Hydroxyethyl starch: does our choice of colloid prevent or add to renal impairment?
The controversy over colloid vs crystalloid has continued for years.1 Against this we need to balance the effects of too much or too little fluid23 and the difficulties of comparing critically ill patients. There is also some evidence that early volume restoration before definitive haemostasis may result in accelerated blood loss, hypothermia, and a dilutional coagulopathy in trauma.45 If this were not enough, we must also deal with the adverse effects of individual types of colloid, in this case, hydroxyethyl starch (HES) solutions.HES solutions appear to be effective volume expanders, which because of their large molecules have the potential to stay in the circulation longer than crystalloids. As a result, biopsy samples from the left ventricle and gastrocnemius demonstrate fewer areas of endothelial swelling and tissue damage in sheep treated with HES rather than crystalloid, suggesting that microvascular surface area for tissue O2 exchange in sepsis may be better preserved with chronically infused colloid.6 In vitro, HES also decreases endothelial cell activation and neutrophil adhesion.7 Clinically, tissue oxygen tension in the deltoid muscle is higher after HES infusion, compared with crystalloids, especially on the first postoperative day, and there is also less endothelial swelling.8
So why with these apparent advantages are there concerns about the renal safety of HES? Histological changes have been noted in the kidney after administration of HES, and these have been associated, on occasions, with clinically important renal impairment. De Labarthe9 reported a 67 yr old patient undergoing transmaxillary buccopharyngectomy who developed acute oliguric renal failure with a creatinine of 443 µmol litre–1. Biopsies showed osmotic-nephrosis-like lesions in the proximal tubule, similar to those previously described in kidney transplant patients who had also received HES.10 Cittanova gave HES to 69 organ-donating brain-dead patients. After kidney donation, 9 of 27 recipient patients required haemofiltration in the HES-treated group, whereas only 1 of 20 needed this in the gelatin group. On biopsy, three of the patients from the HES-treated group also demonstrated osmotic-nephrosis-like lesions.11
Schortgen and colleagues12 investigated HES in septic patients by comparing the effect of colloids in adults with severe sepsis or septic shock. A total of 159 patients were prospectively randomized to receive gelatin or HES as a plasma volume expander. They found an odds ratio of 2.57 that the use of HES led to more acute renal failure than gelatin. However, despite randomization, the baseline creatinine in the HES group was higher than in the patients receiving gelatin. This led to criticism of the study. Bernal and Wendon13 had, like many others, switched away from albumin as a cost saving measure, but unlike many had kept a watchful eye on the consequences. They responded to Schortgen12 with their experience using HES and crystalloid, rather than albumin, in paracetamol-induced hepatic damage. In a comparison of 102 patients, they found no excess in mortality, requirement for renal support, duration of ICU, or hospital stay using HES.
In a study of coronary artery bypass patients, HES resulted in a decrease in GFR in patients undergoing coronary artery bypass grafting on days 3 and 5.14 These patients did have a longer bypass time, but multivariate linear regression suggested that this did not account for the decrease in GFR. However, a systematic review of randomized trials found a 4% excess of deaths compared with crystalloids when colloids were used for fluid resuscitation.1
So is it clear that HES does damage renal function? The American Thoracic Society Consensus Statement looked at this difficult area and produced summary points and some recommendations for therapy, but no definitive answers.15 In a retrospective study, Deman and colleagues16 found renal function in kidney transplant recipients who had received HES was comparable with those who had received gelatin and albumin, up to 14 days after operation. Up to 7 days, there was a difference, with a higher serum creatinine in the HES group, but this was explained by higher donor age and cardiovascular instability.
A Cochrane review comparing albumin, gelatin, dextran, and HES was unable to demonstrate whether one colloid solution was safer than another.17 A study in the elderly in the perioperative period used two HES solutions (HES 6% 70/0.5 and HES 6% 200/0.5) and gelatin 35000D. No major differences were seen and the authors concluded that all three regimes could be safely used.18
If there is doubt over the impact of HES on renal function, how would HES affect patients with pre-existing renal damage? HES 130/0.4 administered to patients with stable renal impairment did not accumulate and there was no evidence of a subsequent worsening of creatinine clearance.19
Could it be that the larger molecular weight HES molecules, which are slower to break down and thus tend to accumulate, are the source of the problem? This appears to be the case with clotting or platelet function problems. Neff20 compared HES 130/0.4 against 200/0.5 in patients with severe head injury. Factor VIII, von Willebrands factor, and ristocetin cofactor were higher with HES 130/0.4. However, there were no differences in mortality, renal function, bleeding, or use of blood products. Langeron21 also found that HES 130/0.4 interfered less with coagulation than HES 200/0.5 in major orthopaedic surgery, but does the same consistently apply to renal function? Boldt and Priebe22 have speculated that using HES with a lower molecular weight and degree of substitution may reduce renal effects, but this viewpoint has its critics.23 The properties of different types of HES have been described by Trieb24 and in a review by Davidson.25 Similarly, Ragaller26 has recommended that colloid solutions should be given in a restricted manner to organ donors and kidney recipients. He also recommended that dosages be limited, low molecular weight HES be used, and colloid oncotic pressure (COP) measured routinely to prevent hyper-oncotic renal failure as described by Moran.27 Europe and USA differ in the availability of low and high molecular weight HES solutions. Could this difference in availability affect the perception of the safety of HES? From a practical standpoint, how many intensive care units record and act on COP?
In this edition of the British Journal of Anaesthesia, Sakr and colleagues28 have demonstrated in a multicentre, pan-European, prospective, observational study involving 3147 patients (34% of whom received HES) that HES had no influence on renal function as assessed by urine output, SOFA score, and creatinine. Although more patients who received HES needed renal replacement therapy (RRT) than non-HES patients, when the figures were assessed using a multivariate analysis, HES administration was not associated with a subsequent need for RRT, whereas sepsis, cardiovascular failure, haematological cancer, and baseline renal SOFA scores were all associated with a higher need for RRT. This illustrates the major problem with observational studies, in that current common practice will influence which patients get which treatment, thereby complicating analysis. In addition, in large studies, it is usually only feasible to record variables that can be collected across many units. Unfortunately, the type of HES administered was not recorded, nor were more sensitive indicators of renal impairment. It would be intriguing to know whether the result would have been the same in an area using higher molecular weight HES solutions. However, the study does show what can be achieved by collaboration across Europe, which enables large amounts of data to be gathered and a perspective put on the size or impact of a potential problem. The fact that administration of HES had no obvious impact on renal function measured in terms of the need for RRT in 1075 patients receiving HES in the ICU is an important finding.
Department of Anaesthesia and Intensive Care
Royal Hallamshire Hospital
Sheffield S10 2JF
UK
E-mail: g.h.mills{at}sheffield.ac.uk
References
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