In the present analysis of fluid therapy in roughly 4500 German ICU patients with predominantly post-operative admission, about half the patients were exclusively treated with crystalloids, whereas the remaining patients also received colloids (mainly 6% HES 130/0.4).
Whereas crude and unadjusted analyses suggested an association of colloids with adverse outcome, a stepwise adjustment for baseline and progress covariables indicates that the use of colloids per se did not affect the risk of mortality. Moreover, the association of colloids with AKI disappeared after multivariable adjustment. In subgroup analyses, the adjusted risk of AKI was lower in patients treated with colloids per se or HES 130/0.4. In the subcohort of patients admitted without severe sepsis, there was also a trend towards reduced ICU mortality with colloids per se or HES 130/0.4. The most important finding of the present study is that the effects of colloids turned from seemingly adverse in the raw data to neutral or potentially beneficial after multivariable analyses. This contradicts findings from randomised controlled trials (RCTs). One main reason for this may be the timing and dose of colloid use being different from the RCTs as detailed below.
RaFTinG is the largest database comparing crystalloids versus colloids in clinical routine for renal and overall outcome. Demographic characteristics indicate its population to be representative for German and international ICUs [20, 21]. Incidence and mortality of severe sepsis were comparable to that observed in a German epidemiological trial [20] but lower than in the Sepsis Occurrence in Acutely Ill Patients (SOAP) study [22].
The present data demonstrated colloids to be reserved for more severely ill patients with risk factors for mortality or AKI beyond the type of i.v. fluids. It is not surprising that the crude incidences of AKI and mortality were higher in “colloid” patients, since the present study was no RCT. Therefore, the observational design of RaFTinG required adjustment for confounders with impact on patient outcome.
Our approach for adjustment included the baseline variables gender, severity of disease (based on risk of mortality derived from SAPS II and APACHE II scores), chronic kidney disease and severe sepsis on admission, which affect outcome in the ICU. However, these variables do not reflect the disease progression on the ICU. Patients with the same baseline risk may develop in opposed directions, with some patients recovering without fluid resuscitation and others deteriorating and require crystalloids and/or colloids for haemodynamic support. Thus, we also included the following variables for adjustment in our final model: SOFA score to reflect the overall severity of organ failure over the course of the ICU stay, indicating a general deterioration of patient status, high-dose vasopressor infusion to reflect haemodynamic instability related to the vasculature as well as transfusions [23], which carry an independent risk of negative outcome. We consider the addition of these factors to the multivariate analysis as mandatory to approach the net effects of colloids on outcome. Nevertheless, it needs to be acknowledged, that the current approach also bears the risk of overadjustment, since some of the adjustment variables may also be affected by colloid infusion itself (e.g. transfusions). To make the data more transparent, we present crude data, baseline adjustment and full adjustment.
After multivariable adjustment for baseline covariables and progress variables, treatment with colloids in general practice did not appear to negatively affect survival. Colloids being still associated with adverse outcomes after adjustment for baseline variables may be explained by evolution of patients’ disease state after ICU admission with some patients improving and others deteriorating further. Since the latter patients are more likely to receive colloids, we also adjusted for variables of disease progress after ICU admission. Notably, the SOAP study used a very similar approach to adjustment in a very similar setting [24]. Surprisingly, our fully adjusted analysis suggests that, in low doses as used in the present cohort, colloids and specifically HES 130/0.4 are neutral in terms of 90-day mortality and might even be associated with reduced risks of AKI and ICU mortality in critically ill patients without severe sepsis. These adjusted results are in strong contrast to the unadjusted results and should therefore be judged with appropriate caution. Nevertheless, they are in agreement with the CRISTAL trial [25], which showed that in untreated shock from any reason initial treatment with crystalloids alone may limit survival. Furthermore, the present results indicate that trials conducted in septic patients may not be extrapolated to non-septic patients [12, 26].
