Studies showing severely compromised blood coagulation and increased bleeding tendency included mostly a HMW-HES preparation (M w >450 kD) and a high MS (>0.7) (Hetastarch). This preparation has been demonstrated to induce a von Willebrand-like syndrome with decreased factor VIII coagulant activity and von Willebrand factor (vWF) antigen and factor VIII-related ristocetin cofactor.5–7 In animal experiments, it has been shown that in low-substituted HES (MS 0.42), the M w is not a key factor in deteriorating coagulation.8 Impaired platelet function has also been reported after administration of HES.6–11 With reduced factor VIII-related ristocetin cofactor, there is reduced binding to platelet membrane receptor proteins GPIb and GPIIb/IIIa, resulting in decreased platelet adhesion.9 HES with a high M w, high MS, and a high C 2/C 6 hydroxyethylation ratio (e.g., HES 450/0.7 or HES 200/0.62) reduced concentrations of vWF and factor VIII:c more than HES with lower M w and a lower MS. As the result of all reports on HES with a high M w and a high MS, the FDA approved a major change in the labeling of 6% Hetastarch in saline (M w >450 kD, MS >0.7) which applied specifically to cardiopulmonary bypass surgeries and did not recommend Hetastarch in this situation.10 Because of this inhibition of hemostasis, there appear to be few reasons to use such HES preparations in other clinical settings as well. Subsequently, more rapidly degradable HES preparations with lower M w (200 kD) and MS (0.5) were shown to improve safety with regard to coagulation (“second generation” HES).11–13 The last, “third-generation” HES has a M w of 130 kD and a MS of <0.5 and appears to be associated with negligible negative effects on coagulation. No platelet function abnormalities have been observed in in vitro studies using HES 130/0.4.14 Using SONOCLOT-analysis and in vitro hemodilution, HES 130/0.4 affected the maturation process significantly less than other HES preparations.15 In another in vitro study, infusion of HES 450/0.7/4.6 had the greatest effect on thrombelastography parameters, whereas HES 130/0.4/9 has the smallest effect.16 In a double-blind multicenter study in patients scheduled for coronary artery bypass grafting (CABG), Gallandat Huet et al.17 compared HES 130/0.4 with HES 200/0.5. In this study, vWF increased significantly more in the HES 130/0.4- than in HES 200/0.5-treated patients. Blood loss and transfusion requirements were lower in patients receiving HES 130/0.4, indicating considerable benefits with HES 130/0.4.
However, negative effects of modern HES preparations on coagulation have also been reported. In a prospective, double-blind, placebo-controlled, crossover study, the influence of HES 130/0.4, HES 200/0.62, and lactated Ringer’s solution (LR) on platelet function were studied in chronic back pain patients scheduled for peridural anesthesia.22 The platelet-inhibiting effect of HES 200 was more than that of HES 130. Adenosine diphosphate- (ADP) and epinephrine-induced platelet function was also significantly reduced by HES 130; the changes, however, were within normal range, indicating that these were statistically, but not clinically, significant changes. In 60 patients undergoing minor elective surgery, the effects of 20 mL/kg of LR, HES 200/0.5, and HES 130/0.4 on expression of platelet membrane glycoprotein cluster differentiation (CD) CD42b, CD41/61, and CD62p in vivo on nonstimulated platelets and ADP-activated platelets were assessed.23 Platelet dysfunction was observed in both HES groups, but recovery of platelets to normal function was faster after HES 130/0.4 than after HES 200/0.5. In a study in orthopedic surgery patients, HES 130/0.4 showed more pronounced disturbances of fibrinogen/fibrin polymerization than gelatins or LR.24
Dissolving modern HES preparations in a plasma-adapted, balanced solution rather than in saline solution further improved safety with regard to coagulation. In an in vitro study, the effects of HES 130/0.42 prepared in a balanced solution on hemostasis were compared with a conventional HES preparation in saline.25 The balanced HES preparation overall showed less negative effects on thrombelastographic data and platelet aggregation than the saline HES preparation, especially when using a higher dilution. In another in vitro study, it was shown that in contrast to a nonbalanced HES 130/0.4, a HES 130/0.42 preparation dissolved in a physiologically balanced electrolyte solution did not affect activated partial thromboplastin time, FVIII:C and vWF.26 The balanced, but not the nonbalanced, HES preparation increased the expression of activated platelet GP IIb/IIIa induced by ADP, indicating improved hemostasis with this balanced HES preparation.
