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Effects of hydroxyethyl starch in critically ill patients: Author response
- Yasser Sakr, Jean-Louis Vincent (15 March 2007)
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Soap and starches in critical care: Author response
- Yasser Sakr, Jean-Louis Vincent (15 March 2007)
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Soap and starches in critical care - beware of confounders and conclusions !
- Frank Martin Brunkhorst, F Schortgen, Réanimation Médicale, 94000 Créteil-France (13 March 2007)
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Soap and starches in critical care - beware of confounders and conclusions !
- FM Brunkhorst, F Schortgen, Réanimation Médicale, 94000 Créteil-France (27 February 2007)
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Effects of hydroxyethyl starch in critically ill patients
- Olumuyiwa A Bamgbade, Sean J McAfee; Raja Jayaram (16 February 2007)
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Yasser Sakr , Jean-Louis Vincent
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We appreciate the constructive appraisal by Dr. Bamgbade et al. of our paper investigating the effect of hydroxyethyl starch (HES) administration on renal function in critically ill patients (1). As the collection of data on fluid administration is notoriously difficult, we decided not to collect data concerning the different types or concentrations of HES used. We agree that 6% HES 130/0.42 solutions may be less likely to have adverse renal effects than other pentastarch solutions (2). The possible effects of HES on coagulation or its association with blood group in critically ill patients are interesting questions but beyond the scope of our analysis. Our study has some limitations that, we believe, were adequately discussed in our published manuscript (1). The type of admission, whether medical or surgical, was included in the multivariate analysis and did not influence outcome in patients who received HES. The presence of sepsis also did not influence outcomes. Dr. Bamgbade et al. are correct to mention that the median amount of HES administered to patients was just over 500 ml per day. We agree that larger amounts may have caused adverse renal effects; however, the amounts reported in our study reflect the real life situation and every-day practice in our ICUs. This is actually a strength of our study. Dr Bamgbade et al. have probably misinterpreted the data in Table 2, looking at absolute numbers and not percentages; patients who received HES were indeed more likely to require renal replacement therapy (11 vs. 9%) and mechanical ventilation (84 vs. 54%) than those who did not receive HES. References: 1. Sakr Y, Payen D, Reinhart K, et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98:216-24. 2. Boldt J, Schollhorn T, Munchbach J, Pabsdorf M. A total balanced volume replacement strategy using a new balanced hydroxyethyl starch preparation (6% HES 130/0.42) in patients undergoing major abdominal surgery. Eur J Anaesthesiol 2007; 24: 267-75. Conflict of Interest:None declared |
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Yasser Sakr , Jean-Louis Vincent
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Drs Brunkhorst and Schortgen seem to be upset by our results. The Sepsis Occurrence in Acutely ill Patients (SOAP) study (1) was a collaborative effort involving more than 200 European investigators. The use of hydroxyethyl starch (HES) and its effects on renal function is one of the post-hoc analyses of this database (2). We agree with Drs Brunkhorst and Schortgen that cohort studies must be planned in such a way that available data about potential confounding factors is of good quality, and these elements were carefully considered in the SOAP study. Definitions and guidelines were provided to the investigators before data collection. Data management was done centrally with daily plausibility analyses to assure good quality of data. Data to be collected were pre- specified by the steering committee. If the aim of the SOAP study was solely to investigate the epidemiology of sepsis, we would not have collected data on many therapeutic measures, including fluid therapy. Indeed, the intention was to use the SOAP database to address a number of questions in critical care medicine. Useful data have been reported previously from similar databases and have contributed to our understanding of several aspects in the management of critically ill patients. To give only one example, the SUPPORT study (3), whose aim was to improve end-of-life decision making and care served as a basis for a famous study by Connors et al (4) challenging the use of the pulmonary artery catheter! Drs Brunkhorst and Schortgen claim that the multivariate analyses we have presented in our paper (2) compared groups with different definitions for renal replacement therapy (RRT), but this is not true. Events should follow predisposition. It was logical to define the 'subsequent need for RRT' as the initiation of RRT at least 24 h after HES administration or 24 h after ICU admission in patients who did not receive HES because preadmission events could have led to renal failure already being present on ICU admission. It is also logical to adjust for the degree of organ failure, procedures, and sepsis