Effect of dextran-70 on outcome in severe sepsis; a propensity-score matching study

The optimal fluid therapy for patients with severe sepsis and septic shock is debated [1‐3]. Colloids have theoretical advantages compared to crystalloids because they are more efficacious plasma expanders than crystalloids and may minimize harmful effects of fluid overload [4‐11]. Some support for the use of albumin as an adjunct to the crystalloids may be inferred from the subgroup analyses of data from two large randomized trials showing improved outcomes in patients that received albumin compared to those treated only with saline [12, 13]. Moreover, the surviving sepsis guidelines support the use of albumin in patients requiring large amounts of fluid for hemodynamic stabilisation [14]. However, albumin is expensive, availability is limited and transfer of viruses remains a possibility in albumin products derived from human donors. Taken together, this provides a rational for the study of alternatives to albumin in patients with sepsis requiring large amounts of fluid.

Given that the use of hydroxyletyl starches (HES) in septic patients is discouraged [15‐18] dextrans are a group of colloids that are of potential interest. Dextrans are branched glucose polysaccharides and dextran-70 is a more efficacious plasma volume expander than albumin [8, 19, 20]. In addition, dextrans possess antithrombotic and rheological effects [21]. Two small studies have suggested that the use of dextran-70 in sepsis may be associated with increased bleeding and increased risk of acute kidney injury thus raising safety concerns [22, 23]. In attempt to further investigate safety of dextran-70 as an alternative to albumin we propensity-score matched patients with severe sepsis or septic shock who received dextran-70 to those who did not receive dextran-70 in a cohort of patients treated in a single intensive care unit (ICU). Effects of dextran-70 on measures of organ failure, on incidence of severe bleeding and on mortality were then investigated.

A Consort chart of patients is presented in Fig. 1. Of 6776 admissions, 932 (13.8%) were diagnosed with severe sepsis or septic shock and a total of 342 control patients and 436 dextran-70 treated patients were eligible for inclusion in the propensity score match. At total of 490 of these patients were matched at a 1:1 ratio, i.e. 245 unique patients in the control group and 245 unique patients in the dextran group. The median number of propensity score matched patients included each year was 24 (min-max range 14–48) in the control group and 28 (min-max range 20–33) in the dextran group. For number of patients included in the dextran and control groups stratified by year of admission see Additional file 1.

Baseline demographics, pre-existing medical conditions, and clinical, physiologic, and laboratory data in the unmatched and matched study population are summarized in Table 1. Matching reduced standardized differences between the groups in baseline variables to ≤10% for all variables. The dose of dextran-70 in the dextran group the first day was 1000 ml (interquartile range 500–1000 ml) and for the first 5 days 399 ml/day (interquartile range 200–656 ml/day) (Table 3). Cumulative dose of dextran-70 for the ICU stay was 1483 ml (interquartile range 1000–2000 ml), which corresponds to 17 ml/kg (interquartile range 12–27 ml/kg).

There was a signal for a higher maximal AKIN score in the dextran group than in the control group (p = 0.06) but this was not reflected in incidence of RRT or days alive and free of RRT (Table 2). Other measures of organ failure and number of severe bleeding episodes were similar in the two groups. The 180-day mortality was lower in the dextran group than in the control group whereas mortality at 28- and 90 days did not differ between the groups (Table 2 and Fig. 2). For details concerning fluid administration and fluid balance please see Table 3. In summary the dextran group received less 5% and 20% albumin during the first 5 days in the ICU, the dextran group also received more crystalloids at day 1 in the ICU. The volume of packed red blood cells during the first five days in the ICU was higher than in the control group. Urinary output was lower and fluid balance more positive in the dextran group during the first days in the ICU compared to the control group. Number of patients in the dextran and control groups that experienced a bleeding episode did not differ between the groups (Table 2).

A pre-specified analysis was performed to investigate the interaction between dose of dextran-70 and outcome. In this analysis only patients receiving >900 ml dextran-70 the first 5 days after admission were included in the dextran group. The propensity score matching rendered 219 patients in the control group and 219 patients in the dextran group. The dose of dextran-70 in the dextran group the first day was 1000 ml (interquartile range 1000–1483 ml) and for the first 5 days in the treated patients was 413 ml/day (interquartile range 300–750 ml/day), and the cumulative dose for the ICU stay was 1500 ml (interquartile range 1000–2500 ml), which corresponds to 20 ml/kg (interquartile range 14–32 ml/kg). Matching produced well-matched groups and reduced standardized differences in baseline variables to ≤10% for all variables but age (Additional file 2). The differences between the groups in the secondary analyses were essentially unchanged compared to the primary analyses. For baseline data before and after propensity score matching and outcomes in the secondary analyses, see Additional files 2, 3, 4.

Mortality at 180 days was lower in the dextran group whereas mortality at earlier time points did not differ. The use of dextran-70 was associated with more transfusions and a more positive fluid balance compared to patients that only received crystalloids and albumin. No effect of dextran on number of severe bleeding episodes could be detected. A signal for worsening of AKI was detected in the dextran group but other measures of organ failure were similar in the dextran and control groups.

