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Renal side effects of hydroxyethyl starch 130/0.4 in cardiac surgery
- Ingemar J. Davidson (28 May 2008)
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Comparison of gelatin and a modern hydroxyethylstarch on renal function
- Norman Kufakwaro (13 April 2008)
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Ingemar J. Davidson Division of Surgical Transplantation, The University of Texas Southwestern Medical Center at Dallas
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Nephrotoxicity and acute renal failure (ARF) remain prime concerns with the use of hydroxyethyl starch (HES) for fluid management.1 2 For instance, in the nonrandomized observational Sepsis Occurrence in Acutely ill Patients (SOAP) study of 3147 intensive care unit (ICU) patients, HES administration was associated with an increased requirement for renal replacement therapy (RRT), as well as higher ICU and hospital mortality.3 Furthermore, at baseline the percentage of HES recipients on RRT (2.2%) was only half that (p < 0.001) of unexposed patients (4.4%), and the cumulative HES dose (1000 ml) was relatively low. The association between HES administration and RRT requirement did not persist in a multivariate statistical analysis; however, the reliability of the analysis was limited by the comparatively high number of variables evaluated relative to events observed. It has been a recurring hypothesis that HES solutions of lower molecular weight and substitution might minimise renal risk, although a systematic review failed to support this hypothesis.1 Boldt and colleagues now describe in the British Journal of Anaesthesia a new randomized trial of a HES solution with 130 kDa molecular weight and 0.4 molar substitution (HES 130/0.4) for perioperative fluid management in 60 elderly cardiac surgery patients over 2 days.4 Surprisingly, they do not mention their earlier trial of the same design in 40 elderly cardiac surgery patients.5 In the earlier trial, postoperative kidney impairment was observed in patients receiving HES 130/0.4, as judged by elevations in four sensitive markers of renal injury. The magnitudes of the elevations were similar to those in patients receiving gelatin, an artificial colloid that itself has also been shown to affect kidney function adversely.1 In the new trial, Boldt et al. have again measured one of the four markers, namely, glutathione transferase-alpha, and again postoperative levels were abnormally high in both the HES 130/0.4 and gelatin groups. A fifth marker, neutrophil gelatinase-associated lipocalin, was also elevated in both groups of the new trial. While the magnitude of the neutrophil gelatinase-associated lipocalin increase was greater in the gelatin group, the mean cumulative HES 130/0.4 volume infused was 540 ml lower than that in the earlier trial. The new trial provides evidence confirming the deleterious renal effects of HES 130/0.4 observed in the earlier trial. Both trials shared the limitations of other prior investigations assessing the renal impact of HES 130/0.4, i.e. small size and short duration. Importantly, no trial of adequate size and duration has ever been reported on the incidence of ARF after infusion of HES 130/0.4. This dearth of key evidence may explain the HES 130/0.4 Prescribing Information newly approved by the US Food and Drug Administration (www.fda. gov/cber/ndalabel/voluvenLB.pdf; accessed 27 May 2008), in which HES 130/0.4 is contraindicated for patients with renal failure and oliguria or anuria not related to hypovolemia and for patients undergoing dialysis. Warnings and precautions in the Prescribing Information include the need to adjust HES 130/0.4 dosage in patients with renal impairment and to monitor kidney function in all patients receiving HES 130/0.4. Meanwhile, evidence continues to mount that lower molecular weight and substitution cannot effectively mitigate the nephrotoxicity of HES. In a randomized trial of 62 aortic aneurysm surgery patients, no differences between HES 200/0.62 and HES 130/0.4 could be detected in renal function, as assessed by serum urea, serum creatinine, urinary alpha1- microglobulin/creatinine ratio and urinary immunoglobulin G/creatinine ratio.6 Similarly, no difference in incidence of delayed graft function after kidney transplantation was demonstrable between recipients of HES 200/0.62 and HES 130/0.4 in a retrospective study of 64 brain-dead donors.7 The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) multicenter randomized trial evaluated a modern HES solution in 537 patients with severe sepsis or septic shock.8 Patients received a median cumulative dose of 70.4 ml kg-1 10% HES 200/0.5 over up to 21 days or crystalloid. The proportion of patients with preexisting renal dysfunction in the HES 200/0.5 group (5.3%) was lower (p = 0.02) than that in the control group (10.9%). Despite the lower baseline renal risk, HES 200/0.5 administration nearly doubled the odds of ARF and resort to RRT. Mortality was increased in patients receiving > 22 ml kg-1 HES 200/0.5 for at least one day vs. lower doses. It is improbable that use of a hyperoncotic