) Serum creatinine levels were significantly increased (P = 0.004) and b) Urine output was significantly decreased (p=0.003)in the HES group, as compared with the saline group, during the first 7 days

Other secondary outcomes HES NS RR p

Tertiary outcomes

Adverse effects

Discussion a) Primary outcome- The similar mortality rates in either group may be d/t a) exclusion of patients with intracranial hemorrhage

and those whom clinicians considered unlikely to survive.

b) the inclusion of patients who had undergone elective surgery.c) recruitment after admission to the ICU, when the requirements for fluid resuscitation are often less than those for patients in the ER/OR

b) Secondary outcome –

Incidence of AKI as defined by RIFLE criteria

Use of HES was associated with significantly lesser no of patients in the Risk and Injury group as per RIFLE criteria.

There was no statistically significant difference in patients inFailure group.

This was contrary to the postulate on which the project was conducted that HES may cause more incidence of AKI

But post hoc analysis showed significantly higher creatinine levels and lower urine output in initial 7 days suggesting a progressive reduction in creatinine clearance and more severe acute kidney injury.

HES was associated with increased urine output inpatients with less severe AKI , which may have been due to a) Increased intravascular volume or b) Through a diuretic effect.

Initiation of RRT- Though the criteria not been defined and decision for initiation was of nephrologist unaware of patient belongs to which group , significantly higher no of patients in HES group required initiation of RRT. (21% relative increase)

This itself says about risk of AKI associated with HES

New organ failureThough HES group had less incidence of cardiovascular failure, they had significantly high incidence of hepatic failure.The former can be explained due to the better intravascular volume expansion by HES but this did not reflect on the end organ perfusion parameters like HR, MAP, Lactates.

HES group additionally required more blood products

Adverse effects were more with HES esp pruritus

Mechanism by which HES CausesPruritus- Deposition in Reticuloendothelial system

AKI- Osmotic nephrosis: AKI with accumulation of proximal tubular lysosomes ( Dickenmann - Am J Kidney Dis 2008;51:491-503.)

Hepatic Failure- Lysosomal accumulation in hepatocytes

Limitation of study

Was carried out in patients with lesser risk of mortality, selected patients were from a controlled scenario like ICU.

Previous studies (like 6S) which evaluated HES as resucitative fluid had much sicker patients (severe sepsis, EMS, Emergency surgery etc)

Conclusion- CHEST TRIAL There is no evidence that resuscitation with 6% HESas compared with saline, in the ICU provides anyclinical benefit to the patient.

Indeed, the use of HES resulted in an increased rate of RRT.

Thus, the selection of resuscitation fluid in critically ill patients requires careful consideration of its safety and its cost.

Few eye openers- HESFirst launched by Fresenius (Germany ) 1974, never ever its safety has been assessed as per recent standards.

Every time new composition is launched when previous one noticed to have safety issues.

B.BRAUN (Tretraspan) and FRESENIUS KABI (Voluven) are two major players, turnover worth billions USD.

Cost for 500 ml – 380- 400 INR

After the 6S trial, the principal author (Dr Perner) and NEJM was threatened by FRESENIUS of legal suit for the losses it might incur.

6S used Tetraspan and not Voluven, but both are exactly the same.

Later the threat was withdrawn with authors specifying the brand name Tetraspan in revised fresh online copy.

Funding of CHEST trial by FRESENIUS KABI may reflect some conflict of interest.

Dr Joschiam Boltj (German researcher) whose field of interest been HES , with over 90 publications has been suspended as a faculty, his articles withdrawn from the 16 journals and proceedings of scientific misconduct are on.

He has been presenting favourable results for HES in all his papers.

Multiple meta-analysis included his papers on HES

Eg- Meta- analysis of the use of HES in critically ill(Zachyranski R et al.- JAMA 20 Feb- 2013)

Of 90 studies used , 7 were of BOLTJOnly his papers favour HES.Include them- no increase in mortalityExclude them- significant increase.

Considered biggest medical fraud, amounting to 10 yrs rigorous imprisonement and fine.Suspected to have favours from makers of HES