Older patients with significant comorbidities are at greater risk of developing kidney failure. As hypovolemia is an important etiology of kidney dysfunction, especially in the critically ill patient, correcting hypovolemia is fundamental to maintaining kidney integrity. There is increasing interest concerning the effects of HES on renal function. Several hypotheses and risk factors have been proposed to explain the mechanism of renal dysfunction with HES. Some histological studies have shown reversible swelling of renal tubular cells after the administration of certain HES preparations (“osmotic nephrosis like lesions”) probably secondary to reabsorption of macromolecules.27 Similar tubular lesions have been described with other substances as well (e.g., mannitol).
The most likely mechanism of renal dysfunction is the induction of hyperviscosity of the urine by infusion of hyperoncotic colloids in dehydrated patients. Glomerular filtration of hyperoncotic molecules from colloids may cause a hyperviscous urine and stasis of tubular flow, resulting in obstruction of the tubular lumen.28 The effective glomerular filtration pressure (P eff) is P eff = (P cap − P bow) − P pla (where P cap is hydrostatic capillary pressure, P bow is hydrostatic pressure in Bowman space, and P pla is plasma colloid oncotic pressure). An increase in plasma oncotic pressure by hyperoncotic colloids may be one reason for subsequent renal dysfunction.29 Considering this pathogenesis, it can be hypothesized that all hyperoncotic colloids can induce renal impairment (“hyperoncotic acute renal failure”). Adequate hydration using crystalloids may prevent this injury.
Information on the effects of HES in the clinical setting is not uniform. In a retrospective study, Legendre et al.30 reported 80% rate of “osmotic nephrosis-like lesions” (vacuolization of the proximal tubular cells) in transplanted kidneys after administration of HES with a medium M w (200 kD) and a high MS (0.62) to brain-dead donors. These changes, however, had no adverse effects on graft function or serum creatinine after transplantation. Cittanova et al.31 also demonstrated that the use of 6% HES 200/0.62 in brain-dead donors resulted in impaired renal function in kidney transplant recipients. In a multicenter, prospective study, 129 patients with sepsis or septic shock received either gelatin or HES 200/0.62 for intravascular volume replacement.32 Acute renal failure (defined as a twofold increase in serum creatinine concentration [sCr] or need for renal replacement therapy [RRT]) developed in 42% of the HES- and in 23% of the gelatin-treated patients (P < 0.028). Unfortunately, the two groups of patients are difficult to compare, because they had different baseline creatinine levels before the start of volume therapy. The need for RRT and mortality were not significantly different between the two groups. In another multicenter study of patients with septic shock, use of a hypertonic (10%), second generation HES preparation with a medium MS and a medium M w (10% HES 200/0.5), without regard to exclusion criteria (creatinine levels >3.6 mg/dL) and dose limitations (20 mL · kg−1 · d−1) resulted in a significantly higher incidence of late acute renal failure (>28 days after infusion) than in LR-treated patients (34.9% vs 22.8%).33 Interestingly, other colloids (including dextrans) had been used in almost 30% of the HES-treated patients. Two meta-analyses not distinguishing the different HES preparations, including different kinds of patients (general/cardiac/trauma surgery, septic/severe septic/septic shock patients) and patients with and without preexisting kidney dysfunction, using fixed volumes or goal guided-directed therapy and using varying definitions of “renal dysfunction” concluded that HES possesses a significant negative effect on renal function.34,35 In contrast, a large observational study in 3147 critically ill patients in ICU, 1075 of whom received HES (not separated concerning the type of HES given), did not show a significantly higher incidence of acute renal failure requiring RRT.36 No significant differences in renal failure scores were documented in patients treated with other plasma substitutes (including albumin).