syndromes at the onset of HES administration in patients who received HES and at admission in patients who did not receive HES because the latter group has no equivalent time point. The evolution of renal variables in patients with length of stay (LOS) > 24 hours can be extrapolated from Figures 2 and 3 (patients with LOS < 24 hours contribute logically only to the first box or column); there was no evidence for an adverse effect of HES on renal function. Drs Brunkhorst and Schortgen seemed also to have overlooked the data presented in our paper, when they claim that we used patients who received only crystalloids as a comparator to the HES group. Data on the use of other colloids were provided and adjusted for in the multivariate analysis. In addition, the no-HES group included patients who received other colloid solutions. Drs Brunkhorst and Schortgen describe the amount of HES administered in the SOAP study as unusual, but again these are the data. Our study is the first large observational study, to date, to report the type and amount of intravenous fluids in European countries. One cannot compare the amounts of fluids used in an observational study with those used in interventional studies. Finally, we feel that "subsequent need for RRT" is an adequate end- point in our observational study, especially in view of the large number of centers. We included a large number of factors in our analysis, including the most relevant confounding factors known to influence renal function and outcome of critical illness. References 1. Vincent JL, Sakr Y, Sprung CL et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344-53. 2. Sakr Y, Payen D, Reinhart K, et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98: 216-24 3. The SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). JAMA 1995; 274: 1591-1598 4. Connors AF Jr, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA 1996; 276: 889-897 Conflict of Interest:None declared |
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Frank Martin Brunkhorst, Department of Anesthesiology and Intensive Care Medicine University of Jena, Erlanger Allee 101, F Schortgen, Réanimation Médicale, 94000 Créteil-France
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Amended letter (see below) Again, the Sepsis Occurrence in Acutely ill Patients (SOAP) trial group 1 published another analysis from their database (1). After the pulmonary artery catheter, dopamine and albumin, hydroxyethyl starch (HES) and its effects on renal function has come into focus of investigation (2). However, we are concerned that the methods used were not adequate and the conclusions which were drawn "that HES had no influence on renal function or the need for renal replacement therapy (RRT)" must therefore be viewed with caution. Among others, these are our main concerns: 1) Cohort studies must be planned in such a way that available data about potential confounding factors is of good quality. To ensure this, outcome events must be clearly prespecified in the protocol and the data which will be collected must specifically address the question (3,4) . Unfortunately, this is not the case with the SOAP protocol. Its short case report form is quite condensed, and was primarily designed to study the epidemiology of sepsis and related therapeutic measures, not to answer nearly every open question in critical care medicine. 2) "The ‘subsequent need for RRT’ was defined in the SOAP protocol as the initiation of RRT in the ICU at least 24 h after HES administration or 24 h after admission in patients who did not receive HES." Thus, the multivariate analyses compared groups with differing definitions for RRT, which is not acceptable. 3) Median LOS in the ICU in the whole cohort of 3147 patients was only 3 days. Multivariate analysis was done on the 1970/3147 patients who stayed more than 24 hours in the ICU. Since the multivariate analysis was undertaken in this subgroup, these patients would need to be characterized in more detail regarding evolution of renal parameters and frequency of "subsequent need for RRT". 4) "A total of 1287 received only crystalloids" - this means that 41% of patients either did not receive colloids or did not need volume expansion. This does not mean that 41% of the patients received fluid resuscitation with only crystalloids. As crystalloids are often infused as maintenance fluids over 24 hours period, this heterogenous patient group cannot serve as a comparator to the HES group. 5) “The degree of organ failure assessed by the SOFA score, procedures (mechanical ventilation and pulmonary artery catheter), and the presence of sepsis syndromes on admission in patients who did not receive HES and at onset of HES administration in those who did, were also included as independent variables.” Again, adjustment of confounding factors was performed for different time periods in HES and non-HES groups. 6) The median amount of HES administered was 555 (IQR, 500-1000) ml per day and the total amount was only 1000 (500-2250) ml per patient. This is an unusually low HES dosage compared to other studies, in which patients with sepsis received median cumulative HES dosages of 4550 ml or 31 mL/kg (IQR 19–51), respectively (5,6). 