In the late 19th century, physiologists were fascinated by the movement of fluid between the intravascular and interstitial compartments and its effect on the circulating volume. Ernest Starling, working from his laboratory at Guy’s Hospital in London, proposed that the net transudation of fluid depends on two forces. The capillary pressure tends to drive fluid out, while the colloid osmotic pressure, driven by proteins, enables reabsorption of fluid into the intravascular compartment. The pursuit of synthetic colloids with the potential to remain in circulation for a longer duration compared with crystalloids became the focus of interest in the early 20th century.
The commercial starch solution, available from the early 1960s, was manufactured from potatoes, or sorghum, a type of corn. Starch solutions, composed primarily of amylopectin, are unstable and undergo enzymatic degradation in the blood. They are treated with ethylene oxide to prevent enzymatic hydrolysis, resulting in the creation of the hydroxyethyl compound. Hydroxyethyl starch was considered superior to crystalloid solutions. It was reasonably priced and with a molecular weight of around 400,000, it persisted in circulation for a longer duration – sometimes for several weeks (1). Even in the early days of clinical use, questions were raised regarding assimilation into tissues, with possible adverse outcomes. Initial studies revealed efficacy in animal models of hemorrhagic shock (2). A later clinical trial suggested that plasma volume expansion may be almost twice as much with hydroxyethyl starch solutions compared with plasma, gelatin solutions, or dextran 70 (3).
Shortly after its introduction to clinical practice, concerns were raised regarding the safety profile of hydroxyethyl starch. Excessive bleeding was reported, possibly related to the depletion of clotting factors, including factor VIII, fibrinogen, and Von Willebrand factor (4). Microcirculatory abnormalities and platelet dysfunction were also implicated. Renal dysfunction related to hydroxyethyl starch use was reported in patients with pre-existing nephropathy who underwent hemodilution (5). Besides, histological lesions in transplanted kidneys were also observed (6). Adding fuel to the fire were accusations of fraud and falsification of data in numerous trials of hydroxyethyl starch by Joachim Boldt, a German anesthesiologist. Subsequently, more than 90 studies authored by Boldt that favored the use of hydroxyethyl starch were withdrawn by international medical journals (7). A subsequent meta-analysis of clinical trials that excluded studies by Boldt revealed significantly higher mortality and acute kidney injury with hydroxyethyl starch compared to other resuscitation fluids (8).
Background to the trial
Subsequent clinical trials underscored the risk of acute kidney injury with the use of hydroxyethyl starch, particularly with the 10% solutions (9,10). A large randomized controlled trial (RCT) from Scandinavia also reported increased mortality with the use of 6% hydroxyethyl starch for the resuscitation of septic patients (11). The Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group conducted the CHEST (Crystalloid versus Hydroxyethyl Starch Trial) RCT to evaluate the efficacy and safety of fluid resuscitation with a 6% hydroxyethyl starch solution in saline with a molecular weight of 130 kD (HES) in a heterogeneous group of ICU patients. The study fluid was compared with a control group who underwent resuscitation with normal saline (12).
Population and design
The CHEST trial was a multicentric RCT conducted across 32 medical-surgical ICUs in Australia and New Zealand between December 2009 and January 2012. Patients admitted to the ICU who required fluid resuscitation according to the treating clinician were eligible. Fluid resuscitation was defined as any bolus administration in addition to maintenance or replacement fluids. The requirement for bolus fluid was based on clinician judgment, supported by objective criteria. The volume of fluid administered was titrated based on clinical findings. The study excluded patients who received ≥1000 ml of HES before ICU admission and those in whom renal replacement therapy was ongoing or imminent. Patients with intracranial hemorrhage, burns, and those who underwent cardiac surgery or liver transplant were also excluded. HES was ceased if renal replacement therapy was required. Among these patients, normal saline was recommended; however, any alternative, appropriate fluid could be used. The administration of resuscitation fluids in locations outside the ICU (e.g., intraoperative fluid administration) was not controlled.
Patients were randomized to receive HES for resuscitation. HES was administered up to a maximum limit of 50 ml/kg/day; if any extra fluid was required, open-label normal saline was administered.
Normal saline was administered in identical 500 ml bags.
The use of maintenance fluids, nutrition, type of hemodynamic monitoring, vasoactive medication, respiratory, and renal support were based on clinician discretion. The pre-assigned fluid type was administered until discharge from ICU, death, or 90 days post-randomization.