There is a paucity of high quality data regarding effects of dextran solutions on outcomes despite the fact that dextrans have been used clinically for more than 60 years. In the present study, propensity score matching was used in attempt to reduce bias and to estimate treatment effects of dextran-70. The finding that standardized differences were below 10% for all covariates included in the main analysis indicates that matching was successful in reducing imbalances between the treatment groups [30]. However, as discussed in more detail below, it must be stressed we cannot exclude that remaining imbalances in covariates, that were not accounted for in the propensity score model, may have influenced our results.

There are conflicting data with regard to effects of dextran-70 on renal function in patients suffering from septic shock. Thus it was recently reported that incidence of RRT in a cohort of patients with septic shock resuscitated with mainly Ringers acetate was lower than in historical controls resuscitated with a combination isotonic saline, albumin and dextran-70 (23% vs 48%) [23]. In contrast, a somewhat larger study using a similar design could not demonstrate a change in incidence of RRT by dextran-70 [22]. The present result of a similar incidence of RRT of about 20% in both the control and dextran groups does not provide support for adverse renal effects of dextran-70. It should be noted that the incidence of RRT in the present study is in the same range as that reported in several recent randomized controlled trials investigating effects of fluid therapy in sepsis and septic shock [12, 17, 18, 32]. In an attempt to increase sensitivity to detect changes in renal function that may be of importance for long-term mortality [33] we investigated maximum AKIN score during the first 10 days after admission. There was a signal for an increase in maximum AKIN score, which could indicate that dextran may be injurious to kidneys even if patient important outcomes such as events of RRT and days alive and free of organ failure were not affected. Alternatively this signal represents a chance finding.

Our finding that patients in the dextran group received more packed red blood cells during the 5 first days at the ICU, compared to patients in the control group is in line with the two previous studies investigating effects of dextran-70 in sepsis [22, 23]. However, in contrast to the above studies the present study could not demonstrate a difference in the number of episodes with severe bleedings between the dextran and control groups. Two mechanisms could be responsible for the increased transfusions of packed red cells in the dextran group. Firstly dextran-70 is suggested to induce a von Willebrand-like syndrome and [34] and to weaken fibrinogen polymerization [35, 36]. Weather these effects of dextran-70 increases clinically significant bleeding is unclear. Randomized trials were performed of dextran-70 versus crystalloids in the study of septic shock due to dengue in children [37] and a small study in shocked, adult trauma patients [38]. Neither of these trials reported increased bleeding with dextran-70. Nevertheless, increased bleeding incidence in the dextran group cannot be ruled out as the cause for the need of more blood transfusions in the present study. Secondly, dextran-70 is a more potent plasma expander than albumin and hemodilution will therefore occur to larger extent in dextran-70 resuscitated patients [7, 8, 37, 39]. Because hemoglobin level is controlled by the clinician, iatrogenic hemodilution is likely to contribute to the increased number of transfusions in the dextran group.

The finding that use of dextran-70 was associated with decreased use of albumin is in keeping with our hypothesis that dextran-70 can be used to reduce use of albumin. However, the use of dextran-70 was also associated with a more positive fluid balance during the first 5 days of admission. The positive balance could mainly be referred to the use of dextran-70 in excess of the relatively small reduction in volume of albumin and to a minor extent to the increase in transfusion of packed red cells (Table 3). This seems to be in in disagreement with the experimental and clinical data discussed above suggesting that dextran-70 is a better plasma expander than crystalloids, [7, 8, 37, 39] which would be expected to lessen the need for other fluids in dextran-70 group. This result may have several explanations. As mentioned above a more pronounced hemodilution by dextran-70 is likely to have led to transfusions contributing to a more positive fluid balance in the dextran group. Also, although the groups we carefully matched with regard physiological and laboratory parameters reflecting severity of illness, it is possible dextran-70 was more likely to be given to patients with more severe vascular leak and a higher need of fluid. Naturally it could be argued that a dextran-70 induced increase in vascular leak may have increased the volume requirements and contributed to the more positive fluid balance. However, dextrans are not known to influence on macromolecular permeability and have in fact been suggested to decease fluid permeability in experimental models [40, 41].

In attempt to evaluate if effects of dextran were dose-dependent we performed a second propensity score matching in which only patients receiving >900 ml dextran-70 were available for matching. This sensitivity analysis did not provide evidence for a dose dependent negative or positive effect of dextran-70 administration. Our finding that the effect of dextran on 90-day and 180-day mortality appeared to be more marked, aligns with the results of the main analysis. However, this finding may also be due to a statistical type 1 error since we did not correct for multiple testing and should be interpreted cautiously.

No evidence to support a detrimental effect of dextran-70 on kidney function or need for organ support or mortality in patients with severe sepsis or septic shock could be detected. Treatment with dextran-70 was associated with increased transfusion of packed red cells and a more positive fluid balance in the first 5 days after admission but no support for an increased incidence of severe bleeding episodes was found. A prospective large trial with low risk of bias is needed to further evaluate effects of dextran-70 before it can be recommended as an alternative to albumin in the resuscitation of septic patients.