7) Finally, "subsequent need for RRT" is an inadequate end point because it is highly dependent on ICU practices, especially in a study with 198 participating ICUs from 24 European countries. What does the study by Sakr et. al. add to our knowledge? –The results from this purely observational study should be taken with extreme caution. No conclusions for clinical practice can be drawn in view of the limitations of the study methods. For answers to outcome related questions we still need to await results of large prospective randomized trials or well designed independent post-approval prospective cohort studies (4). Reference: 1. http://www.intensive.org/soap/soap_study.doc as assessed by 10-2- 07 2. Sakr Y, Payen D, Reinhart K, et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98: 216-24 3. Wunsch H, Linde-Zwirble WT, Angus DC. Methods to adjust for bias and confounding in critical care health services research involving observational data. J Crit Care. 2006; 21: 1-7 4. Hunter D. First, gather the data. N Engl J Med 2006; 354: 329-331 5. Boldt J, Heesen M, Muller M, Pabsdorf M, and Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients. Anesth. Analg. 1996 83: 254-261. 6. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001; 357: 911-6 This is an amended copy of the former letter; we like to delete the sentence: "Furthermore, among five pharmaceutical sponsors of the SOAP study, two are manufacturer of HES solutions and thus not without potential bias." from our previous letter, since we are not convinced that such a bias exist. Correspondence: Frank Martin Brunkhorst, MD Department of Anesthesiology and Intensive Care Medicine, Friedrich- Schiller University of Jena, Erlanger Allee 101, 07747 Jena, Germany Telephone: +49 3641 9323383, Fax: +49 3641 9323102, E-mail: frank.brunkhorst@med.uni-jena.de Frédérique Schortgen, MD Réanimation Médicale Hôpital Henri Mondor 94000 Créteil-France Tel: (33) 1 49 81 43 85/23 89 Fax: (33) 1 42 07 99 43 E-mail: frederique.schortgen@hmn.ap-hop-paris.fr Conflict of Interest:None declared |
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FM Brunkhorst, Department of Anesthesiology and Intensive Care Medicine Friedrich-Schiller University of Jena, Erlanger Allee 101, 07747 Jena, Germany, F Schortgen, Réanimation Médicale, 94000 Créteil-France
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Again, the Sepsis Occurrence in Acutely ill Patients (SOAP) trial group 1 published another analysis from their database (1). After the pulmonary artery catheter, dopamine and albumin, hydroxyethyl starch (HES) and its effects on renal function has come into focus of investigation (2). However, we are concerned that the methods used were not adequate and the conclusions which were drawn "that HES had no influence on renal function or the need for renal replacement therapy (RRT)" must therefore be viewed with caution. Among others, these are our main concerns: 1) Cohort studies must be planned in such a way that available data about potential confounding factors is of good quality. To ensure this, outcome events must be clearly prespecified in the protocol and the data which will be collected must specifically address the question (3,4) . Unfortunately, this is not the case with the SOAP protocol. Its short case report form is quite condensed, and was primarily designed to study the epidemiology of sepsis and related therapeutic measures, not to answer nearly every open question in critical care medicine. 2) "The ‘subsequent need for RRT’ was defined in the SOAP protocol as the initiation of RRT in the ICU at least 24 h after HES administration or 24 h after admission in patients who did not receive HES." Thus, the multivariate analyses compared groups with differing definitions for RRT, which is not acceptable. 3) Median LOS in the ICU in the whole cohort of 3147 patients was only 3 days. Multivariate analysis was done on the 1970/3147 patients who stayed more than 24 hours in the ICU. Since the multivariate analysis was undertaken in this subgroup, these patients would need to be characterized in more detail regarding evolution of renal parameters and frequency of "subsequent need for RRT". 4) "A total of 1287 received only crystalloids" - this means that 41% of patients either did not receive colloids or did not need volume expansion. This does not mean that 41% of the patients received fluid resuscitation with only crystalloids. As crystalloids are often infused as maintenance fluids over 24 hours period, this heterogenous patient group cannot serve as a comparator to the HES group. 5) “The degree of organ failure assessed by the SOFA score, procedures (mechanical ventilation and pulmonary artery catheter), and the presence of sepsis syndromes on admission in patients who did not receive HES and at onset of HES administration in those who did, were also included as independent variables.” Again, adjustment of confounding factors was performed for different time periods in HES and non-HES groups. 6) The median amount of HES administered was 555 (IQR, 500-1000) ml per day and the total amount was only 1000 (500-2250) ml per patient. This is an unusually low HES dosage compared to other studies, in which patients with sepsis received median cumulative HES dosages of 4550 ml or 31 mL/kg (IQR 19–51), respectively (5,6). 