The advantage of the RaFTinG registry compared to previous RCTs [5, 7, 8, 25] is that colloids or crystalloids infusion was based exclusively on the clinical scenario, without being influenced by study protocols. The latter do often not reflect “real-life” fluid therapy, as has been demonstrated previously [5, 7, 8]. However, this also represents a major weakness, since the study cohorts are markedly different and the statistical analysis is sophisticated. Nevertheless, the present data give an estimate of the current use and dosing of fluid therapy and its changes throughout the ICU stay. This is important, as most positive and negative effects seen with colloids and fluids per se depend on timing and dosage [1, 9]. Therefore, RaFTinG not only adds relevant data but also helps to separate clinically relevant from artificial effects and allows the design of appropriate control groups for future RCTs. In this study, colloid use was completely different from that in VISEP [5], 6S [8] or CHEST [7]. Colloids were mainly given during the first day of ICU stay, with a consistent decline thereafter. When the interventional period of recent trials began, less than 60% of the RaFTinG population still received colloids. Furthermore, patients received median volumes of only 500 mL daily, which is considerably less than the amount that patients received on average per day in previous trials, e.g. 6S (1000–1500 mL) [8]. Neither physiology nor clinical practice randomises patients for several days into “colloid” and “crystalloid receivers”. Rather, the decision to infuse the drug “fluid” should be the result of a careful and permanently re-evaluated individual assessment of the expected benefit versus the potential risk.
The current discussion about colloids, especially on the safety of HES, might have caused significant indication bias by some investigators. For example, severely ill patients may be prone to receive more colloids as their cardiac preload is thought to be more compromised. Additionally, in patients with renal impairment, some physicians might prefer gelatine, according to the results of mainly one clinical trial [27], or sole crystalloids instead of HES. Indeed, CKD at baseline was highest in patients who received gelatine in RaFTinG.
Most patients in our study were post-operative without severe sepsis on admission (Table 1). Many patients in the RCTs suggesting negative effects of HES solutions, by contrast, were admitted to the ICU due to severe sepsis [5, 7, 8]. For patients in the perioperative setting, there is no evidence for harm with the use of 6% HES 130/0.4 [28, 29] or HES solutions in general [30] from the recent literature.
The results of the present multivariable analysis are in accordance with the previous literature on 6% HES 130/0.4 in non-septic and perioperative patients, which does not suggest an adverse effect on kidney function or survival.
Limitations of the present study
Our study has several limitations. Since it is observational, unblinded outcome assessment is unavoidable. Patients were not randomised and the cohorts are heterogeneous, with significant imbalances at baseline (e.g. severity scores, prevalence of sepsis) and many potential confounders on outcome. Even though we are confident that we were able to identify most of them and perform an appropriate adjustment, several approaches to adjusting the data are possible. It appears virtually impossible to account for the different severity of illness in the colloid cohort versus the crystalloid cohort without using adjustment parameters that are also influenced by disease progress. Thus, both risks of residual confounding and overadjustment exist. As a consequence, the adjusted results should be interpreted with caution. However, the small adjusted confidence intervals around or below 1 strongly suggest neutrality of the investigated colloids in terms of mortality and AKI. Unfortunately, although the analysis plan for the major endpoints (AKI, 90-day and ICU mortality) was designed a priori, no statistical analysis plan has been pre-published, which would have further strengthened the present results.
The present study did not investigate pre-admission fluid therapy or haemodynamics and can therefore not provide an estimate of the indication and effectiveness, which would have required a different study design [31]. Nevertheless, the timing of colloid infusion suggests colloids were used predominantly for initial or post-operative resuscitation (with pre-ICU fluid therapy, e.g. in the OR, being a blind spot).
Subcohorts having received other colloids than HES 130/0.4 were small compared to HES 130/0.4 or crystalloids. Any comparison between these subgroups must be done with caution, if at all.
Furthermore, the incidence of RRT may be a unreliable outcome measure, since most centres had no clear protocol for it. Any conclusion based on RRT should therefore be drawn with great caution.
It also needs to be acknowledged that an estimated mortality risk calculation by combining APACHE II and SAPS II (as available) may be less accurate than having a full set of both scores.
Finally, the follow-up might be considered incomplete. Besides that, missing information was not evenly distributed between both analysed groups with more incomplete baseline data with crystalloids only and more incomplete 90-day follow-up with colloids. The reason for this imbalance in missing data remains unknown, although we found that patients lost to follow-up were less severely ill on ICU admission. It is unclear how this finding may have led to a lower follow-up rate in the colloid cohort. Therefore, it is possible that unknown confounders influenced follow-up rates in the two cohorts. Nevertheless, a 90-day follow-up rate of 77.5% appears to be reasonably high when compared to 50–80% in other epidemiological cohort studies [32].
We also checked the effect of missing data on our full multivariable analysis with a best-/worst-case scenario. As expected, all risks were “diluted” by the assumption that all patients without follow-up had died. However, the risk associated with colloid use did not increase by this approach although colloid use was associated with greater loss to 90-day follow-up. Thus, the best-case/worst-case analysis suggests that missing follow-up data did not substantially affect the overall result.
