The intention of our review article was to describe pharmacologically and clinically important differences of hydroxyethyl starch (HES) products.1We appreciate the interest in this article and take the opportunity to comment on the points raised in the letters.

In 2007, the Sepsis Occurrence in Acutely Ill Patients study group, with Dr. Reinhart as coauthor, reported that the use of HES had no influence on renal function or the need for renal replacement therapy in critically ill patients.2After the publication of the Volume Substitution and Insulin Therapy in Severe Sepsis trial,3which failed its coprimary endpoints, that is, differences in the rate of death at 28 days and the mean score for organ failure, Dr. Reinhart and associates have vigorously argued against the use of HES. They repeatedly and polemically stated that all HES types are the same.4,5This claim may reflect flaws in the Volume Substitution and Insulin Therapy in Severe Sepsis study design and considerable protocol violations that accounted for renal dysfunction and death of 26 patients treated with a hyperoncotic pentastarch solution. To date, the authors of the Volume Substitution and Insulin Therapy in Severe Sepsis trial have not provided a pharmacologic justification why HES 200/0.5 (10%), with known accumulation in the plasma and tissue was used, although the more modern and more rapidly metabolizable HES 130/0.4 (6%) was available since 1999. In this context, it is especially noteworthy that acute kidney injury after administration of hyperoncotic colloids had repeatedly been shown before.6–9 

Although Reinhart et al.  refer to the importance of cumulative doses of starches, they refrain from quantitative pharmacologic considerations. For example, kidney storage after 52 days in the cited rat model amounted to 0.019% of the given cumulative dose of 12,600 mg/kg, merely reflecting continued renal excretion and amounting to 2.4 mg/kg body weight HES substance in the organ, a small proportion of the total dose given, which can hardly be interpreted as relevant accumulation.10Hagne et al.  11describe a case report of a patient who received repetitive HES infusions, although suffering from dialysis-dependent renal failure, which is a well-documented contraindication for HES. In the study cited for coagulopathy,12and in another trial,13chest tube drainage was not higher after HES 130/0.4 than after albumin (means: 895 vs.  990 ml, P = 0.98). Data reporting less blood loss and transfusion needs after HES 130/0.4 compared with HES 200/0.514–16have been ignored.

Although pruritus is a known side effect of all HES preparations, it is strongly dependent on dose and storage characteristics.17,18Notably, the patient referred to in the case report19received a cumulative dose of 1.2 kg of different HES types. The liver trauma animal experiment of Zaar et al.  20is cited and interpreted incorrectly. The HES animals were not lost before the end of the experiment but were followed up longer than Ringer's lactate animals. Fixed doses of crystalloid versus  colloid were applied in the early phase, with expectedly stronger hemodilution and higher mean arterial pressures in the colloid group, and with consecutive larger bleeding in the colloid group. In the setting of uncontrolled hemorrhage, however, higher mean arterial pressure values are not necessarily beneficial, even when using crystalloids only.21In the isolated kidney model of Hüter et al. ,22the authors reported significant differences of HES 200/0.5 (10%) and HES 130/0.4 (6%), showing a more proinflammatory effect of HES 200/0.5 and less tubular damage for both Ringer's lactate and HES 130/0.4 (6%) compared with HES 200/0.5 (10%).

The documentation of Food and Drug Administration approval has been cited selectively. In fact, the Food and Drug Administration concluded that compared with hetastarch, HES 130/0.4 (6%) was similarly effective but associated with less side effects, for example, fewer bleeding events. Importantly, no safety signal for worsening renal function was apparent.*

In the retrospective analysis of Schabinski et al. ,23it was shown that a change of a predominantly HES 130/0.4 (6%)-based volume therapy to a predominantly gelatin-based therapy did not change the rate of renal failure of renal replacement therapy. For both colloids, there was a similar association of high cumulative amounts with renal events, which by no means can be interpreted as proof of causation, especially because of the lack of an explanatory mechanism for gelatin. Ongoing large studies with third-generation starches in critically ill patients†will hopefully settle these areas of disagreement.

We thank Dr. Bennett-Guerrero et al.  for their letter, which allows some further clarification regarding the complex topic of maximum doses of starches, beyond the restricted possibilities of a table. For hetastarch, regulatorily approved maximum doses by health authorities in Europe have always been restricted to 20 ml/kg.‡U.S. Food and Drug Administration-labeled texts for hetastarches including Hextend (Hospira Inc., Lake Forest, IL) are less strict, but the dosage recommendation§is usually 500-1000 ml, and volumes in excess of 1,500 ml/day have been used where severe blood loss has occurred, although generally only in conjunction with the administration of blood and blood products and with a reference to warnings in the patient information. Because there is no adequate high-dose study available for Hextend, we regard this as confirmation that 20 ml/kg should not be exceeded without a good reason. In the absence of a regulatory limit, this could be a pragmatic medical definition of “maximum dose” for the clinician. Given the 20-30 times lower clearance and consecutive plasma accumulation of hetastarch, including Hextend, in comparison with HES 130/0.4,24we see no good reason to recommend higher Hextend doses. However, we agree that the exact value of approved maximum doses may be somewhat arbitrary and is clearly dependent on individual drug history. Despite potential side effects and disadvantages when compared with third-generation starches,25,26there is no approved maximum dose for gelatins. For newer starch products, such as HES 130/0.4 (6%), regulatorily approved maximum doses (i.e. , up to 50 ml/kg) are based on clinical data. Doses higher than these approved maximum doses (70 ml/kg for several days) have already been used successfully in a study of patients with cerebral trauma.27 

University Hospital of Muenster, Muenster, Germany.

Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H: Hydroxyethyl starches. Different products—different effects. Anesthesiology 2009; 111:187–202
Sakr Y, Payen D, Reinhart K, Sipmann F, Zavala E, Bewley J, Marx G, Vincent J: Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98:216–24
Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinksi U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125–39
Hartog C, Reinhart K: Modern starches are not safer than old ones. Anesth Analg 2009; 109:1346
Hartog C, Brunkhorst F, Reinhart K: Hydroxyethyl starch 130/0.4 and surgical blood loss. Anesth Analg 2009; 108:672
Moran M, Kapsner C: Acute renal failure associated with elevated plasma oncotic pressure. N Engl J Med 1987; 317:105–3
Bartels C, Hadzik B, Abel M, Roth B: Renal failure associated with unrecognized hyperoncotic states after pediatric heart surgery. Intensive Care Med 1996; 22:492–4
Rozich JD, Paul RV: Acute renal failure precipitated by elevated colloid osmotic pressure. Am J Med 1989; 87:358–60
Vos SC, Hage JJ, Woerdeman LA, Noordanus RP: Acute renal failure during dextran-40 antithrombotic prophylaxis: report of two microsurgical cases. Ann Plast Surg 2002; 48:193–6
Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F: Tissue storage of 14C-labelled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 2003; 4:331–8
Hagne C, Schwarz A, Gaspert A, Giambarba C, Keusch G: HAES in septic shock—sword of Damocles? Schweiz Med Forum 2009; 9:304–6
Schramko AA, Suojaranta-Ylinen RT, Kuitunen AH, Kukkonen SI, Niemi TT: Rapidly degradable hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: A prospective randomized trial. Anesth Analg 2009; 108:30–6
Hanart C, Khalife M, De Villé A, Otte F, De Hert S, Van der Linden P: Perioperative volume replacement in children undergoing cardiac surgery: Albumin versus hydroxyethyl starch 130/0.4. Crit Care Med 2009; 37:696–701
Gallandat Huet RC, Siemons AW, Baus D, van Rooyen-Butijn WT, Haagenaars JA, van Oeveren W, Bepperling F: A novel hydroxyethyl starch (Voluven®) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth 2000; 47:1207–15
Langeron O, Doelberg M, Ang E-T, Bonnet F, Capdevila X, Coriat P: Voluven®, a lower substituted novel hydroxyethyl starch (HES 130/0.4) causes fewer effects on coagulation in major orthopaedic surgery than HES 200/0.5. Anesth Analg 2001; 92:855–62
Kozek-Langenecker SA, Jungheinrich C, Sauermann W, van der Linden PJ: The effects of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: A pooled analysis of randomized clinical trials. Anesth Analg 2008; 107:382–90
Gröchenig EA, Albegger K, Dieterich HJ, Franke RP, Gerlach E, Jurecka W, Kiesewetter H, Koch G, Ladurner G, Pölz W, Schimetta W, Schneeberger R, Volgger R, Wilhelm HJ, Zelger J: Hydroxyethylstarch-related pruritus: A prospective multicentre investigation of 544 patients. Perfusion 1998; 11:62–9
Rudolf J: Hydroxyethyl starch for hypervolemic hemodilution in patients with acute ischemic stroke: A randomized, placebo-controlled phase II safety study. Cerebrovasc Dis 2002; 14:33–41
Schmidt-Hieber M, Loddenkemper C, Schwartz S, Arntz G, Thiel E, Notter M: Hydrops lysosomalis generalisatus—an underestimated side effect of hydroxyethyl starch therapy? Eur J Haematol 2006; 77:83–5
Zaar M, Lauritzen B, Secher NH, Krantz T, Nielsen HB, Madsen PL, Johansson PI: Initial administration of hydroxyethyl starch vs lactated Ringer after liver trauma in the pig. Br J Anaesth 2009; 102:221–6
Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331:1105–9
Hüter L, Simon TP, Weinmann L, Schuerholz T, Reinhart K, Wolf G, Amann KU, Marx G: Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model. Crit Care 2009; 13:R23
Schabinski F, Oishi J, Tuche F, Luy A, Sakr Y, Bredle D, Hartog C, Reinhart K: Effects of a predominantly hydroxyethyl starch (HES)-based and a predominantly non HESbased fluid therapy on renal function in surgical ICU patients. Intensive Care Med 2009; 35:1539–47
Jungheinrich C, Neff TA: Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinet 2005; 44:681–99
Laxenaire M, Charpentier C, Feldman L; Le Groupe Francais d'Etude de la Tolérance des Substituts Plasmatiques: Anaphylactoid reactions to colloid plasma substitutes: Frequency, risk factors, mechanisms. A French multicenter prospective study. Ann Fr Anesth Réanim 1994;13: 301–10
de Jonge E, Levi M: Effects of different plasma substitutes on blood coagulation: A comparative review. Crit Care Med 2001; 29:1261–7
Neff TA, Doelberg M, Jungheinrich C, Sauerland A, Spahn DR, Stocker R: Repetitive large-dose infusion of the novel hydroxyethyl starch 130/0.4 in patients with severe head injury. Anesth Analg 2003; 96:1453–9