This is the first randomized, controlled, prospective, multicentre, double-blind study of 6% HES 130/0.4 in patients suffering from severe sepsis. The significantly lower volume to achieve initial HDS vs. NaCl confirms the good volume expansion effect of 6% HES130/0.4 [13
]. The safety profile of HES is an ongoing matter of debate. Several factors should be considered when assessing potential drawbacks of HES: the type of HES (concentration, molar substitution, molecular weight, and C2
ratio) and daily and cumulative doses used, underlying baseline kidney dysfunction, the case mix (surgery, trauma, or sepsis), and ensuring patients are sufficiently hydrated.
There have been initial concerns regarding the negative effect of older HES products on kidney function after renal transplant [14
]. More recent studies with third generation HES have not confirmed this effect on kidney function [15
]. For patients with sepsis receiving older HES products for fluid resuscitation, two randomized studies have documented an alteration of renal function [5
]. In the first study, a randomized, multicentre study including 129 septic shock patients, patients resuscitated with 6% HES 200/0.62 had a higher incidence of ARF vs. patients treated with gelatin (42% vs. 23%, P
< 0.03) [5
]. The volumes received and the levels of baseline creatinine before vascular filling in the two treatment arms, however, were different, thus rendering a head-to-head comparison difficult. Nonetheless, multivariate analysis showed that using 6% HES 200/0.62 was an independent risk factor for secondary formation of renal insufficiency. In the second study, a multicenter, two-by-two factorial trial including 537 patients with severe sepsis, resuscitation with a hyperoncotic 10% HES 200/0.5 given at very high cumulative volumes, was associated with higher rates of ARF and RRT vs. Ringer's lactate [6
]. Basic hydration therapy has been criticized as being insufficient in both these trials and in the second study almost 80% of patients were randomized after successful initial HDS. Whether or not the association between ARF and the liberal infusion of the hyperoncotic HES preparation was cause or effect remains elusive.
In the current study, the number of patients presenting with ARF, defined as doubling of the baseline creatinine value or need for RRT, was similar for 6% HES 130/0.4 and NaCl 0.9% (24.5% vs. 20%, respectively). Treatment groups were also comparable for the AKIN and RIFLE classifications. Likewise, results from three urinary biomarker analyses confirmed that 6% HES 130/0.4 did not induce AKI, because neither the tubular, nor the glomerular function was affected. In addition, there was no statistically significant treatment difference in median change in SCr from baseline or peak post-baseline SCr. These findings are in agreement with a recent observational study in patients with severe sepsis or septic shock, which did not find an association of HES 130/0.4 with RRT or renal dysfunction [17
The fact that 6% HES 130/0.4 has a good renal safety profile [18
] was recently confirmed in a randomized trauma study [23
]. Even though very high volumes of HES 130/0.4 (approximately 70ml/kg) were infused during initial resuscitation, the incidence of renal dysfunction was lower in the HES group vs. patients treated with NaCl 0.9%. Patients with severe underlying kidney failure were excluded from the present study. However, importantly, in a pharmacokinetic study in which 500 ml 6% HES 130/0.4 was administered to each of 19 patients with pre-existing renal insufficiency of variable degree, the maximum plasma concentration of starch and its terminal half-life were not affected by renal insufficiency [24
Besides the study drug, patients enrolled in the present study received basic daily rehydration therapy with 500 ml of infused isotonic saline per two bags of study drug. The cumulative volume of study drug was restricted to a maximum of 4,000 ml on day 1 (50 ml/kg) and 2,000 ml/day for days 2 to 4 (10 L in total). As a consequence, the mean cumulative volume of 2,500 to 3,000 ml was much lower, and the duration of 6% HES 130/0.4 administration much shorter (4 days) compared to the 'prospective randomized multicenter study on the influence of colloid vs. crystalloid volume resuscitation and of intensive vs. conventional insulin therapy on outcome in patients with severe sepsis and septic shock' (VISEP) trial, where 38% of patients repeatedly received more than the allowed maximum daily dose for a second generation starch and duration of administration was >3 weeks for 13% of the patients [6
Apart from concerns regarding effects on kidney function, effects of different HES types on coagulation and bleeding events have been investigated in depth. In this regard, it is important to note that the influence on coagulation of 6% HES 130/0.4 is significantly reduced vs. older HES types. Unlike HES types with a high molar substitution, trials with 6% HES 130/0.4 in doses of up to 50 ml/kg body weight in cardiac surgery [22
], abdominal surgery [25
], and up to 70 ml/kg bodyweight in severe cranio-cerebral trauma [21
] have revealed no deterioration in coagulation. The decreased influence on coagulation and hence decreased incidence of undesirable effects after 6% HES 130/0.4 vs. older products is reflected in decreased blood loss in surgical patients, and subsequent transfusion requirements [26
]. The results of the present study are in harmony with the latter trials and confirm that 6% HES 130/0.4 has no clinically relevant impact on coagulation when used correctly. In the VISEP trial, the component of the SOFA score related to coagulation was more altered in the HES group vs. crystalloids [6
]. Conversely, we did not find any differences in blood loss or RBC transfusion requirements. There was no significant difference between treatment groups for any laboratory coagulation parameters.
Mortality rates were not statistically different between treatment groups. An important finding was a difference in initial mortality rate in the 6% HES 130/0.4 group, possibly due to a higher rate of patients with abdominal sepsis. This difference continued until day 90. Interestingly, the pattern of mortality rates was different from that observed in the VISEP study [6
], where a non-significant separation started after day 30. The type of volume resuscitation used was not an independent risk factor for mortality in our study.
Other side effects were similar between treatment groups. In animal experiments in rats, 6% HES 130/0.4 has been shown to significantly reduce tissue storage (75% lower) for the whole body compared with HES 200/0.5 [27
]. Deposits of HES in skin have been linked to the occurrence of pruritus [28
]. Three patients in each group experienced itching in the current study and our results clearly demonstrate that tetrastarch infusion as used in the present study was not linked to itching.
This study has some limitations. First, no algorithm to assess fluid responsiveness was used and CVP, though still recommended by the surviving sepsis guidelines, is known to be a poor indicator of preloading [29
]. Second, the study was not designed or powered to assess effects on mortality. A previous study has shown a tendency for reduced mortality in patients with severe sepsis if resuscitated with colloids vs. crystalloids [30
]. The 'crystalloid vs. hydroxyl-ethyl starch trials' (CHEST) study, which is using 6% HES 130/0.4, will probably settle this debate [9
]. Finally, though extensive biomarker analyses are provided and objective criteria to assess kidney function were used, effects on kidney function were not powered to assess an effect. Besides the CHEST study, another ongoing larger study [31
] will address this important issue.