The authors estimated a baseline mortality of 26%. The study was powered to detect a 3.5% absolute difference in the 90-day mortality. A sample size of 7000 patients was calculated to provide 90% power at an alpha level of 0.05, assuming a 5% loss to follow-up. Furthermore, the study had 90% power at an alpha level of 0.05 to identify an absolute increase in the incidence of acute kidney injury (AKI) of 1.5%, assuming a baseline of 6%. Analysis was by intention to treat.
A total of 7000 patients, with 3500 in each group, were randomized. After excluding patients who withdrew consent and were lost to follow-up, 3315 patients in the HES group and 3336 patients in the saline group were included in the 90-day analysis. The median APACHE II score was 17.0 in both groups. The incidence of AKI by the Risk, Injury, Failure, Loss, and End-stage renal failure (RIFLE) criteria was 36% in both groups. In the HES group, 29.2% of patients had sepsis compared with 28.4% in the normal saline group. Patients in the HES group received less fluid compared with the normal saline group in the first 4 days of ICU admission (526 ml vs. 616 ml); however, HES-treated patients received more blood products compared with normal saline.
The primary outcome: 90-day mortality
The 90-day mortality was not significantly different between the HES and the normal saline groups (18% vs. 17%; RR: 1.06, 95% CI: 0.96 to 1.18). On predefined subgroup analysis, the 90-day survival was similar in subgroups of patients with acute kidney injury, sepsis, trauma, traumatic brain injury, an APACHE II score of >25, and those who received HES before randomization.
Among the secondary outcomes, acute kidney injury requiring renal replacement therapy was significantly higher among HES-treated patients (7% vs. 5.8%; relative risk 1.21, 95% CI: 1.00 to 1.45; p = 0.04). Besides, based on RIFLE criteria, significantly more patients in the HES group sustained RIFLE-F type of dysfunction, while RIFLE-R and RIFLE-I were more common with normal saline.
No difference was observed between the two groups in the mortality in the ICU, hospital, or at 28 days. The duration of mechanical ventilation, renal replacement therapy, and hospital stay were also similar between the two groups. The incidence of new-onset hepatic failure was more common in the HES group, while new-onset cardiovascular failure was more common in the saline group.
On post hoc analysis, the urine output was significantly lower, and the serum creatinine levels were significantly higher in the HES group during the first week of treatment.
The incidence of adverse events was significantly higher with HES compared with saline (4.6 vs. 3.3%); however, these were generally mild, with pruritus and rash being the most common.
The CHEST trial was an adequately powered, multicentric RCT that evaluated the safety and efficacy of HES compared with normal saline as the resuscitation fluid. The study was double-blinded, thus minimizing bias. It was a pragmatic trial, with the requirement for fluid resuscitation based mainly on clinician judgment, and the volume of fluid administered was based on clinical assessment. The statistical analysis was planned a priori, and analysis was by intention to treat.
In the saline group, 15% of patients received HES before randomization, which may have affected the results. There was a 5% loss to follow-up; however, this was accounted for in the calculation of the sample size. The sample size calculation was based on a mortality rate of 26%; however, the actual mortality was much lower in both groups – this may have resulted in a false negative conclusion. The main secondary outcome was the requirement for renal replacement therapy. However, the decision to perform renal replacement therapy was not based on predefined criteria. The possibility of bias was considered low as the treating clinicians were blinded to the fluid assignment. The administration of resuscitation fluids in locations outside the ICU was not according to assignment, and not considered in the analysis.
The CHEST trial led to the restriction of HES use based on the recommendation by regulatory authorities. Following this, manufacturers of HES appealed against these recommendations, citing inaccuracies and misinterpretations of the trial. The trial sponsor, the George Institute for Global Health, initiated an independent re-analysis of the trial. Although minor differences were observed in some of the secondary and tertiary outcomes, these did not affect the conclusions drawn from the trial. The analysis of the primary and patient-centered outcomes revealed findings that were almost identical to the original trial, thus confirming the integrity of the trial and its conclusions (13).
The CHEST trial, along with the Scandinavian 6S trial that preceded it, settled the seemingly never-ending controversy over the use of HES, a synthetic colloid, as resuscitation fluid in critically ill patients. The use of HES as the resuscitation fluid led to a 21% relative increase in the requirement for renal replacement therapy, thus, convincingly establishing its adverse impact on renal function. The 90-day mortality was not significantly different between the HES and saline groups. The trial results indicated a mortality effect ranging between a relative decrease of 4% to a relative increase of 18% with the use of HES. The serum creatinine levels were consistently higher in HES-treated patients, further reinforcing the adverse impact on renal function. Furthermore, new-onset hepatic dysfunction was also more common with HES resuscitation. Globally, the pendulum has swung away from the use of HES, with many regulatory bodies placing stringent restrictions on its use.
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