STARCH AND SEPSIS

After the former leading researcher on starch solutions, Joachim Boldt fell from grace after his research fraud with colloid therapy, it has been hard to find good evidence on the use of starch solutions in resuscitation and critical care. Anaesthesia and Analgesia just released a meta-analysis of the remaining evidence, and their conclusion is that published studies are of poor quality and report too few events to reliably estimate the benefits or risks of administering 6% HES 130/0.4.

They even conclude that the same conclusion would be reached with or without the abovementioned retracted studies. Given the widespread use of 6% HES 130/0.4, high-quality trials reporting a large number of events are urgently required. Just our luck, there’s one such study just being finished. The 6S trial.
We (sort of) like colloids, because they have the power to raise the intravascular volume quicker, and using less volume, than using crystalloids. Many centers love 130/0.4 HES. It’s certainly the most popular colloid in Scandinavian centers. So maybe more would be better?

10% HES 200/0.5, a stronger starch solution with higher molecular weight starch molecules, has been shown to cause acute kidney failure in septic shock patients. So, no. more is not better.

But 6% HES 130/0.4 could still be a good option? The patients respond quickly to it. And even though Dr. Boldt was rigging his numbers, HES 6% 130/0.4 could still be a good choice in many settings? Maybe so, but probably not in septic patients.

The S6 trial: Scandinavian Starch for Severe Sepsis/Septic Shock Trial.
This multi center, prospective, randomized and double blinded trial has just concluded after including 800 severe sepsis patients, 400 in each arm, receiving either 6% HES 130/0.4 and Ringer solution, or just Ringer. Their main endpoint was 90-day mortality or end stage kidney failure. They received the trial fluid up to 33mL/IBW kg/day, and for any fluid needs above this, they received Ringer lactate. So any effect shouldn’t be due to receiving HES in too high concentrations.

The numbers are just being crunched, and at this time, the HES group comes out with a significantly higher 90-day mortality. 51% compared to 43% for the Ringer lactate group. Now, that’s a real difference. We’ll report back when the full study is available in detail. In the meantime, you might want to stop those colloid infusions and get som crystalloid running.

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S–Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

BACKGROUND: By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis.
METHODS/DESIGN: The 6S trial will randomize 800 patients with severe sepsis in 30 Scandinavian ICUs to masked fluid resuscitation using either 6% HES 130/0.4 in Ringer’s acetate or Ringer’s acetate alone. The composite endpoint of 90-day mortality or end-stage kidney failure is the primary outcome measure. The secondary outcome measures are severe bleeding or allergic reactions, organ failure, acute kidney failure, days alive without renal replacement therapy or ventilator support and 28-day and 1/2- and one-year mortality. The sample size will allow the detection of a 10% absolute difference between the two groups in the composite endpoint with a power of 80%.
DISCUSSION: The 6S trial will provide important safety and efficacy data on the use of HES 130/0.4 in patients with severe sepsis. The effects on mortality, dialysis-dependency, time on ventilator, bleeding and markers of resuscitation, metabolism, kidney failure, and coagulation will be assessed.

What are these different starch solutions anyway?
Different types of hydroxyethyl starches are typically described by their average molecular weight, typically around 130 to 200 kDa (bearing in mind that there will be a range of different-sized molecules in any given solution); and their degree of molar substitution (what proportion of the glucose units on the starch molecule have been replaced by hydroxyethyl units), typically around 0.35 to 0.5.

A solution of hydroxyethyl starch may further be described by its concentration in % (i.e. grams per 100ml). So for example, one commercially available hydroxyethyl starch (Voluven) is described as 6% HES 130 / 0.4.

Larger molecule sized HES solutions have been attractive due to better volume expansion, but shunned due to the risk of acute kidney failure.

At least one of the trials concerning 200/0.5 HES have been critisised for using the stronger 10% solution, and also as using 200/0.5 HES the only resuscitation fluid, so the patient ended up receiving a very high concentration of HES. Still, the concensus seem to lean towards HES 200/0.5 increasing the risk of acute kidney failure. Use with caution, if at all.

Hydroxyethylstarch 200/0.5 – the horse has bolted, Crit Care, 2012

Update: The 6S trial is now live, and lives here:

Hydroxyethyl Starch 130/0.4 versus Ringer’s Acetate in Severe Sepsis, NEJM 2012.

We’ll get back to this as we’ve read through the full paper.

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