The last generation of HES also appears to be safe with regard to long-term renal function effects. In a retrospective, matched-paired study, HES 130/0.4 or HES 200/0.62 was used for resuscitation of brain-dead donors.38 Use of HES 130/0.4 was associated with a better effect on renal function than HES 200/0.62; 1 mo and 1 yr after transplantation, sCr was significantly lower in the HES 130/0.4- than in the HES 200/0.62-treated donors.
Use of extremely high doses of 6% HES 130/0.4 in neurosurgical patients (up to 66 L over 21 days) was not associated with deteriorating kidney function after 7 days.39 In a study in cardiac surgery patients >80 yr, volume therapy with HES 130/0.4 was associated with fewer changes in kidney function than gelatin.40 Creatinine clearance did not change in the HES-treated patients and concentration of kidney-specific proteins recovered to normal 2 days after surgery. Kidney function was without significant differences from baseline even 60 days after discharge from the hospital, and no patient developed acute renal failure requiring RRT after hospital discharge. In another prospective, randomized study, cardiac surgery patients aged >80 yr with preoperative hypoalbuminemia received either 5% human albumin (HA) or 6% HES 130/0.4.41 sCr increased slightly and glomerular filtration rate decreased after bypass and in the ICU in both groups. Approximately 3 mo after hospital discharge both sCr and glomerular filtration rate had returned close to baseline.
Even in patients with altered kidney function, use of the last generation of HES appears to be safe. In volunteers showing mild-to-severe renal dysfunction (mean creatinine clearance <50 mL · min−1 · 1.73 m−2), kidney function was not affected by the administration of 500 mL of HES 130/0.4.42 Use of 6% HES 130/0.4 compared with gelatin in 65 patients with compromised renal function (creatinine clearance <80 mL/min) undergoing abdominal aortic surgery was not associated with changes in serum creatinine up to day 6 after surgery, and the need for RRT also did not differ between the two groups.43 In a study of cardiac surgery patients with preoperative compromised kidney function (serum creatinine >1.5 mmol/L) use of 6% HES 130/0.4 did not negatively influence kidney integrity compared with a HA-based volume replacement strategy up to 2 mo after hospital discharge.44
All colloids used for intravascular volume replacement, including the natural colloid albumin, have the potential to induce anaphylactic/anaphylactoid reactions.45 Most common in frequency and of most intense severity are dextran-induced anaphylactic reactions, and even prophylaxis with monovalent hapten dextran cannot completely eliminate their occurrence.46 In a large clinical trial that included approximately 20,000 patients, it was demonstrated that use of HES was associated with a low incidence of anaphylactic/anaphylactoid reactions similar to that of albumin, and significantly less than that of other colloids.47 No data on the incidence of anaphylactic reactions after IV administration of the last generation of HES are available. However, it is unlikely that the modifications of the M w, the MS, and the C 2/C 6 ratio have resulted in increased anaphylactic potency, because histamine liberation appears to be induced by the substance itself (starch) and not by the modifications of the substrate.
