Existing trial data do not support that hydroxyethyl starch is less harmful when given on more ‘correct’ indications
KeywordsRisk Ratio Early Death Hydroxyethyl Starch Combine Risk Clinical Algorithm
Several misinterpretations of the Scandinavian Starch for Severe Sepsis/Septic Shock trial publication  need correction. First, the exact dose of trial fluid was accounted for in 8,619 of 8,621 (99.98%) trial patient-days. The lack of fluid data after day 3 is thus due to early death or discharge from the ICU. Secondly, the amount of trial fluid did decrease over time because the percentages of patients who received trial fluid were 94%, 78% and 53% for days 1 to 3, respectively. In fact, the majority of trial fluid was given within the first 38 hours because day 1 only lasted 14 hours (median). Finally, we cannot see the claimed ‘conflicts between study protocol specifications and published baseline data’, which also must be a misunderstanding.
We strongly discourage clinical algorithms for HES use, which are not supported by data from high-quality trials and which are against the recommendations by independent, scientific and regulatory organs [3, 4, 5]. Such algorithms for HES use must undergo testing in trials with low risk of bias before critically ill patients are exposed to potential harm.
Patrick Meybohm, Hugo Van Aken, Andrea De Gasperi, Stefan De Hert, Giorgio Della Rocca, Armand RJ Girbes, Hans Gombotz, Bertrand Guidet, Walter Hasibeder, Markus W Hollmann, Can Ince, Matthias Jacob, Peter Kranke, Sibylle Kozek-Langenecker, Stephan Alexander Loer, Claude Martin, Martin Siegemund, Christian Wunder and Kai Zacharowski
We are grateful to Haase and colleagues for their interest in our paper . We appreciate their amendment to the original paper that ‘lack of fluid data after day 3 is thus due to early death or discharge from the ICU’ because this very important issue was not previously mentioned . Further, we fully agree with the authors that ‘such algorithms for HES use must undergo testing in trials with low risk of bias’.
Regarding the subgroup analysis, however, we disagree with the data analysis. Regarding 30-day mortality in the trial by Siegemund and colleagues, 36 out of 125 patients in the control group and 34 out of 119 patients in the HES group died (M Siegemund, personal communication), resulting in a risk ratio of 0.99 (0.67 to 1.47 95% CI). Taking these data into account would yield a combined risk ratio of 1.12 (0.88 to 1.42 95% CI) in the subgroup of trials with ‘high probability of correct fluid indication’ (Figure 1). This combined point estimate for mortality does not indicate an increased risk of mortality in the subgroup of probably correct indication. The estimate rather suggests that, assuming the applied principles of fluid administration are adhered to, the tested interventions are associated with a similar risk for the outcome mortality.
Most importantly, rather than empirically splitting the trials into two groups according to a cutoff value of three points on the scale, we highly recommend performing meta-regression to investigate more appropriately how the different components of the scale did influence treatment effects .
In conclusion, algorithms for HES use must undergo testing in trials with low risk of bias, and identification of patients with correct indication is recommended.
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