colloid per se can account for the VISEP findings, inasmuch as Boldt and coworkers have administered 20% albumin without untoward renal effects in five randomized trials of patients with postoperative sepsis, as summarised in a recent systematic review.9 The in vitro colloid osmotic pressure of 20% albumin (196 mm Hg) is 2.45 fold that of 10% HES 200/0.5 (80 mm Hg).10 No difference in renal function was found after HES 200/0.5 vs. HES 130/0.4 infusion in a randomized trial of 31 cranio- cerebral trauma patients, although intracranial bleeding complications in 33% of the HES 200/0.5 group and 31% of HES 130/0.4 recipients prompted premature termination of the trial.11 Available evidence strongly suggests that renal impairment is a generic effect of all HES solutions. Hence, HES needs to be administered with great caution or avoided altogether. References 1. Davidson IJ. Renal impact of fluid management with colloids: a comparative review. Eur J Anaesthesiol 2006; 23: 721-38 2. Brunkhorst FM, Oppert M. Nephrotoxicity of hydroxyethyl starch solution. Br J Anaesth 2008; 100: 856 3. 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 4. Boldt J, Brosch C, Röhm K, Papsdorf M, Mengistu A. Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients. Br J Anaesth 2008; 100: 457-64 5. Boldt J, Brenner T, Lehmann A, Lang J, Kumle B, Werling C. Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. Intensive Care Med 2003; 29: 763-9 6. Mahmood A, Gosling P, Vohra RK. Randomized clinical trial comparing the effects on renal function of hydroxyethyl starch or gelatine during aortic aneurysm surgery. Br J Surg 2007; 94: 427-33 7. Blasco V, Leone M, Antonini F, Geissler A, Albanese J, Martin C. Comparison of the novel hydroxyethylstarch 130/0.4 and hydroxyethylstarch 200/0.6 in brain-dead donor resuscitation on renal function after transplantation. Br J Anaesth 2008; 100: 504-8 8. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. The German Competence Network Sepsis (SepNet). N Engl J Med 2008; 358: 125-39 9. Wiedermann CJ. Systematic review of randomized clinical trials on the use of hydroxyethyl starch for fluid management in sepsis. BMC Emerg Med 2008; 8: 1-8 10. Tønnessen T, Tølløfsrud S, Kongsgaard UE, Noddeland H. Colloid osmotic pressure of plasma replacement fluids. Acta Anaesthesiol Scand 1993; 37: 424-6 11. 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 Conflict of Interest:None declared |
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Norman Kufakwaro, Specialist Registrar St Barts and The London School of Anaesthesia
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I read with interest the article by J.Boldt(1) and colleagues who compared the effects of gelatin and a modern hydroxyethyl starch(HES) on renal function and inflammmatory response in elderly cardiac patients. I am currently working in a cardiothoracic unit which receives patients that have similar biometric data as the patients in this study. I was surprised that the average stay in ITU was 3-4 days with some patients staying up to 32 days. In our unit the average stay is 2 days post operatively. Second issue concerns the conduct of the research. Despite the patients in the gelatin group having lower urine output at the end of surgery and 5 hours post operatively, they were given more crystalloids than patients in the hydroxy ethyl group.This was in addition to the gelatin group receiving significantly more volume than HES group.They could have monitored extra vasular lung water and tissue oxygenation indices in addition to their surrogate measures The issue of tissue oxygenation is central to this article as they proceed to explain that the significant difference between the groups with regards to the primary outcome(creatinine clearance) was due to improved microcirculation and and tissue oxygention seen with HES. They should have monitored renal oxygenation using urinary oxygen tension as an index of renal blood flow and medullary oxygenation.Aperia(2) and colleagues have demonstrated that urinary oxygen tension can be a sensitive index of renal arteriolar blood flow. Kidney specific proteins -alpha Glutathione s transferase(GST) and Neutrophil gelatinase associated lipocalin(NGAL) were used to assess tubular integrity and they are upregulated in ischaemic renal injury. Monitoring urinary oxygen tension would have shown if the are any differences between the 2 volume strategies with regards to renoprotective effects. On a lighter note I wonder whether their male patients had consumed brussel sprouts prior to the study as Nijhoff(3) and colleagues demonstrated increased alpha GST levels after consumption of brussel sprouts. References 1.Boldt J, Brosch Ch, et al. Comparison of the effects of gelatin and a modern hydroxylethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients. 2.Aperia AC,Liebow AA, et al. Implications of urine p02 for renal medullary blood flow. 3.Nijhoff WA, Mulder TP, et al. Effects of consumption of brussel sprouts on plasma and urinary glutathione s transferase class alpha and pi in humans. Conflict of Interest:None declared |
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