7) Finally, "subsequent need for RRT" is an inadequate end point because it is highly dependent on ICU practices, especially in a study with 198 participating ICUs from 24 European countries. What does the study by Sakr et. al. add to our knowledge? –The results from this purely observational study should be taken with extreme caution. No conclusions for clinical practice can be drawn in view of the limitations of the study methods. Furthermore, among five pharmaceutical sponsors of the SOAP study, two are manufacturer of HES solutions and thus not without potential bias. For answers to outcome related questions we still need to await results of large prospective randomized trials or well designed independent post-approval prospective cohort studies (4). Reference: 1. http://www.intensive.org/soap/soap_study.doc as assessed by 10-2- 07 2. Sakr Y, Payen D, Reinhart K, et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98: 216-24 3. Wunsch H, Linde-Zwirble WT, Angus DC. Methods to adjust for bias and confounding in critical care health services research involving observational data. J Crit Care. 2006; 21: 1-7 4. Hunter D. First, gather the data. N Engl J Med 2006; 354: 329-331 5. Boldt J, Heesen M, Muller M, Pabsdorf M, and Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients. Anesth. Analg. 1996 83: 254-261. 6. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001; 357: 911-6 Correspondence: Frank Martin Brunkhorst, MD Department of Anesthesiology and Intensive Care Medicine, Friedrich- Schiller University of Jena, Erlanger Allee 101, 07747 Jena, Germany Telephone: +49 3641 9323383, Fax: +49 3641 9323102, E-mail: frank.brunkhorst@med.uni-jena.de Frédérique Schortgen, MD Réanimation Médicale Hôpital Henri Mondor 94000 Créteil-France Tel: (33) 1 49 81 43 85/23 89 Fax: (33) 1 42 07 99 43 E-mail: frederique.schortgen@hmn.ap-hop-paris.fr Conflict of Interest:None declared |
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Olumuyiwa A Bamgbade, Consultant Anaesthetist Central Manchester University Hospital, Manchester, UK;, Sean J McAfee; Raja Jayaram
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The article on the renal effects of hydroxyethyl starch (HES) by Sakr et al (1), was interesting and informative. This observational study of 3147 critically ill patients, who underwent treatment on 198 critical care units in 24 European countries, appears reliable. It is reassuring to have such reliable evidence that HES is widely used and has no influence on renal function in critically ill patients. The study is relatively reliable because of the prospective data collection, data quality control, large sample size, patient selection criteria, and detailed analysis. Although there was a lack of standardization of the type of HES used and the indications for fluid therapy across the different centres and countries, these factors may not have significant confounding effects on the results, which appear valid. However, it would be more informative to know the different types or concentrations of HES used in the different centres, to have an idea of the commonest type of HES administered to most patients in the study. A new balanced 6% HES 130/0.42 solution has been shown to have no negative renal effects (2). Although this study by Sakr et al (1) focussed on the renal effects of HES, it would be interesting to analyze the effects of HES on coagulation and any association with blood group in critically ill patients; because this may present a major problem (3,4). The study by Sakr et al (1) has some limitations. The predominant group that received HES were surgical patients while most medical patients received non-HES fluids. This may imply that the HES and non-HES sub- groups are not truly heterogeneous groups and that the two sub-groups are not matched in terms of sample size and case-mix. The use of non-HES fluids in most of the medical patients may have excluded a large group of patients who would have been appropriate to study for the deleterious effects of HES on renal function and coagulation. However, we appreciate the fact that these patients may not have had strong indications for the administration of HES. Regarding the medical or sepsis patients who received HES, was the overall outcome better? It is noteworthy that the median amount of HES administered to patients was just over 500ml per day. Is this amount significant enough to cause any adverse renal effects? Clarification is also required regarding the conflicting report that the patients administered HES received more renal replacement therapy and mechanical ventilation, when the data in table-2 appears to indicate otherwise. References: 1. Sakr Y, Payen D, Reinhart K, et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98:216-24. 2. Boldt J, Schollhorn T, Munchbach J, Pabsdorf M. A total balanced volume replacement strategy using a new balanced hydroxyethyl starch preparation (6% HES 130/0.42) in patients undergoing major abdominal surgery. Eur J Anaesthesiol 2007; 24: 267-75. 3. Egli GA, Zollinger A, Seifert B, et al. Effect of progressive haemodilution with hydroxyethyl starch, gelatin and albumin on blood coagulation. Br J Anaesth 1997; 78: 684-9. 4. Huraux C, Ankri AA, Eyraud D, et al. Hemostatic changes in patients receiving hydroxyethyl starch: the influence of ABO blood group. Anesth Analg 2001; 92:1396-1401. Conflict of Interest:None declared |
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