Depending on the characteristics of the HES preparation, a varying amount of the infused HES leaves the vascular space and is taken up by the reticuloendothelial system or mononuclear phagocytic system. The sequelae of storage of HES preparations are not well delineated, but it does not appear that storage will negatively influence the function of the mononuclear phagocytic system.48
Special features of HES-induced pruritus include long latency of onset and persistence. A dose-dependent uptake of HES was first detected in macrophages and, thereafter, in endothelial and epithelial cells. Patients suffering from pruritus consistently showed additional deposition of HES in small peripheral nerves.50 Pruritus has been reported after use of large doses of HES over a long period, mostly using HES with a high M w or a high MS. Single reports on pruritus have been published, even after a single use of approximately 2000 mL of HES.51 In a prospective multicenter study, more than 500 patients were observed over 3–9 wk postoperatively.52 No significant differences with regard to pruritus were reported between HES-treated and control patients. In a study that included more than 700 patients undergoing minor elective surgery, the incidence of pruritus after infusion of HES 200/0.5 from two different manufacturers was compared with LR.53 There were no differences in the three patient groups: 9.1% and 12.0% in the two HES groups and 11.5% in the LR group. Using the last generation of HES, only rare reports on the incidence of pruritus are available, mostly after high or repetitive doses of HES 130/0.4 in the nonsurgical, non-ICU setting.3,54–57
Whether the choice of plasma substitute can be lifesaving is still a matter of debate. Even the SAFE study58 that included approximately 7000 ICU patients did not show differences between saline- and HA-treated patients. This study, however, was not focused on HES efficacy or influence on outcome but on unwanted side effects of new HES preparations. Two large studies showed increased mortality when using older HES preparations. In a retrospective chart analysis of 19,578 patients undergoing CABG surgery, patients receiving HA or nonprotein colloids (dextrans or HES with a high MS [HES 450/0.7; Hetastarch in saline]) were studied.59 Mortality was lower in the HA group (2.47% vs 3.03%, P = 0.02). Both dextrans and Hetastarch have detrimental effects on coagulation and kidney function. Thus, the FDA has already recommended avoiding the use of Hetastarch in saline in cardiac surgery patients. In a multicenter study of 537 patients with septic shock, the use of large doses (>22 mL · kg−1 · d−1) of a hypertonic (10%) HES 200/0.5 solution was associated with a higher mortality than use of LR.30 The recommended maximum dose of this HES preparation is reported to be <20 mL · kg−1 · d−1. In a subgroup analysis, the group in whom <22 mL · kg−1 · d−1 of HES had been administered showed the lowest mortality rate, even lower than the group in whom LR has been given for volume therapy.
Although millions of units of the new generation of HES preparations have been used for almost 10 yr in several countries, there is no large study showing increased mortality with the new HES preparations.
A well-balanced intravascular volume therapy is essential in the surgical, the burn, and in the patient in ICU. The ideal plasma substitute for volume replacement remains a matter of debate. HES is the most widely used plasma substitute in the Europe and is widely used in the rest of the world. The efficacy of HES in restoring hypovolemia and thus improving systemic hemodynamics as well as microcirculation appears to be without doubt.
What did we learn with regard to safety of HES over the years? All volume replacement strategies have their risks and benefits. Because of the important physicochemical differences between the varying HES preparations, it would be inappropriate to categorize them all as a “HES group.” The majority of studies indicate that unwanted alterations in coagulation and increased bleeding (aside from that induced by extensive hemodilution) appear to no longer be a clinically relevant problem when using HES preparations with a M w of 130 kD and a MS <0.5. Dissolving modern HES preparations in a plasma adapted, balanced solution has further improved safety with regard to changes in hemostasis.
There is no evidence that timely, limited use (e.g., intraoperatively or in acute trauma care) of modern HES preparations has negative effects on kidney function in patients with normal kidney function. The propensity of HES to negatively influence kidney function in patients with preexisting renal disease depends on the HES preparation and its proper use. The importance of using substance specific, recommended doses for each HES preparations cannot be overemphasized: “Dosis sola veneum facit”—the dose is poisoning (Paracelsus 1493–1541). The “critical” serum creatinine level below which HES preparations should not be used is still unknown. By accepting a sCr of >2.5 mmol/L as an exclusion criterion, modern HES preparations with a M w of 130 kD and a MS <0.5 appear to be safe with regard to kidney function. Unfortunately, current evidence in this area is lacking.
Whether the choice of fluid has an impact on patient outcome is still not clear but appears to be unlikely.60–62 Conflicting results with regard to patient outcome are most likely due to variations in clinical protocols, selection of patients, criteria for volume administration, and the type of plasma substitute administered. More than 10 yr ago, Warren and Durieux63 asked “HES: safe or not.” They concluded that “HES should be used with caution ….” like all other drugs. Medical therapy has developed rapidly over the last few years, and safety issues have become increasingly important. When respecting its limitations, there seems to be no good reason to avoid modern HES preparations for correcting hypovolemia. There also appears to be no argument against using HES dissolved in a balanced solution instead of unphysiological saline solution. Modern (“third-generation”) HES preparations dissolved in a balanced solution have added another piece in the puzzle of finding a safe, nonblood volume replacement strategy.
This review was not supported by a specific funding of a pharmaceutical company.
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